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.

Transthyretin (TTR) binds amyloid-ß (Aß) and may reduce brain Aß, 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. Outpatients were randomized 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 (ß = -0.172, p = 0.028). Thus, n - 3 FA treatment appeared to increase plasma-TTR in patients with AD. Since TTR may influence Aß deposition in the brain, the results warrant further exploration.

Targeted delivery of nerve growth factor via encapsulated cell biodelivery in Alzheimer disease: a technology platform for restorative neurosurgery.

OBJECT: The authors describe the first clinical trial with encapsulated cell biodelivery (ECB) implants that deliver nerve growth factor (NGF) to the cholinergic basal forebrain with the intention of halting the degeneration of cholinergic neurons and the associated cognitive decline in patients with Alzheimer disease (AD). The NsG0202 implant (NsGene A/S) consists of an NGF-producing, genetically engineered human cell line encapsulated behind a semipermeable hollow fiber membrane that allows the influx of nutrients and the efflux of NGF. The centimeter-long capsule is attached to an inert polymer tether that is used to guide the capsule to the target via stereotactic techniques and is anchored to the skull at the bur hole. METHODS: Six patients with mild to moderate AD were included in this Phase Ib open-label safety study and were divided into 2 dose cohorts. The first cohort of 3 patients received single implants targeting the basal nucleus of Meynert (Ch4 region) bilaterally (2 implants per patient), and after a safety evaluation, a second cohort of 3 patients received bilateral implants (a total of 4 implants per patient) targeting both the Ch4 region and the vertical limb of the diagonal band of Broca (Ch2 region). Stereotactic implantation of the devices was successfully accomplished in all patients. Despite extensive brain atrophy, all targets could be reached without traversing sulci, the insula, or lateral ventricles. RESULTS: Postoperative CT scans allowed visualization of the barium-impregnated tethers, and fusion of the scans with stereotactic MR images scan was used to verify the intended positions of the implants. Follow-up MRI at 3 and 12 months postimplantation showed no evidence of inflammation or device displacement. At 12 months, implants were successfully retrieved, and low but persistent NGF secretion was detected in half of the patients. CONCLUSIONS: With refinement, the ECB technology is positioned to become an important therapeutic platform in restorative neurosurgery and, in combination with other therapeutic factors, may be relevant for the treatment of a variety of neurological disorders. Clinical trial registration no.: NCT01163825.

Cerebrospinal Fluid Alzheimer Markers in Depressed Elderly Subjects with and without Alzheimer's Disease.

BACKGROUND: The aim of this study was to explore the relationship between cerebrospinal fluid Alzheimer's disease (AD) markers and depression in elderly people. METHOD: We included subjects with AD as well as persons with subjective cognitive impairment and normal cognition. Depression was assessed with the Cornell Scale for Depression in Dementia, and a cut-off score of >6 was used to define depression. Cerebrospinal fluid was analyzed using commercially available assays for ß-amyloid 1-42, total tau, and phosphorylated tau 181. RESULTS: A total of 183 participants (66.7% female) were included (92 with AD and 91 with subjective cognitive impairment), with a mean age (±SD) of 67.6 ± 7.4 years, a Mini-Mental State Examination score of 26.0 ± 4.0, and a median Cornell Scale for Depression in Dementia score of 5 (range 0-19). Depression scores were not associated with higher phosphorylated tau 181 and total tau or reduced ß-amyloid 1-42 in AD or non-demented subjects. CONCLUSIONS: These results suggest that AD pathology does not contribute to depression, indicating that other factors may be more important. Further studies of the aetiology of depression in elderly people with and without AD are warranted.

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.

Dementia diagnosis differs in men and women and depends on age and dementia severity: data from SveDem, the Swedish Dementia Quality Registry.

