A Randomized Placebo-Controlled Pilot Trial of Omega-3 Fatty Acids and Alpha Lipoic Acid in Alzheimer’s Disease Essential fatty acids in Alzheimer's disease. Omega-3 fatty acid supplementation effects on weight and appetite in patients with Alzheimer's disease: the omega-3 Alzheimer's disease study. Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells: the OmegAD study[S] Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. Effects of docosahexaenoic acid-rich n-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: the OmegAD study. Effects of DHA- Rich n-3 Fatty Acid Supplementation on Gene Expression in Blood Mononuclear Leukocytes: The OmegAD Study A neuropsychological test battery for use in Alzheimer disease clinical trials. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Effect of low dose ω-3 poly unsaturated fatty acids on cognitive status among older people: a double-blind randomized placebo-controlled study The effects of omega-3 fatty acids monotherapy in Alzheimer's disease and mild cognitive impairment: A preliminary randomized double-blind placebo-controlled study Reduced prostaglandin F2α release from blood mononuclear leukocytes after oral supplementation of ω3 fatty acids: the OmegAD study Plasma Fatty Acid Profiles in Relation to Cognition and Gender in Alzheimer's Disease Patients During Oral Omega-3 Fatty Acid Supplementation: The OmegAD Study. Impact of nutritional status on the evolution of Alzheimer's disease and on response to acetylcholinesterase inhibitor treatment. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. Key Methodological Features of Randomized Controlled Trials of Alzheimer’s Disease Therapy Malnutrition in community-dwelling adults with dementia (Nutrialz Trial) Effects of supplementation with omega-3 fatty acids on oxidative stress and inflammation in patients with Alzheimer's disease: the OmegAD study. Effects on transthyretin in plasma and cerebrospinal fluid by DHA-rich n - 3 fatty acid supplementation in patients with Alzheimer's disease: the OmegAD study. Docosahexaenoic acid supplementation improves the moderately severe dementia from thrombotic cerebrovascular diseases Effects of Omega-3 Fatty Acids on Inflammatory Markers in Cerebrospinal Fluid and Plasma in Alzheimer’s Disease: The OmegAD Study Determining the minimum clinically important differences for outcomes in the DOMINO trial. Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. An Inventory to Assess Activities of Daily Living for Clinical Trials in Alzheimer's Disease Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer's disease: the OmegAD study.
Oxidative stress , inflammation , and increased cholesterol levels are all mechanisms that have been associated with Alzheimer ’s disease ( AD ) pathology . Several epidemiologic studies have reported a decreased risk of AD with fish consumption . This pilot study was design ed to evaluate the effects of supplementation with omega-3 fatty acids alone ( ω-3 ) or omega-3 plus alpha lipoic acid ( ω-3 + LA ) compared to placebo on oxidative stress biomarkers in AD . The primary outcome measure was peripheral F2-isoprostane levels ( oxidative stress measure ) . Secondary outcome measures included performance on : Mini-Mental State Examination ( MMSE ) , Activities of Daily Living/Instrumental Activities of Daily Living ( ADL/IADL ) , and Alzheimer Disease Assessment Scale-cognitive subscale ( ADAS-cog ) . Thirty-nine AD subjects were r and omized to one of three groups : 1 ) placebo , 2 ) ω-3 , or 3 ) ω-3 + LA for a treatment duration of 12 months . Eighty seven percent ( 34/39 ) of the subjects completed the 12-month intervention . There was no difference between groups at 12 months in peripheral F2-isoprostane levels ( p = 0.83 ) . The ω-3 + LA and ω-3 were not significantly different than the placebo group in ADAS-cog ( p = 0.98 , p = 0.86 ) and in ADL ( p = 0.15 , p = 0.82 ) . Compared to placebo , the ω-3+LA showed less decline in MMSE ( p < 0.01 ) and IADL ( p= 0.01 ) and the ω-3 group showed less decline in IADL ( p < 0.01 ) . The combination of ω-3+LA  slowed cognitive and functional decline in AD over 12 months . Because the results were generated from a small sample size , further evaluation of the combination of omega-3 fatty acids plus alpha-lipoic acid as a potential treatment in AD is warranted Concentrations of essential fatty acids ( EFAs ) in plasma and red blood cell phospholipids were found to be abnormal in patients with Alzheimer 's disease . A double-blind , placebo-controlled trial of treatment with EFAs plus appropriate antioxidants was carried out in 36 patients with Alzheimer 's disease . After 20 weeks both the EFA and placebo groups had improved , but the degree of improvement was consistently greater in the EFA group OBJECTIVES To study the effects of omega (Omega)-3 fatty acid ( FA ) supplements on weight and appetite in patients with mild to moderate