Yvonne Freund-Levi

Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study

BACKGROUND Alzheimers disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group. METHODS Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Abeta(42):tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia. FINDINGS The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26.8, 95% CI 1.6-456.4). INTERPRETATION AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up. FUNDING European Commission; Ana Aslan International Foundation.

Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage.

Three sets of research criteria are available for diagnosis of Alzheimers disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimers disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimers disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimers disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimers disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimers disease at the mild cognitive impairment stage and progression to Alzheimers disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimers disease. Their 3-year progression rate to Alzheimers disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimers disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimers disease. Their 3-year progression rate to Alzheimers disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimers disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimers disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimers disease likelihood group. The 3-year progression rate to Alzheimers disease-type dementia was 59% in the high Alzheimers disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimers disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimers disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimers disease likelihood group or the International Working Group-2 prodromal Alzheimers disease group could be considered.

Omega-3 fatty acids enhance phagocytosis of Alzheimer's disease-related amyloid-β42 by human microglia and decrease inflammatory markers.

The use of supplements with omega-3 (ω3) fatty acids (FAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is widespread due to proposed beneficial effects on the nervous and cardiovascular systems. Many effects of ω3 FAs are believed to be caused by down-regulation and resolution of inflammation. Alzheimers disease (AD) is associated with inflammation mediated by microglia and astrocytes, and ω3 FAs have been proposed as potential treatments for AD. The focus of the present study is on the effects of DHA and EPA on microglial phagocytosis of the AD pathogen amyloid-β (Aβ), on secreted and cellular markers of immune activity, and on production of brain-derived neurotrophic factor (BDNF). Human CHME3 microglial cells were exposed to DHA or EPA, with or without the presence of Aβ42. Phagocytosis of Aβ42 was analyzed by flow cytometry in conjunction with immunocytochemistry using antibodies to cellular proteins. Secreted proteins were analyzed by ELISA. Both DHA and EPA were found to stimulate microglial phagocytosis of Aβ42. Phagocytosis of Aβ42 was performed by microglia with a predominance of M2 markers. EPA increased the levels of BDNF in the culture medium. The levels of TNF-α were decreased by DHA. Both DHA and EPA decreased the pro-inflammatory M1 markers CD40 and CD86, and DHA had a stimulatory effect on the anti-inflammatory M2 marker CD206. DHA and EPA can be beneficial in AD by enhancing removal of Aβ42, increasing neurotrophin production, decreasing pro-inflammatory cytokine production, and by inducing a shift in phenotype away from pro-inflammatory M1 activation.

Detection of amyloid in Alzheimer’s disease with positron emission tomography using [11C]AZD2184

PurposeCurrent positron emission tomography (PET) radioligands for detection of Aβ amyloid in Alzheimer’s disease (AD) are not ideal for quantification. To improve the signal to noise ratio we have developed the radioligand [11C]AZD2184 and report here the first clinical evaluation.MethodsEight AD patients and four younger control subjects underwent 93-min PET measurements with [11C]AZD2184. A ratio approach using the cerebellum as reference region was applied to determine binding parameters.ResultsBrain uptake of [11C]AZD2184 peaked within 1 min at 3–4% of injected radioactivity. AD patients had high radioactivity in cortical regions while controls had uniformly low radioactivity uptake. Specific binding peaked within 30 min at which time standardized uptake value ratios (SUVR) ranged between 1.19 and 2.57.Conclusion[11C]AZD2184 is a promising radioligand for detailed mapping of Aβ amyloid depositions in Alzheimer’s disease, due to low non-specific binding, high signal to background ratio and reversible binding as evident from early peak equilibrium.

