Cognitive protection and brain entropy changes from omega-3 polyunsaturated fatty acids supplement in late-life depression: A 52-week randomized controlled trial.

BACKGROUND: Late-life depression (LLD) is associated with risk of dementia, yet intervention of LLD provides an opportunity to attenuate subsequent cognitive decline. Omega-3 polyunsaturated fatty acids (PUFAs) supplement is a potential intervention due to their beneficial effect in depressive symptoms and cognitive function. To explore the underlying neural mechanism, we used resting-state functional MRI (rs-fMRI) before and after omega-3 PUFAs supplement in older adults with LLD. METHODS: A 52-week double-blind randomized controlled trial was conducted. We used multi-scale sample entropy to analyze rs-fMRI data. Comprehensive cognitive tests and inflammatory markers were collected to correlate with brain entropy changes. RESULTS: A total of 20 patients completed the trial with 11 under omega-3 PUFAs and nine under placebo. While no significant global cognitive improvement was observed, a marginal enhancement in processing speed was noted in the omega-3 PUFAs group. Importantly, participants receiving omega-3 PUFAs exhibited decreased brain entropy in left posterior cingulate gyrus (PCG), multiple visual areas, the orbital part of the right middle frontal gyrus, and the left Rolandic operculum. The brain entropy changes of the PCG in the omega-3 PUFAs group correlated with improvement of language function and attenuation of interleukin-6 levels. LIMITATIONS: Sample size is small with only marginal clinical effect. CONCLUSION: These findings suggest that omega-3 PUFAs supplement may mitigate cognitive decline in LLD through anti-inflammatory mechanisms and modulation of brain entropy. Larger clinical trials are warranted to validate the potential therapeutic implications of omega-3 PUFAs for deterring cognitive decline in patients with late-life depression.

Effects of Vitamin D Supplementation on Cognitive Outcomes: A Systematic Review and Meta-Analysis.

Clinical studies examining the effects of vitamin D on cognition have reported inconsistent results. To date, no comprehensive study has examined this effect on the basis of sample characteristics or intervention model-related factors. This systematic review and meta-analysis of randomized controlled trials investigated the effects of vitamin D supplementation on global cognitive function and specific cognitive domains. This review was preregistered in the PROSPERO database (CRD42021249908) and comprised 24 trials enrolling 7557 participants (mean age: 65.21 years; 78.54% women). The meta-analysis revealed that vitamin D significantly influenced global cognition (Hedges' g = 0.128, p = .008) but not specific cognitive domains. A subgroup analysis indicated that the effect size of vitamin D was stronger for vulnerable populations (Hedges' g = 0.414) and those with baseline vitamin D deficiency (Hedges' g = 0.480). On the basis of subgroup analyses in studies without biological flaws (Hedges' g = 0.549), we suggest that an intervention model should correct baseline vitamin D deficiency. Our results indicate that vitamin D supplementation has a small but significant positive effect on cognition in adults.

Treating fibromyalgia with electrical neuromodulation: A systematic review and meta-analysis.

OBJECTIVE: Several types of electrical neuromodulation (such as transcranial direct current stimulation, tDCS; transcutaneous electrical nerve stimulation) have been applied in the treatment of fibromyalgia. These trials had different outcome measurements, such as subjective pain, pain threshold, depression, anxiety, and functioning. We intended to integrate data from different trials into a meta-analysis to clearly present the clinical value of electrical neuromodulation in fibromyalgia. METHODS: A systematic review and meta-analysis of randomized controlled trials comparing the effect of all types of electrical neuromodulation in patients with fibromyalgia was conducted. The main outcome was subjective pain; the secondary outcomes included depression, anxiety, and functioning. RESULTS: Twenty-five studies and 1061 fibromyalgia patients were included in the quantitative analysis. Active electrical neuromodulation and active tDCS both showed significant effects on subjective pain, depression, and functioning. For different anode tDCS electrode positions, only F3-F4 revealed a significant effect on depression. Meta-regression tDCS effects on depression were significantly associated with age. CONCLUSIONS: Electrical neuromodulation is significantly effective in treating pain, depression, and functioning in patients with fibromyalgia. SIGNIFICANCE: The results may help clinicians to arrange effective treatment plans for patients with fibromyalgia, especially in those patients who reveal limited response to pharmacotherapy and psychotherapy.