Alzheimer 's disease ( AD ) in relation to inflammatory biomarkers and apolipoprotein E epsilon4 ( APOEepsilon4 ) . DESIGN R and omized , double-blind , placebo-controlled trial . SETTING Specialist memory clinics in the Stockholm catchment area . PARTICIPANTS Two hundred four patients ( aged 73+/-9 , 52 % women ) with mild to moderate AD . INTERVENTION Patients with AD received 1.7 g of docosahexaenoic acid ( DHA ) and 0.6 g of eicosapentaenoic acid ( EPA ) ( Omega-3/Omega-3 group ; n=89 , aged 73+/-9 , 57 % women ) or placebo 0.6 g of linoleic acid per day ( placebo/Omega-3 group ; n=85 , aged 73+/-9 , 46 % women ) for 6 months . After 6 months , all patients received DHA and EPA for another 6 months . MEASUREMENTS Anthropometry , biochemical nutritional and inflammatory markers , and appetite assessed by caregiver . RESULTS Mean weight and body mass index ( kg/m(2 ) ) at baseline were 70.0+/-11.8 kg and 24.3+/-3.0 kg/m(2 ) , respectively . At 6- and 12-month follow-up , weight had increased 0.7+/-2.5 kg ( P=.02 ) and 1.4+/-2.9 kg ( P<.001 ) in the Omega-3/Omega-3 group . In the placebo group , weight was unchanged at 6 months but had increased ( P=.01 ) at 12 months follow-up after Omega-3 supplementation was initiated . Appetite improved in the Omega-3/Omega-3 group over the treatment period ( P=.01 ) . In logistic regression analyses , not carrying the APOEepsilon4 allele and high plasma DHA concentrations were independently related to weight gain in the combined group of patients at 6 months follow-up . CONCLUSION A DHA-enriched Omega-3 FA supplement may positively affect weight and appetite in patients with mild to moderate AD . Not carrying the APOEepsilon4 allele and high DHA were independently associated with weight gain 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 r and omized , 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 ( P BMC s ) were obtained before and after the trial . Analysis of the culture medium of P BMC s 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 P BMC s of AD patients , which was associated with changes in cognitive function IMPORTANCE Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease ( AD ) , evidence is limited in mild to moderate AD . OBJECTIVE To determine if vitamin E ( alpha tocopherol ) , memantine , or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor . DESIGN , SETTING , AND PARTICIPANTS Double-blind , placebo-controlled , parallel-group , r and omized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers . INTERVENTIONS Participants received either 2000 IU/d of alpha tocopherol ( n = 152 ) , 20 mg/d of memantine ( n = 155 ) , the combination ( n = 154 ) , or placebo ( n = 152 ) . MAIN OUTCOMES AND MEASURES Alzheimer 's Disease Cooperative Study /Activities of Daily Living ( ADCS-ADL ) Inventory score ( range , 0 - 78 ) . Secondary outcomes included cognitive , neuropsychiatric , functional , and caregiver measures .  RESULTS Data from 561 participants were analyzed ( alpha tocopherol = 140 , memantine = 142 , combination = 139 , placebo = 140 ) , with 52 excluded because of a lack of any follow-up data . Over the mean ( SD ) follow-up of 2.27 ( 1.22 ) years , ADCS-ADL Inventory scores declined by 3.15 units ( 95 % CI , 0.92 to 5.39 ; adjusted P = .03 ) less in the alpha tocopherol group compared with the placebo group . In the memantine group , these scores declined 1.98 units less ( 95 % CI , -0.24 to 4.20 ; adjusted P = .40 ) than the placebo group 's decline . This change in the alpha tocopherol group translates into a delay in clinical progression of 19 % per year compared with placebo or a delay of approximately 6.2 months over the follow-up period . Caregiver time increased least in the alpha tocopherol group . All-cause mortality and safety analyses showed a difference only on the serious adverse event of " infections or infestations , " with greater frequencies in the memantine ( 31 events in 23 participants ) and combination groups ( 44 events in 31 participants ) compared with placebo ( 13 events in 11 participants ) . CONCLUSIONS AND RELEVANCE Among patients with mild to moderate AD , 2000 IU/d of alpha tocopherol compared with placebo result ed in slower functional decline . There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol . These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00235716 BACKGROUND Dietary fish or fish oil rich in n-3 fatty acids ( n-3 FAs ) , eg , docosahexaenoic acid ( DHA ) and eicosapentaenoic acid ( EPA ) , ameliorate inflammatory reactions by various mechanisms . Whereas most studies have explored the effects of predominantly EPA-based n-3 FAs preparations , few have addressed the effects of n-3 FAs preparations with DHA as the main FA . OBJECTIVE The objective was to determine the effects of 6 mo of dietary supplementation with an n-3 FAs preparation rich in DHA on release of cytokines and growth factors from peripheral blood