Jan Palmblad

BACKGROUND: Epidemiologic and animal studies have suggested that dietary fish or fish oil rich in omega-3 fatty acids, for example, docosahexaenoic acid and eicosapentaenoic acid, may prevent Alzheimer disease (AD). OBJECTIVE: To determine effects of dietary omega-3 fatty acid supplementation on cognitive functions in patients with mild to moderate AD. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. PARTICIPANTS: Two hundred four patients with AD (age range [mean +/- SD], 74 +/- 9 years) whose conditions were stable while receiving acetylcholine esterase inhibitor treatment and who had a Mini-Mental State Examination (MMSE) score of 15 points or more were randomized to daily intake of 1.7 g of docosahexaenoic acid and 0.6 g of eicosapentaenoic acid (omega-3 fatty acid-treated group) or placebo for 6 months, after which all received omega-3 fatty acid supplementation for 6 months more. MAIN OUTCOME MEASURES: The primary outcome was cognition measured with the MMSE and the cognitive portion of the Alzheimer Disease Assessment Scale. The secondary outcome was global function as assessed with the Clinical Dementia Rating Scale; safety and tolerability of omega-3 fatty acid supplementation; and blood pressure determinations. RESULTS: One hundred seventy-four patients fulfilled the trial. At baseline, mean values for the Clinical Dementia Rating Scale, MMSE, and cognitive portion of the Alzheimer Disease Assessment Scale in the 2 randomized groups were similar. At 6 months, the decline in cognitive functions as assessed by the latter 2 scales did not differ between the groups. However, in a subgroup (n = 32) with very mild cognitive dysfunction (MMSE >27 points), a significant (P<.05) reduction in MMSE decline rate was observed in the omega-3 fatty acid-treated group compared with the placebo group. A similar arrest in decline rate was observed between 6 and 12 months in this placebo subgroup when receiving omega-3 fatty acid supplementation. The omega-3 fatty acid treatment was safe and well tolerated. CONCLUSIONS: Administration of omega-3 fatty acid in patients with mild to moderate AD did not delay the rate of cognitive decline according to the MMSE or the cognitive portion of the Alzheimer Disease Assessment Scale. However, positive effects were observed in a small group of patients with very mild AD (MMSE >27 points).

Abstract Treutiger CJ, Mullins GE, Johansson A‐SM, Rouhiainen A, Rauvala HME, Erlandsson‐Harris H, Andersson U, Yang H, Tracey KJ, Andersson J, Palmblad JEW (Center for Infectious Medicine; Center for Inflammation and Haematology Research; Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden, Finnish Red Cross Blood Transfusion Service; Institute of Biotechnology, University of Helsinki; Helsinki, Finland, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden and North Shore‐Long Island Jewish Research Institute, NY, USA). High mobility group 1 B‐box mediates activation of human endothelium. J Intern Med 2003; 254: 375–385. Objectives. Severe sepsis and septic shock is a consequence of a generalized inflammatory systemic response because of an invasive infection that may result in acute organ dysfunction. Mortality is high despite access to modern intensive care units. The nuclear DNA binding protein high mobility group 1 (HMGB1) protein has recently been suggested to act as a late mediator of septic shock via its function as a macrophage‐derived pro‐inflammatory cytokine ( J Exp Med 2000; 192: 565, Science 1999; 285: 248). We investigated the pro‐inflammatory activities of the A‐box and the B‐box of HMGB1 on human umbilical venular endothelial cells (HUVEC). Design. The HUVEC obtained from healthy donors were used for experiments. Recombinant human full‐length HMGB1, A‐box and B‐box were cloned by polymerase chain reaction (PCR) amplification from a human brain quick‐clone cDNA. The activation of HUVEC was studied regarding (i) upregulation of adhesion molecules, (ii) the release of cytokines and chemokines, (iii) the adhesion of neutrophils to HUVEC, (iv) the activation of signalling transduction pathways and (v) the involvement of the receptor for advanced glycation end‐products (RAGE). Results. The full‐length protein and the B‐box of HMGB1 dose‐dependently activate HUVEC to upregulate adhesion molecules such as ICAM‐1, VCAM‐1 and E‐selectin and to release IL‐8 and G‐CSF. The activation of HUVEC could be inhibited to 50% by antibodies directed towards the RAGE. HMGB1‐mediated HUVEC stimulation resulted in phosphorylation of the ELK‐1 signal transduction protein and a nuclear translocation of p65 plus c‐Rel, suggesting that HMGB1 signalling is regulated in endothelial cells through NF‐ κ B. Conclusions. The HMGB1 acts as a potent pro‐inflammatory cytokine on HUVEC and the activity is mainly mediated through the B‐box of the protein. HMGB1 may be a key factor mediating part of the pro‐inflammatory response occurring in septic shock and severe inflammation.

BACKGROUND: Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic inflammation, which is known as part of the pathology in the brain of individuals with Alzheimer's disease (AD). METHODS: Specialized pro-resolving mediators (SPMs), receptors, biosynthetic enzyme, and downstream effectors involved in resolution were analyzed in postmortem hippocampal tissue from AD patients and non-AD subjects. SPMs were analyzed in cerebrospinal fluid (CSF). RESULTS: SPMs and SPM receptors were detected in the human brain. Levels of the SPM lipoxin A4 (LXA4) were reduced in AD, both in the CSF and hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in AD brains. LXA4 and RvD1 levels in CSF correlated with Mini-Mental State Examination (MMSE) scores. CONCLUSIONS: A resolution pathway exists in the brain and the alterations described herein strongly suggest a dysfunction of this pathway in AD. MMSE correlations suggest a connection with cognitive function in AD.