Trough Melatonin Levels Differ between Early and Late Phases of Alzheimer Disease.

OBJECTIVE: Melatonin has been considered to have an essential role in the pathophysiology of Alzheimer's disease (AD) for its regulatory function on circadian rhythm and interaction with glutamate for the modulation of learning and memory. Previous studies revealed that melatonin levels decreased in patients with AD. However, melatonin supplement didn't show promising efficacy for AD. This study compared trough melatonin levels among elderly people with different severities of cognitive deficits. METHODS: We enrolled 270 elder individuals (consisting four groups: healthy elderly, amnestic mild cognitive impairment [MCI], mild AD, and moderate-severe AD) in the learning cohort. Trough melatonin levels in plasma were measured using ELISA. Cognitive function was evaluated by Clinical Dementia Rating Scale (CDR) and Mini-Mental State Examination (MMSE). An independent testing cohort, also consisting of four groups, was enrolled for ascertainment. RESULTS: In the learning cohort, trough melatonin levels decreased in the MCI group but elevated in the mild and moderate to severe AD groups. Trough melatonin levels were associated with CDR and MMSE in MCI or AD patients significantly. In the testing cohort, the results were similar to those in the learning cohort. CONCLUSION: This study demonstrated that trough melatonin levels in the peripheral blood were decreased in MCI but increased with the severity of AD. The finding supports the trials indicating that melatonin showed efficacy only in MCI but not in AD. Whether trough melatonin level has potential to be a treatment response biomarker for AD, especially its early phase needs further studies.

A meta-analytic review of polyunsaturated fatty acid compositions in dementia.

OBJECTIVE: To determine whether the levels of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), arachidonic acid (AA), total n-3 polyunsaturated fatty acids (PUFAs), and total n-6 PUFAs were changed in patients with dementia or predementia syndrome. DATA SOURCES: PubMed was searched for studies from first date available to July 2011 using the following search terms: (dementia OR cognitive impairment OR mild cognitive impairment) AND (omega-3 OR omega-6 OR polyunsaturated fatty acid OR docosahexaenoic acid OR DHA OR eicosapentaenoic acid OR EPA). The search was limited to literature in English and to human studies. The references of relevant articles and review articles were searched for citations not indexed in PubMed. STUDY SELECTION: Studies were included if they measured levels of EPA, DHA, AA, total n-3 PUFAs, or total n-6 PUFAs from peripheral blood tissues in subjects with cognitive deficits (dementia or predementia syndrome) and elderly controls and were published in peer-reviewed journals. The search yielded 10 articles including 2,280 subjects. DATA EXTRACTION: The study design, sample size, PUFA levels for both patients and control subjects, sampling tissue, diagnoses and diagnostic criteria for cognitive deficits, and distribution of mean age and gender of included subjects were extracted for each study. RESULTS: In a random-effects model, we found that the levels of EPA (effect size [ES] = -0.47, P < .0001), DHA (ES = -0.33, P = .017), and total n-3 PUFAs (ES = -0.46, P = .001) were decreased in patients with dementia. However, the levels of EPA (ES = -0.44, P = .002), but not DHA or other PUFAs, were significantly lower in patients with predementia syndrome. CONCLUSIONS: Our results support the important role of n-3 PUFAs in the pathophysiology of dementia. In addition, the analyses of predementia studies indicate that EPA might be not only a disease-state marker but also a risk factor for cognitive impairment.

Associations between n-3 PUFA concentrations and cognitive function after recovery from late-life depression.