mononuclear cells ( P BMC s ) . DESIGN In a r and omized , double-blind , placebo-controlled trial , 174 Alzheimer disease ( AD ) patients received daily either 1.7 g DHA and 0.6 g EPA ( n-3 FAs group ) or placebo for 6 mo . In the present study blood sample s were obtained from the 23 first r and omized patients , and P BMC s were isolated before and after 6 mo of treatment . RESULTS Plasma concentrations of DHA and EPA were significantly increased at 6 mo in the n-3 FAs group . This group also showed significant decreases of interleukin (IL)-6 , IL-1beta , and granulocyte colony-stimulating factor secretion after stimulation of P BMC s with lipopolysaccharide . Changes in the DHA and EPA concentrations were negatively associated with changes in IL-1beta and IL-6 release for all subjects . Reductions of IL-1beta and IL-6 were also significantly correlated with each other . In contrast , this n-3 FA treatment for 6 mo did not decrease tumor necrosis factor-alpha , IotaL-8 , IL-10 , and granulocyte-macrophage colony-stimulating factor secretion . CONCLUSION AD patients treated with DHA-rich n-3 FAs supplementation increased their plasma concentrations of DHA ( and EPA ) , which were associated with reduced release of IL-1beta , IL-6 , and granulocyte colony-stimulating factor from P BMC s. This trial was registered at clinical trials.gov as NCT00211159 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 sample s were obtained from a subgroup of 16 patients originating from the r and omized 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 sample s 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 Clinical Trials.gov OBJECTIVE To report the psychometric properties of an alternative instrument to the cognitive subscale of the Alzheimer 's Disease Assessment Scale , a neuropsychological test battery ( NTB ) for measuring drug efficacy in Alzheimer disease clinical trials . DESIGN The NTB was evaluated in a r and omized , double-blind , placebo-controlled trial of  AN1792(QS-21 ) ( synthetic beta-amyloid plus an adjuvant ) ( 300 patients ) and isotonic sodium chloride solution ( 72 patients ) . The test-retest reliability of the NTB was examined , and the NTB was correlated with other cognitive ( cognitive subscale of the Alzheimer 's Disease Assessment Scale and Mini-Mental State Examination ) and functional ( Disability Assessment Scale for Dementia and Clinical Dementia Rating Sum of Boxes ) measures . In addition , a factor analysis was performed on NTB components . Finally , the sensitivity of the NTB to change was assessed as a function of Mini-Mental State Examination performance . RESULTS The NTB had high test-retest reliability at 6 ( Pearson product moment correlation [ r ] = 0.92 ) and 12 ( r = 0.88 ) months . Internal consistency was high ( Cronbach alpha = 0.84 ) . The correlations between the NTB z score and scores on traditional measures of cognition and function were significantly different from 0 ( P < .001 ) . A factor analysis yielded " memory " and " executive function " factors . The NTB z score declined linearly over 1 year in patients receiving placebo and , in contrast to the Alzheimer 's Disease Assessment Scale cognitive subscale , demonstrated similar declines in patients with high ( 21 - 26 ) and low ( 15 - 20 ) Mini-Mental State Examination scores at baseline . CONCLUSIONS The NTB exhibits excellent psychometric properties and seems to be a reliable and sensitive measure of cognitive change in patients with mild to moderate Alzheimer disease . The psychometric properties of the NTB suggest that it may have particular utility in evaluating drug efficacy in clinical trials in which patients with mild Alzheimer disease are included 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 R and omized , 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 r and omized 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 r and omized 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 ) Background Cognitive impairment is a prevalent health problem in older people and its global prevalence tends to increase parallel to the extended life expectancy in world . The beneficial effect of ω-3 PUFAs on cognitive impairment has been demonstrated in some experimental and cohort studies . In this study we aim ed to assess the effect of low dose docosahexaenoic acid ( DHA ) and eicosapentaenoic acid ( EPA ) supplementation on cognitive status in the elderly . Methods In a double-blind , r and omized placebo-controlled study , 199 individuals aged ≥65 years with normal or mild to moderate cognition impairment were assigned to receive either 180 mg of DHA plus 120 mg of EPA or placebo for 180 days . Cognitive status was assessed using Mini-Mental State Examination ( MMSE ) and Abbreviated Mental Test ( AMT ) score . Results MMSE and AMT scores were not different at the time of allocation [ 18.84 ( 5.37 ) , 18.55 ( 5.12 ) , ( P = 0.70 ) and 4.81 ( 2.79 ) and 4.64 ( 2.77 ) , ( P = 0.67 ) respectively ] and over 6 months between the ω-3 PUFA- and placebo- treated groups [ 18.57 ( 5.21 ) , 18.39 ( 5.10 ) , ( P = 0.80 ) and 4.64 ( 2.77 ) and 4.48 ( 2.69 ) and ( P = 0.67 ) ] . The participants were categorized based on MMSE score into normal cognition , mild and moderate cognitive impairment . After multivariate adjustment , there was no significant difference among categorized groups regarding the ω-3 PUFA effect except in normal cognition group , that amount of decline in AMT in ω-3 poly unsaturated fatty acids ( PUFAs ) was less than placebo group . Conclusions It seems that prescription of low dose ω-3 PUFAs for 6 months had no significant beneficial effects on improvement of cognition or prevention of cognitive decline in older people A 24-week , r and omized , double-blind placebo-controlled study was carried out to test the feasibility of using omega-3 polyunsaturated fatty acids ( PUFAs ) monotherapy in people with cognitive impairment and to explore its effects on cognitive function and general clinical condition in these participants . Twenty three participants with mild or moderate Alzheimer 's disease and twenty three with mild cognitive impairment were r and omized to receive omega-3 PUFAs 1.8 g/day or placebo ( olive oil ) . The data of 35 ( 76 % ) participants with at least one post-treatment visit was analyzed . There were no severe adverse effects in either group and it suggests that omega-3 PUFAs were well tolerable in this population . The treatment group showed better improvement on the Clinician 's Interview-Based Impression of Change Scale ( CIBIC-plus ) than those in the placebo group over the 24 week follow-up ( p=0.008 ) . There was no significant difference in the cognitive portion of the Alzheimer 's Disease Assessment Scale ( ADAS-cog ) change during follow-up in these two groups . However , the omega-3 fatty acids group showed significant improvement in ADAS-cog compared to the placebo group in participants with mild cognitive impairment ( p=0.03 ) , which was not observed in those with Alzheimer 's disease . Higher proportions of eicosapentaenoic acid on RBC membranes were also associated with better cognitive outcome ( p=0.003 ) . Further studies should be considered with a larger- sample size , diet registration , higher dosages , comparisons between different combinations of PUFAs , and greater homogeneity of participants , especially those with mild Alzheimer 's disease and mild cognitive impairment Omega-3 fatty acids , e.g. , dokosahexaenoic acid ( DHA ) and eikosapentaenoic acid ( EPA ) , ameliorate inflammatory reactions by various mechanisms , but the role of prostagl and ins 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 ( P BMC ) . 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 . P BMC s from the 21 ( 9 on fish oil and 12 on placebo ) first-r and omized 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 P BMC 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 P BMC 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 BACKGROUND ω3 fatty acids ( ω3 FAs ) may slow the rate of decline in cognitive performance in mild forms of cognitive impairment and Alzheimer 's disease ( AD ) . However , the relationship between changes of plasma ω3 FA levels and cognitive performance , as well as effects of gender , are poorly known . OBJECTIVE To study the effect of 6-month administration of DHA-rich ω3 FA supplementation on plasma FA profiles in patients with mild to moderate AD in relation to cognitive performance and gender . This investigation is part of the OmegAD Study . METHODS 174 AD patients ( 74 ± 9 years ) were r and omized to a daily intake of 2.3 g ω3 FA or placebo for 6 months ; subsequently all received the ω3 FA preparation for the next 6 months . Baseline as well as changes in plasma levels of the main ω3 FAs in 165 patients , while receiving ω3 FA supplementation for 6 months , were analyzed for association to cognitive performance ( assessed by ADAS-cog and MMSE scores ) as well as to gender . RESULTS Preservation of cognitive functioning , assessed by ADAS-cog or its sub-items ( but not MMSE ) scores , was significantly associated to increasing plasma ω3 FA levels over time . Thus , the higher ω3 FA plasma levels rose , the lower was the rate of cognitive deterioration . This effect was not related to gender ; since although females displayed higher ω3 FA plasma levels than did males after 6 months of supplementation , this difference disappeared when adjusted for body weight . CONCLUSIONS Since our study suggests dose-response relationships between plasma levels of ω3 FA and preservation of cognition , future ω3 FA trials in patients with mild AD should consider exploring grade d ( and body weight adjusted ) doses of ω3 FA BACKGROUND Weight loss is frequently observed in patients with Alzheimer 's disease ( AD ) , as