AIMS: We examine the dementia assessment with focus on age and gender differences. METHODS: Data from the national quality database, Swedish Dementia Registry (SveDem), including 6,937 dementia patients diagnosed during 2007-2009 at memory clinics were used. We have studied the use of investigations for dementia diagnostics such as cognitive tests, blood and cerebrospinal fluid analyses, electroencephalography, radiological examinations and assessments of functions. Severity of cognitive impairment was assessed with the Mini Mental State Examination (MMSE). RESULTS: There was a significant decrease in the number of total tests used in the elderly group (>75 years) when compared with the middle-aged group (65-75 years) and younger patients (<65 years). The oldest group was examined with 4 of 11 possible tests, the middle-aged group had 5/11 tests performed and the youngest age group 6/11 tests. There was also a significant gender difference in the diagnostic workup, however, mostly attributable to age. The number of tests positively correlated with the level of cognition assessed by the MMSE. CONCLUSION: We show here for the first time the impact of age, gender and MMSE score on the dementia diagnostic workup in a large memory clinic patient population in one country.

Encapsulated cell biodelivery of nerve growth factor to the Basal forebrain in patients with Alzheimer's disease.

BACKGROUND/AIMS: Degeneration of cholinergic neurons in the basal forebrain correlates with cognitive decline in patients with Alzheimer's disease (AD). Targeted delivery of exogenous nerve growth factor (NGF) has emerged as a potential AD therapy due to its regenerative effects on the basal forebrain cholinergic neurons in AD animal models. Here we report the results of a first-in-man study of encapsulated cell (EC) biodelivery of NGF to the basal forebrain of AD patients with the primary objective to explore safety and tolerability. METHODS: This was an open-label, 12-month study in 6 AD patients. Patients were implanted stereotactically with EC-NGF biodelivery devices targeting the basal forebrain. Patients were monitored with respect to safety, tolerability, disease progression and implant functionality. RESULTS: All patients were implanted successfully with bilateral single or double implants without complications or signs of toxicity. No adverse events were related to NGF or the device. All patients completed the study, including removal of implants at 12 months. Positive findings in cognition, EEG and nicotinic receptor binding in 2 of 6 patients were detected. CONCLUSIONS: This study demonstrates that surgical implantation and removal of EC-NGF biodelivery to the basal forebrain in AD patients is safe, well tolerated and feasible.

Higher cathepsin B levels in plasma in Alzheimer's disease compared to healthy controls.

Cathepsin B is suggested to be involved in amyloid-ß (Aß) processing and Alzheimer's disease (AD). Studies of cathepsin B levels in plasma and cerebrospinal fluid (CSF) have not been previously performed. We examined cathepsin B levels in plasma and CSF samples in persons with AD, mild cognitive impairment (MCI), and healthy controls in order to test the hypothesis that cathepsin B levels can discriminate persons with AD or MCI from healthy controls. Cathepsin B, Cystatin C, Aß1-40 and Aß1-42, total tau, phosphorylated tau, and albumin levels in plasma and CSF were analyzed by ELISA (Cathepsin B) turbidimetry (cystatin C), xMAP Luminex technology (Aß1-40 and Aß1-42 and tau), and Cobas C501 analyzer (albumin) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Plasma cathepsin B levels were higher in persons with AD compared to healthy controls, both in unadjusted models and in multivariable models adjusting for age, gender, APOE genotype, cystatin C, and albumin levels: Odds ratio (OR) for AD per 1 SD of plasma cathepsin B; 2.04, 95% confidence interval (CI); 1.01-4.14, p= 0.05. There was no difference between diagnostic groups in cathepsin B levels in CSF: OR for AD per 1 SD of CSF cathepsin B; 0.93, 95% CI; 0.37-2.30, p= 0.87. Plasma cathepsin B levels were higher in persons with AD compared to healthy controls whereas there was no difference between diagnostic groups in cathepsin B levels in CSF. Further investigation of cathepsin B as a predictor of AD is warranted.

Cystatin C levels are positively correlated with both Abeta42 and tau levels in cerebrospinal fluid in persons with Alzheimer's disease, mild cognitive impairment, and healthy controls.