BACKGROUND: Lower concentrations of n-3 PUFAs have been reported to be associated with cognitive impairment and dementia, but also with depression-itself a potential risk factor for cognitive decline. OBJECTIVE: The aims of this study were to investigate associations between n-3 PUFA concentrations in erythrocyte membrane or plasma and cognitive function in an at-risk sample of older people with previous major depression and to explore specificity with respect to cognitive domains. DESIGN: A cross-sectional sample of 132 eligible participants who had recovered from major depression (mean ± SD age: 67.8 ± 6.6 y) were enrolled from outpatient psychiatric services. A series of cognitive tests and a structured questionnaire were administered. Fasting blood samples were collected for n-3 PUFA measurements. RESULTS: Higher EPA and total n-3 PUFA concentrations and a lower ratio of arachidonic acid to EPA in erythrocyte membranes were associated with a higher cognitive composite score: independent of age and sex, but no longer significant after adjustment for education. No associations were found with plasma concentrations of any fatty acid. Considering individual cognitive tests, the strongest and most consistent correlations were found between immediate recall and concentrations of total n-3 PUFAs and α-linolenic acid (ALA) in erythrocytes, which were observed only in participants with recurrent depression. CONCLUSIONS: Total erythrocyte n-3 PUFA concentrations are positively associated with cognitive function, particularly immediate recall, in older people with previous depression. Lower concentrations of n-3 PUFAs or ALA in erythrocyte membranes may be good predictors for cognitive impairment in older people with previous recurrent depression.

The effects of omega-3 fatty acids monotherapy in Alzheimer's disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study.

A 24-week, randomized, 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 randomized 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.

Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study.

CONTEXT: Agents that enhance N-methyl-D-aspartate (NMDA) function through the glycine modulatory site (D-serine, glycine, or D-cycloserine) or through glycine transporter 1 (sarcosine) improve the symptoms of patients with stable chronic schizophrenia. OBJECTIVE: To determine whether NMDA-glycine site agonists or glycine transporter-1 inhibitors have better efficacy and whether NMDA receptor-enhancing agents have beneficial effects for acute exacerbation of schizophrenia. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Inpatient units of 2 major medical centers in Taiwan. Patients Sixty-five schizophrenic inpatients with acute exacerbation. INTERVENTIONS: Six weeks of treatment with sarcosine (2 g/d), D-serine (2 g/d), or placebo and concomitant optimal risperidone therapy. MAIN OUTCOME MEASURES: Positive and Negative Syndrome Scale (PANSS) and Scale for the Assessment of Negative Symptoms (SANS) (20 and 17 items) total scores. RESULTS: The sarcosine group revealed more reductions in PANSS total scores than the placebo (P = .04) and D-serine (P<.001) groups. Sarcosine adjunctive treatment was also superior to placebo in reducing SANS-20 (P = .007) and SANS-17 (P = .003) scores and to D-serine in decreasing SANS-20 (P = .006) and SANS-17 (P = .002) scores. The PANSS-general, PANSS-cognitive, and PANSS-depressive symptoms scores and SANS-alogia and SANS-blunted affect scores improved significantly more in sarcosine-cotreated patients than in risperidone monotherapy patients (P< or =.02 for all). Sarcosine adjunctive therapy also surpassed D-serine in terms of PANSS-general, PANSS-positive, PANSS-negative, and PANSS-depressive symptoms scores (P< or =.04 for all). D-serine and risperidone cotreatment did not differ significantly from risperidone monotherapy in all efficacy domains. CONCLUSIONS: This first short-term treatment study on NMDA receptor-enhancing agents suggests that sarcosine, superior to D-serine, can benefit not only patients with long-term stable disease but also acutely ill persons with schizophrenia. This finding indicates that a glycine transporter 1 inhibitor may be more efficacious than NMDA-glycine site agonists for adjuvant treatment of schizophrenia, at least during the acute phase. Further studies are needed.