observed in clinical practice and reported in the literature . However , information on the evolution of nutritional status and its impact on the prognosis of AD is still scarce . OBJECTIVE Our aim was to determine the impact of nutritional status on the evolution of AD and on the response to treatment with acetylcholinesterase inhibitors ( AChEI ) by prospect i ve one-year follow-up of AD patients living at home . METHODS We studied a cohort of 523 patients with Alzheimer 's disease referred from 1994 to 2002 to an Alzheimer centre . After diagnosis , they were followed for one year in a prospect i ve observational study in clinical practice . At entry and every 6 months , patients underwent st and ardised neurocognitive and geriatric evaluation ( MMSE , ADAS-cog , IADL , MNA , caregiver burden ) .  These evaluations were accompanied by complete clinical examination , st and ard para clinical investigations and recording of treatment received . RESULTS Of our patients , 25.8 % presented at inclusion a risk of undernutrition with an MNA score of 23.5 or less . During follow-up , the number of patients with rapid loss on the MMSE ( 3 points or more in one year ) was higher in subjects who presented a risk of undernutrition at inclusion ( 53.6 % ) than in well-nourished subjects ( 43.2 % ) ( P = 0.07 ) . Similarly , increased dependence at one year was more frequent in subjects at risk of undernutrition at inclusion ( 57.7 % versus 44.4 % , P = 0.0219 ) . The beneficial effect of AChEI treatment on cognitive function was not influenced by initial nutritional status ; on the contrary , among the subjects at risk of undernutrition at inclusion , the risk of rapid loss on the MMSE in one year was decreased in subjects treated during follow-up compared with untreated subjects ( 43.9 % versus 73.1 % ; OR = 0.29 ; 95 % CI = 0.10 - 0.83 ; P = 0.0219 ) . This relationship was not found in subjects whose initial MNA score was greater than 23.5 . CONCLUSION Our work indicates that AD patients living at home with a caregiver are frequently at risk of undernutrition . Undernourished patients seem to present more rapid aggravation of the disease , but paradoxically , these patients appear to be those who best respond to AChEI treatment CONTEXT Docosahexaenoic acid ( DHA ) is the most abundant long-chain polyunsaturated fatty acid in the brain . Epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of Alzheimer disease . Animal studies demonstrate that oral intake of DHA reduces Alzheimer-like brain pathology . OBJECTIVE To determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease . DESIGN , SETTING , AND PATIENTS A r and omized , double-blind , placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease ( Mini-Mental State Examination scores , 14 - 26 ) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer 's Disease Cooperative Study . INTERVENTION Participants were r and omly assigned to algal DHA at a dose of 2 g/d or to identical placebo ( 60 % were assigned to DHA and 40 % were assigned to placebo ) . Duration of treatment was 18 months . MAIN OUTCOME MEASURES Change in the cognitive subscale of the Alzheimer 's Disease Assessment Scale ( ADAS-cog ) and change in the Clinical Dementia Rating ( CDR ) sum of boxes . Rate of brain atrophy was also determined by volumetric magnetic resonance imaging in a sub sample of participants ( n = 102 ) . RESULTS A total of 402 individuals were r and omized and a total of 295 participants completed the trial while taking study medication ( DHA : 171 ; placebo : 124 ) . Supplementation with DHA had no beneficial effect on rate of change on ADAS-cog score , which increased by a mean of 7.98 points ( 95 % confidence interval [ CI ] , 6.51 - 9.45 points ) for the DHA group during 18 months vs 8.27 points ( 95 % CI , 6.72 - 9.82 points ) for the placebo group ( linear mixed-effects model : P = .41 ) . The CDR sum of boxes score increased by 2.87 points ( 95 % CI , 2.44 - 3.30 points ) for the DHA group during 18 months compared with 2.93 points ( 95 % CI , 2.44 - 3.42 points ) for the placebo group ( linear mixed-effects model : P = .68 ) . In the sub population of participants ( DHA : 53 ; placebo : 49 ) , the rate of brain atrophy was not affected by treatment with DHA . Individuals in the DHA group had a mean decline in total brain volume of 24.7 cm(3 ) ( 95 % CI , 21.4 - 28.0 cm(3 ) ) during 18 months and a 1.32 % ( 95 % CI , 1.14%-1.50 % ) volume decline per year compared with 24.0 cm(3 ) ( 95 % CI , 20 - 28 cm(3 ) ) for the placebo group during 18 months and a 1.29 % ( 95 % CI , 1.07%-1.51 % ) volume decline per year ( P = .79 ) . CONCLUSION Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline  in patients with mild to moderate Alzheimer disease . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00440050 Background : The results of clinical trials are routinely presented in terms of statistical significance , which may or may not indicate clinical significance . Analysis of the minimal clinical ly important difference ( MCID ) of cognitive scales has received little attention to date . Objectives : By review ing the key method ological features ( sample size , duration , statistical and clinical significance ) of clinical trials examining the efficacy of tacrine in the treatment of Alzheimer ’s disease ( AD ) , we assessed their ability to detect clinical ly important changes in cognition . Design : The value for the MCID of the  Mini-Mental State Examination ( MMSE )  was determined by surveying specialists in neurology and geriatric medicine . This value was then used to interpret the clinical significance of the results of published r and omized controlled trials ( RCTs ) assessing the efficacy of tacrine in the treatment of AD and to retrospectively determine their optimal sample size and trial duration . Results : The mean survey MCID for the MMSE was 3.72 ( 95 % confidence interval 3.50–3.95 ) points . Only 2 of 12 tacrine RCTs using the MMSE found a statistically significant difference in MMSE scores for patients taking tacrine  compared with those taking placebo . These improvements were not clinical ly significant when compared with the survey MMSE MCID . For parallel trials of tacrine in AD , the smallest sample size and minimum trial duration required to demonstrate a clinical ly significant difference were calculated to be 53 subjects and 1 year , respectively . Five of the 7 parallel trials met the required sample size ; however , none of them met the criteria for trial duration . Conclusions : When using the MMSE as an outcome measure , no tacrine trial reported results that were clinical ly significant as perceived by clinicians working with dementia patients . Application of a range of plausible MCIDs to the parallel design RCTs also demonstrated that 2 of 7 of these trials did not have sufficient sample size , and none had sufficient duration of treatment to reliably detect clinical ly meaningful changes in cognition . Future clinical trials in this area will need to incorporate the evolving knowledge of MCIDs in order to increase their chance of detecting clinical ly relevant results Objectives The objective of this study is to assess the nutritional status , measured by the MNA , in community-dwelling elderly individuals with dementia and to identify clinical risk factors for nutritional risk or malnutrition . Design Cross-sectional analysis of a cluster r and omized clinical trial ( Nutrialz ) . Setting Community-dwelling individuals attending dementia clinics . Participants 940 individuals . Measurements The clinical scales assessed were  Mini Nutritional Assessment ( MNA ) , Eating Behaviour Scale ( EBS ) , Charlson comorbidity index , Clinical Dementia Rating ( CDR ) , Mini-Mental State Examination ( MMSE ) , Basic Activities of Daily Living ( BADL ) score , Instrumental Activities of Daily Living ( IADL ) score , Neuropsychiatric Inventory Question naire ( NPI-Q ) , Cornell depression scale and Zarit Caregiver Burden Interview .  Results 5.2 % of participants were classified as being malnourished , 42.6 % as being at risk of malnutrition and 52.2 % as well nourished . Malnutrition by type of dementia was more frequent in Lewy bodies dementia ( 18.2 % ) than in the other types . Worse nutritional status is significantly related to more advanced age and worse cognitive , functional and behavioural profile , as well as increased burden for caregivers . Presence of behavioural symptoms is significantly related to worse nutritional level for all NPI-Q symptoms but depression , exaltation , lack of inhibition and irritability . The items more strongly related to malnutrition are appetite/feeding and hallucinations . Dependence in any basic or instrumental ADL is significantly related to higher risk of malnutrition . Dependence on feeding is a strongly related risk factor , while food preparation is only a moderate one . A logistic regression model to predict at risk/malnutrition kept as significant risk factors EBS ( Odds Ratio ( OR ) 0.84 , 95%CI 0.78 to 0.91 ) , Cornell ( OR 1.12 , 95%CI 1.09 to 1.16 ) , the number of dependent BADL ( OR 1.29 , 95%CI 1.17 to 1.42 ) , age ( OR 1.04 , 95%CI 1.02–1.06 ) , MMSE ( OR 0.95 , 95%CI 0.92 to 0.98 ) and Charlson ( OR 1.18 , 95%CI 1.05 to 1.34 ) . A similar model built for prediction of malnutrition retained as significant covariables only EBS , Cornell and the number of dependent BADL . Conclusion These results will allow a better underst and ing of the clinical stage previous to malnutrition . An adequate diagnosis and treatment of identified modifiable factors like functional impairment , eating behaviours and depression could delay or avoid malnutrition BACKGROUND Oxidative stress and inflammation are two key mechanisms suggested to be involved in the pathogenesis of Alzheimer 's 