Cystatin C is suggested to be involved in neurodegeneration and the development of Alzheimer's disease (AD) by binding to soluble amyloid-beta (Abeta) peptides. Studies of cystatin C levels in cerebrospinal fluid (CSF) in relation to risk of AD are conflicting and relations between cystatin C, Abeta42, and tau levels in CSF in AD, mild cognitive impairment (MCI), and healthy controls are unknown. The objective of this study was to investigate cystatin C, Abeta42, and tau levels in CSF in AD, MCI, and controls. As a secondary aim, the relationships between cystatin C, Abeta42, and tau levels across disease groups were investigated. Cystatin C, Abeta42, total tau, and phosphorylated tau levels in CSF were analyzed by turbidimetry (cystatin C) and xMAP Luminex technology (Abeta and tau) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Mean cystatin C levels were similar in cases of AD (5.6 micromol/L +/- 1.7), MCI (5.4 micromol/L +/- 1.48), and controls (5.6 micromol/L +/- 1.6). However, CSF cystatin C levels were strongly and positively correlated with total tau and phosphorylated tau levels (r=0.61-0.81, p< 0.0001) and Abeta42 (r=0.35-0.65, p< 0.001) independent of age, gender, and APOE genotype. Mean CSF cystatin C levels did not differ between patients with AD and MCI and healthy controls. Interestingly, cystatin C levels were positively correlated with both tau and Abeta42 levels in CSF independent of age, gender, and APOE genotype.

Reduced prostaglandin F2 alpha release from blood mononuclear leukocytes after oral supplementation of omega3 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 PGF(2alpha) 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. PGF(2alpha) release from LPS- (but not from PHA-) stimulated PBMC was significantly diminished in this group; no change was noted in the placebo group. PGF(2alpha) changes correlated inversely with changes in plasma DHA and EPA. Decreased IL-6 and IL-1(beta) levels correlated with decreased PGF(2alpha) levels. The stimulus-specific PGF(2alpha) 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 omega-3 fatty acids on inflammatory markers in cerebrospinal fluid and plasma in Alzheimer's disease: the OmegAD study.

BACKGROUND: omega-3 fatty acids (omega-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 omega-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 omega-3 FAs or placebo for 6 months. The inflammatory markers interleukin (IL)-6, tumour necrosis factor-alpha 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 beta-amyloid (Abeta(1-42)) 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 omega-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 Abeta(1-42) levels in CSF. CONCLUSIONS: Treatment of AD patients with omega-3 FAs for 6 months did not influence inflammatory or biomarkers in CSF or plasma. The correlation between sIL-1RII and Abeta(1-42) may reflect the reciprocal interactions between IL-1 and Abeta peptides.

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 (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: Randomized, 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.

Relatives' experiences of encountering the older person with acute confusional state: experiencing unfamiliarity in a familiar person.

Aims and objectives. The aim was to understand the lived experience of close relatives encountering older persons with acute confusional state. Background. Little is known about relatives of patients with acute confusional state and their experiences while encountering a family member exhibiting acute confusional state. Design. A descriptive phenomenological research approach was used. Methods. Data were collected by interviewing 10 close relatives of older people with acute confusional state at two hospital wards. Results. Relatives experience the encounter as encountering a familiar person who has suddenly become unfamiliar, struggling to separate the familiar from the unfamiliar and trying to understand the causes of acute confusional state and the behaviour of the person. Six constituents illuminate the phenomenon: 'change in the other person', 'rapid and unexpected changes', 'experiencing insecurity in the encounter', 'trusting or mistrusting the other person', 'experiencing loss' and 'experiencing exposure'. Relevance to clinical practice. It is important for professional carers to support relatives on how to encounter the person with acute confusional state, and to co-operate with relatives to gain knowledge about the unique person behind the acute confusional state. Conclusion. Relatives' difficulties in dealing with strong emotions evoked within the encounter, experiencing limitation and lack of trust is essential knowledge for professional carers in all care settings.

Omega-3 supplementation in mild to moderate Alzheimer's disease: effects on neuropsychiatric symptoms.