Effects of Omega-3 Fatty Acids on Inflammatory Markers in Cerebrospinal Fluid and Plasma in Alzheimer’s Disease: The OmegAD Study

Background: ω-3 fatty acids (ω-3 FAs) found in dietary fish or fish oils are anti-inflammatory agents that may influence Alzheimer’s disease (AD). Objective: To study the effects of dietary ω-3 FA supplementation on inflammatory markers in cerebrospinal fluid (CSF) and plasma from patients with mild to moderate AD. Methods: Thirty-five patients (70.3 ± 8.2 years) were randomized to a daily intake of 2.3 g ω-3 FAs or placebo for 6 months. The inflammatory markers interleukin (IL)-6, tumour necrosis factor-α and soluble interleukin-1 receptor type II (sIL-1RII) were analysed in CSF and plasma at baseline and at 6 months. The AD markers tau-protein, hyperphosphorylated tau-protein and β-amyloid (Aβ1–42) were assessed in CSF. High-sensitivity C-reactive protein was assessed in plasma. A possible relation to the APOE genotype was investigated. Results: There was no significant treatment effect of ω-3 FAs on inflammatory and AD biomarkers in CSF or on inflammatory markers in plasma, nor was there any relation with APOE. A significant correlation was observed at baseline between sIL-1RII and Aβ1–42 levels in CSF. Conclusions: Treatment of AD patients with ω-3 FAs for 6 months did not influence inflammatory or biomarkers in CSF or plasma. The correlation between sIL-1RII and Aβ1–42 may reflect the reciprocal interactions between IL-1 and Aβ peptides.

Effects of DHA- Rich n-3 Fatty Acid Supplementation on Gene Expression in Blood Mononuclear Leukocytes : The OmegAD Study

Background Dietary fish oil, rich in n-3 fatty acids (n-3 FAs), e.g. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), regulate inflammatory reactions by various mechanisms, e.g. gene activation. However, the effects of long-term treatment with DHA and EPA in humans, using genome wide techniques, are poorly described. Hence, our aim was to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global gene expression in peripheral blood mononuclear cells. Methods and Findings In the present study, blood samples were obtained from a subgroup of 16 patients originating from the randomized double-blind, placebo-controlled OmegAD study, where 174 Alzheimer disease (AD) patients received daily either 1.7 g of DHA and 0.6 g EPA or placebo for 6 months. In blood samples obtained from 11 patients receiving n-3 FA and five placebo, expressions of approximately 8000 genes were assessed by gene array. Significant changes were confirmed by real-time PCR. At 6 months, the n-3 FAs group displayed significant rises of DHA and EPA plasma concentrations, as well as up- and down-regulation of nine and ten genes, respectively, was noticed. Many of these genes are involved in inflammation regulation and neurodegeneration, e.g. CD63, MAN2A1, CASP4, LOC399491, NAIP, and SORL1 and in ubiqutination processes, e.g. ANAPC5 and UBE2V1. Down-regulations of ANAPC5 and RHOB correlated to increases of plasma DHA and EPA levels. Conclusions We suggest that 6 months of dietary n-3 FA supplementation affected expression of genes that might influence inflammatory processes and could be of significance for AD. Trial Registration ClinicalTrials.gov NCT00211159

Omega‐3 Fatty Acid Supplementation Effects on Weight and Appetite in Patients with Alzheimer's Disease: The Omega‐3 Alzheimer's Disease Study

OBJECTIVES: To study the effects of omega (Ω)‐3 fatty acid (FA) supplements on weight and appetite in patients with mild to moderate Alzheimers disease (AD) in relation to inflammatory biomarkers and apolipoprotein E ɛ4 (APOEɛ4).

Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells : the OmegAD study

Specialized proresolving mediators (SPMs) induce resolution of inflammation. SPMs are derivatives of n-3 and n-6 PUFAs and may mediate their beneficial effects. It is unknown whether supplementation with PUFAs influences the production of SPMs. Alzheimer’s disease (AD) is associated with brain inflammation and reduced levels of SPMs. The OmegAD study is a randomized, double-blind, and placebo-controlled clinical trial on AD patients, in which placebo or a supplement of 1.7 g DHA and 0.6 g EPA was taken daily for 6 months. Plasma levels of arachidonic acid decreased, and DHA and EPA levels increased after 6 months of n-3 FA treatment. Peripheral blood mononuclear cells (PBMCs) were obtained before and after the trial. Analysis of the culture medium of PBMCs incubated with amyloid-β 1–40 showed unchanged levels of the SPMs lipoxin A4 and resolvin D1 in the group supplemented with n-3 FAs, whereas a decrease was seen in the placebo group. The changes in SPMs showed correspondence to cognitive changes. Changes in the levels of SPMs were positively correlated to changes in transthyretin. We conclude that supplementation with n-3 PUFAs for 6 months prevented a reduction in SPMs released from PBMCs of AD patients, which was associated with changes in cognitive function.

Reduced prostaglandin F2α release from blood mononuclear leukocytes after oral supplementation of ω3 fatty acids: the OmegAD study

Omega-3 fatty acids, e.g., dokosahexaenoic acid (DHA) and eikosapentaenoic acid (EPA), ameliorate inflammatory reactions by various mechanisms, but the role of prostaglandins remains unclear. Our aim was to determine if dietary supplementation with a DHA-rich fish oil influenced the release of PGF2α from peripheral blood mononuclear cells (PBMC). In the OmegAD study, 174 Alzheimer disease patients received either 1.7 g DHA plus 0.6 g EPA or a placebo daily for six months. PBMCs from the 21 (9 on fish oil and 12 on placebo) first-randomized patients were stimulated with either lipopolysaccharide (LPS) or phytohemagglutinin (PHA) before and after 6 months. Our results showed that plasma concentrations of DHA and EPA increased significantly at 6 months in the omega-3 group. PGF2α release from LPS- (but not from PHA-) stimulated PBMC was significantly diminished in this group; no change was noted in the placebo group. PGF2α changes correlated inversely with changes in plasma DHA and EPA. Decreased IL-6 and IL-1β levels correlated with decreased PGF2α levels. The stimulus-specific PGF2α release from PBMC after 6 months of oral supplementation with the DHA-rich fish oil might be one event related to reduced inflammatory reactions associated with omega-3 fatty acid intake.

Effects of Supplementation with Omega-3 Fatty Acids on Oxidative Stress and Inflammation in Patients with Alzheimer's Disease : The OmegAD Study

BACKGROUND Oxidative stress and inflammation are two key mechanisms suggested to be involved in the pathogenesis of Alzheimers disease (AD). Omega-3 fatty acids (ω-3 FAs) found in fish and fish oil have several biological properties that may be beneficial in AD. However, they may also auto-oxidize and induce in vivo lipid peroxidation. OBJECTIVE The objective of this study was to evaluate systemic oxidative stress and inflammatory biomarkers following oral supplementation of dietary ω-3 FA. METHODS Forty patients with moderate AD were randomized to receive 1.7 g DHA (22:6) and 0.6 g EPA (20:5) or placebo for 6 months. Urinary samples were collected before and after supplementation. The levels of the major F2-isoprostane, 8-iso-PGF2α, a consistent in vivo biomarker of oxidative stress, and 15-keto-dihydro-PGF2α, a major metabolite of PGF2α and biomarker of inflammatory response, were measured. RESULTS F2-isoprostane in urine increased in the placebo group after 6 months, but there was no clear difference in treatment effect between supplemented and non-supplemented patients on the urinary levels of F2-isoprostanes and 15-keto-dihydro-PGF2α. At baseline, the levels of 15-keto-dihydro-PGF2α showed negative correlative relationships to ω-3 FAs, and a positive correlation to linoleic acid. 8-iso-PGF2α correlated negatively to the ω-6 FA arachidonic acid. CONCLUSION The findings indicate that supplementation of ω-3 FAs to patients with AD for 6 months does not have a clear effect on free radical-mediated formation of F2-isoprostane or cyclooxygenase-mediated formation of prostaglandin F2α. The correlative relationships to FAs indicate a potential role of FAs in immunoregulation.