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 r and omized to receive 1.7 g DHA ( 22:6 ) and 0.6 g EPA ( 20:5 ) or placebo for 6 months . Urinary sample s 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 prostagl and in F2α . The correlative relationships to FAs indicate a potential role of FAs in immunoregulation Transthyretin ( TTR ) binds amyloid-β ( Aβ ) and may reduce brain Aβ , a pathological feature in Alzheimer 's disease ( AD ) . N - 3 fatty acids ( FA ) , docosahexaenoic ( DHA ) , and eicosapentaenoic acid ( EPA ) may increase TTR transcription in rat hippocampus . We studied effects of n - 3 FA supplementation on TTR-levels in patients with AD . Out patients were r and omized to receive 1.7 g DHA and 0.6 g EPA ( n - 3/n - 3 group ) or placebo ( placebo/n - 3 group ) during 6 months . After 6 months , all patients received n - 3 FA for another 6 months . TTR and FA were measured in plasma in all subjects , whereas TTR in cerebrospinal fluid ( CSF ) was measured in a subgroup . The study was completed by 89 patients in the n - 3/n - 3 group ( 75 y , 57 % w ) and 85 in the placebo/n - 3 group ( 75 y , 46 % w ) . Baseline plasma-TTR was within normal range in both groups . After 6 months , plasma-TTR decreased in the placebo/n - 3 group ( p < 0.001 within and p < 0.015 between the groups ) . No changes were observed in CSF TTR . From 6 to 12 months when both groups were supplemented , plasma-TTR increased significantly in both groups . Repeated measures ANOVA indicated an increase in TTR over time ( p = 0.04 ) in those receiving n - 3 FA for 12 months . By linear regression analyses , n - 3 FA treatment was independently associated with increased plasma-TTR at 6 months ( β = -0.172 , p = 0.028 ) . Thus , n - 3 FA treatment appeared to increase plasma-TTR in patients with AD . Since TTR may influence Aβ deposition in the brain , the results warrant further exploration T. Terano a , * , S. Fujishiro b , T. Ban c , K. Yamamoto d , T. Tanaka e , Y. Noguchi e , Y. Tamura ~ , K. Yazawa g and T. Hirayama h aDepartment of Internal Medicine , Chiba Municipal Hospital Chiba 260 , bKyoundou Hospital , Tokyo , ~Kuniyoshi Hospital , Chiba , dKimitsu Central Hospital , Chiba , e2nd Department Internal Medicine , Chiba University , Chiba , ~Kyoundou Hiratsuka Hospital , Kanagawa , gSagami Chemical Research Center , Kanagawa , and hHirayama Hospital , Chiba , 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 r and omized 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 BACKGROUND Although less likely to be reported in clinical trials than expressions of the statistical significance of differences in outcomes , whether or not a treatment has delivered a specified minimum clinical ly important difference ( MCID ) is also relevant to patients and their caregivers and doctors . Many dementia treatment r and omised controlled trials ( RCTs ) have not reported MCIDs and , where they have been done , observed differences have not reached these . METHODS As part of the development of the Statistical Analysis Plan for the DOMINO trial , investigators met to consider expert opinion- and distribution-based values for the MCID and triangulated these to provide appropriate values for three outcome measures , the  St and ardised Mini-mental State Examination ( sMMSE ) , Bristol Activities of Daily Living Scale ( BADLS ) and Neuropsychiatric Inventory ( NPI ) . Only st and ard deviations ( SD ) were presented to investigators who remained blind to treatment allocation . RESULTS Adoption of values for MCIDs based upon 0.4 of the SD of the change in score from baseline on the sMMSE , BADLS and NPI in the first 127 participants to complete DOMINO yielded MCIDs of 1.4 points for sMMSE , 3.5 for BADLS and 8.0 for NPI . CONCLUSIONS Reference to MCIDs is important for the full interpretation of the results of dementia trials and those conducting such trials should be open about the way in which they have determined and chosen their values for the MCIDs This article reports the development and psychometric properties of the Alzheimer 's Disease Cooperative Study - Clinical Global Impression of Change ( ADCS-CGIC ) . At present , a number of unvali date d CGIC scales are used in clinical trials , with various methods for making ratings . The ADCS-CGIC was design ed on the basis of a survey of  ADCS clinicians  and by adapting existing instruments . It includes an organized but unstructured format , with which a clinician can address clinical ly relevant change . The instrument 's reliability and validity were assessed in a prospect i ve trial of Alzheimer 's disease ( AD ) and healthy subjects over a 12-month period . It showed good short-term reliability at 1 and 2 months , with 90 and 94 % of AD subjects , respectively , rated as having changed not at all or only minimally . The ADCS-CGIC 's  face validity was demonstrated by untreated . AD subjects rated as having worsened