BACKGROUND: Epidemiological and animal studies have suggested that dietary fish or fish oil rich in omega-3 fatty acids (omega3), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may have effects in psychiatric and behavioral symptoms in Alzheimer's disease (AD). An association with APOEomega4 carriers and neuropsychiatric symptoms in AD has also been suggested. OBJECTIVE: To determine effects of dietary omega3 supplementation to AD patients with mild to moderate disease on psychiatric and behavioral symptoms, daily functions and a possible relation to APOEgenotype. METHODS: Randomized, double-blind, placebo-controlled clinical trial where 204 AD patients (74+/-9 years) with acetylcholine esterase inhibitor treatment and a MMSE>15 points were randomized to daily intake of 1.7 g DHA and 0.6 g EPA (omega3 group) or placebo for 6 months. Then, all received the omega3 supplementation for 6 more months. Neuropsychiatric symptoms were measured with Neuropsychiatric Inventory (NPI) and Montgomery Asberg Depression Scale (MADRS). Caregivers burden and activities of daily living (Disability Assessment for Dementia, DAD) were also assessed. RESULTS: One hundred and seventy-four patients fulfilled the trial. 72% were APOEomega4 carriers. No significant overall treatment effects on neuropsychiatric symptoms, on activities of daily living or on caregiver's burden were found. However, significant positive treatment effects on the scores in the NPI agitation domain in APOEomega4 carriers (p=0.006) and in MADRS scores in non-APOEomega4 carriers (p=0.005) were found. CONCLUSIONS: Supplementation with omega3 in patients with mild to moderate AD did not result in marked effects on neuropsychiatric symptoms except for possible positive effects on depressive symptoms (assessed by MADRS) in non-APOEomega4 carriers and agitation symptoms (assessed by NPI) in APOEomega4 carriers. ClinicalTrials.gov identifier: NCT00211159

Increasing CSF phospho-tau levels during cognitive decline and progression to dementia.

BACKGROUND: Little is known about longitudinal changes of cerebrospinal fluid (CSF) biomarkers during cognitive decline in neurodegenerative disease progression. OBJECTIVE: To investigate longitudinal changes in CSF biomarkers--total-tau (T-tau), phospho-tau (P-tau) and beta-amyloid (Abeta42)--during cognitive decline. METHODS: Forty memory clinic patients (47.5% females), aged 61.3+/-7.6 (S.D.) years, non-demented at baseline, underwent lumbar puncture and neuropsychological testing at two occasions. Baseline mean MMSE-score was 28.3+/-1.8. Patients were divided into three groups based on baseline memory functioning; severely impaired (SIM), moderately impaired (MIM) and no impairment (NIM). RESULTS: There was a significant increase in P-tau in the SIM-group during follow-up, while P-tau in MIM and NIM did not change. Eighty-three percent of the SIM-patients converted to dementia (80% AD), while most MIM- and NIM-patients remained non-demented. T-tau- and Abeta42-levels did not change in any of the memory groups during follow-up. CONCLUSION: Increasing P-tau levels during cognitive decline and conversion to dementia suggest that P-tau may be useful as a longitudinal marker of the neurodegenerative process.

Pre-operative mild cognitive dysfunction predicts risk for post-operative delirium after elective cardiac surgery.

BACKGROUND AND AIMS: To identify pre-operative risk factors for delirium in patients undergoing elective cardiac surgery, using clearly defined diagnostic criteria for delirium, and a thorough clinical assessment. METHODS: The incidence of post-operative delirium in 107 patients >or=60 years undergoing elective cardiac surgery was calculated. None of the patients included suffered from dementia. Pre-operative cognitive function in all patients was assessed using the Mini Mental State Examination (MMSE) and post-operative delirium was diagnosed using the Confusion Assessment Method (CAM). Post-operative clinical and cognitive assessments were carried out for all patients. RESULTS: Twenty-five patients (23.4%) developed delirium post-operatively. Clinical parameters, including age, gender, co-morbidities, medications, and peri-operative parameters, were similar in patients with and without post-operative delirium. Patients with pre-operative subjective memory complaints and lower MMSE scores, undergoing valve operation or valve + coronary artery bypass grafting (CABG), exhibited an increased risk of developing post-operative delirium. Additionally, delirious patients had a significant decline in post-operative MMSE score compared with the non-delirious ones. CONCLUSIONS: The main pre-operative risk factors for post-operative delirium after elective cardiac operations were subjective memory complaints, mild cognitive impairment, and type of cardiac surgery, such as valve procedures. This study suggests that cognitive evaluation should be included in pre-operative assessment.