over time at both 6 months ( 56 % rated as having worsened ) and 12 months ( 81 % rated as having worsened ) , whereas only 2 % of control subjects showed minimal worsening . As a measure of predictive validity , ADCS-CGIC ratings at 12 months were significantly associated with change on four severity scales . As with other measures , change ratings were sensitive to dementia severity . Moderately impaired subjects showed greater worsening than other subjects . ADCS-CGIC ratings of greater worsening were made after the informant interview , regardless of whether informants or subjects were interviewed first . The ADCS-CGIC is a valid and reliable instrument for use in clinical trials We developed a set of informant-based items describing performance of activities of daily living ( ADL ) by patients with Alzheimer 's disease ( AD ) to identify which ADL are useful for assessment of patients in clinical trials .  Evaluation of ADL is an important outcome measure in AD clinical trials . For clinical trial measurement , ADL should have broad applicability , good test-retest reliability , scaling to cover a range of performance , and sensitive to detect change in disease progression . A total of 45 ADL items developed from literature review and clinical experience were administered to informants of 242 AD patients and 64 elderly controls as part of the multicenter Alzheimer 's Disease Cooperative Study Instrument protocol . Half of the subjects were re-evaluated at 1 and 2 months and all at 6 and 12 months . Controls performed virtually all ADL items optimally at baseline and at 12 months . Among subjects with AD , 27 of the 45 ADL were widely applicable , i.e. , performed at baseline or premorbidly by > 90 % of subjects ; showed good test-retest reliability between baseline and 1 and 2 months ; correlated with MMSE scores of AD patients cross-sectionally ; and showed a decline in performance from baseline to 12 months in at least 20 % of AD patients . ADL could be identified that capture change in functional ability in patients across the entire range of the MMSE . The remaining 18 ADL included several that may be useful for trials that target specific population s , e.g. , women with AD . Because change on specific items depends on baseline MMSE , ADL evaluation should include items relevant to the severity of dementia of patients enrolled in a clinical trial OBJECTIVE Little is known about the transfer of essential fatty acids ( FAs ) across the human blood-brain barrier ( BBB ) in adulthood . In this study , we investigated whether oral supplementation with omega-3 ( n-3 ) FAs would change the FA profile of the cerebrospinal fluid ( CSF ) . METHODS A total of 33 patients ( 18 receiving the n-3 FA supplement and 15 receiving placebo ) were included in the study . These patients were participants in the double-blind , placebo-controlled r and omized OmegAD study in which 204 patients with mild Alzheimer 's disease ( AD ) received 2.3 g n-3 FA [ high in docosahexaenoic acid ( DHA ) ] or placebo daily for 6 months . CSF FA levels were related to changes in plasma FA and to CSF biomarkers of AD and inflammation . RESULTS At 6 months , the n-3 FA supplement group displayed significant increases in CSF ( and plasma ) eicosapentaenoic acid ( EPA ) , DHA and total n-3 FA levels ( P < 0.01 ) , whereas no changes were observed in the placebo group . Changes in CSF and plasma levels of EPA and n-3 docosapentaenoic acid were strongly correlated , in contrast to those of DHA . Changes in DHA levels in CSF were inversely correlated with CSF levels of total and phosphorylated tau , and directly correlated with soluble interleukin-1 receptor type II . Thus , the more DHA increased in CSF , the greater the change in CSF AD/inflammatory biomarkers . CONCLUSIONS Oral supplementation with n-3 FAs conferred changes in the n-3 FA profile in CSF , suggesting transfer of these FAs across the BBB in adults
BACKGROUND Omega-3 polyunsaturated fatty acids ( omega-3 PUFAs ) from fish and plant sources are commonly considered as a promising non-medical alternative to improve brain functions and slow down the progression of dementia .
This assumption is mostly based on findings of pre clinical studies and epidemiological research .
Result ing explanatory models aim at the role omega-3 PUFAs play in the development and integrity of the brain 's neurons , their protective antioxidative effect on cell membranes and potential neurochemical mechanisms directly related to Alzheimer-specific pathology .
Epidemiological research also found evidence of malnutrition in people with dementia .
Considering this and the fact that omega-3 PUFA can not be synthesis ed by humans , omega-3 PUFAs might be a promising treatment option for dementia .
OBJECTIVES To assess the efficacy and safety of omega-3 polyunsaturated fatty acid ( PUFA ) supplementation for the treatment of people with dementia .