Donepezil in Alzheimer's disease: what to expect after 3 years of treatment in a routine clinical setting.

BACKGROUND/AIMS: Clinical short-term trails have shown positive effects of donepezil treatment in patients with Alzheimer's disease. The outcome of continuous long-term treatment in the routine clinical settings remains to be investigated. METHODS: The Swedish Alzheimer Treatment Study (SATS) is a descriptive, prospective, longitudinal, multicentre study. Four hundred and thirty-five outpatients with the clinical diagnosis of Alzheimer's disease, received treatment with donepezil. Patients were assessed with Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), global rating (CIBIC) and Instrumental Activities of Daily Living (IADL) at baseline and every 6 months for a total period of 3 years. RESULTS: The mean MMSE change from baseline was positive for more than 6 months and in subgroups of patients for 12 months. After 3 years of treatment the mean change from baseline in MMSE-score was 3.8 points (95% CI, 3.0-4.7) and the ADAS-cog rise was 8.2 points (95% CI, 6.4-10.1). This is better than expected in untreated historical cohorts, and better than the ADAS-cog rise calculated by the Stern equation (15.6 points; 95% CI, 14.5-16.6). After 3 years with 38% of the patients remaining, 30% of the them were unchanged or improved in the global assessment. CONCLUSION: Three-year donepezil treatment showed a positive global and cognitive outcome in the routine clinical setting.

Differential CSF biomarker levels in APOE-epsilon4-positive and -negative patients with memory impairment.

OBJECTIVES: To investigate the relationships between episodic memory, APOE genotype, CSF markers (total tau, T-tau; phospho-tau, P-tau; beta-amyloid, Abeta42) and longitudinal cognitive decline. METHODS: 124 memory clinic patients were retrospectively divided into 6 groups based on (i) episodic memory function (Rey Auditory Verbal Learning Test, RAVLT): severe, moderate or no impairment (SIM, MIM or NIM), and (ii) APOE genotype (epsilon4+ or epsilon4-). CSF marker levels and cognitive decline were compared across groups. RESULTS: Episodic memory function, according to RAVLT scores, was significantly correlated with CSF marker levels only among epsilon4+ subjects and not among epsilon4- subjects. When comparing the 6 subgroups, SIM epsilon4+ and MIM epsilon4+ groups showed significantly lower Abeta42 levels than the other groups. T-tau and P-tau levels were significantly increased in SIM epsilon4+ when compared to all the other groups, including the SIM epsilon4- group. However, both SIM epsilon4+ and SIM epsilon4- declined cognitively during the follow-up. CONCLUSION: It remains to be determined whether APOE genotype affects the expression of biomarkers in CSF, or whether the different biomarker patterns reflect different types of disease processes in patients with progressive cognitive dysfunction.

Nerve growth factor in treatment and pathogenesis of Alzheimer's disease.

The etiology of Alzheimer's disease (AD) is still unknown. In addition, this terrible neurodegenerative disease will increase exponentially over the next two decades due to longer lifespan and an aging "baby-boomer" generation. All treatments currently approved for AD have moderate efficacy in slowing the rate of cognitive decline in patients, and no efficacy in halting progression of the disease. Hence, there is an urgent need for new drug targets and delivery methods to slow or reverse the progression of AD. One molecule that has received much attention in its potential therapeutic role in AD is nerve growth factor (NGF). This review will demonstrate data from humans and animals which promote NGF as a potential therapeutic target by (1) outlining the hypothesis behind using NGF for the treatment of AD, (2) reviewing both the normal and AD altered signaling pathways and effects of NGF in the central nervous system (CNS), and (3) examining the results of NGF treatment obtained from animal models of AD and AD patients.

Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial.

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).