Oxidized Products of Omega-6 and Omega-3 Long Chain Fatty Acids Are Associated with Increased White Matter Hyperintensity and Poorer Executive Function Performance in a Cohort of Cognitively Normal Hypertensive Older Adults.

BACKGROUND: Cerebrovascular disease is a common cause of dementia in older adults, and potentially preventable with early intervention. Oxylipins are produced from the oxidation of long-chain polyunsaturated fatty acids (PUFA) possessing potent vascular effects. Oxylipins generated from the cytochrome P450 pathway are enzymatically converted to diols by soluble epoxide hydrolase (sEH); sEH products have been associated with small vessel ischemic disease. Little is known about oxylipins' impact on markers of dementia risk. OBJECTIVE: An exploratory examination of the association between omega-6 and omega-3 derived oxylipins, brain MRI, and cognition. METHODS: Thirty-seven non-demented participants with controlled hypertension (mean age 65.6 years) were enrolled in a dementia prevention study investigating fish oil and lipoic acid on preserving cognitive function. Baseline associations between plasma oxylipins, white matter hyperintensity (WMH), and Trails-B were examined using linear regression. P450-derived diol/epoxide ratio was an indirect measure of sEH activity. RESULTS: Omega-6 derived 9-HODE was associated with increased WMH (p = 0.017) and reduced grey matter volume (p = 0.02). Omega-6 P450-derived diol/epoxide ratio 9,10-DiHOME/9,10-EpOME was associated with increased WMH (p = 0.035) and poorer performance on Trails-B (p = 0.05); ratio14,15-DHET/14,15-EET was associated with increased WMH (p = 0.045). Omega-3 P450-derived diol/epoxide ratio 19,20-DiHDPE/19,20-EpDPE was associated with increased WMH (p = 0.04) and poorer performance on Trails-B (p = 0.04). Arachidonic acid was associated with better performance on Trails-B (p = 0.012); Omega-3 derived 16,17-EpDPE was associated with decreased WMH (p = 0.005). CONCLUSIONS: With the exception of arachidonic acid, it was specific oxylipin products, not their parent PUFAs, that were associated with unfavorable and favorable MRI and cognitive markers of dementia risk.

Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice.

Centella asiatica (CA) herb is a traditional medicine, long reputed to provide cognitive benefits. We have reported that CA water extract (CAW) treatment improves cognitive function of aged Alzheimer's disease (AD) model Tg2576 and wild-type (WT) mice, and induces an NRF2-regulated antioxidant response in aged WT mice. Here, CAW was administered to AD model 5XFAD female and male mice and WT littermates (age: 7.6 +/ - 0.6 months), and object recall and contextual fear memory were tested after three weeks treatment. CAW's impact on amyloid-ß plaque burden, and markers of neuronal oxidative stress and synaptic density, was assessed after five weeks treatment. CAW antioxidant activity was evaluated via nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2) and NRF2-regulated antioxidant response element gene expression. Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden, and marginally increased synaptic density markers in the hippocampus and prefrontal cortex. CAW treatment increased Nrf2 in hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit). Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice. We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.

Oral lipoic acid as a treatment for acute optic neuritis: a blinded, placebo controlled randomized trial.

BACKGROUND: Lipoic acid, an antioxidant, has beneficial effects in experimental acute optic neuritis and autoimmune encephalomyelitis. Optical coherence tomography can detect retinal nerve fiber layer thinning, representing axonal degeneration, approximately 3-6 months after acute optic neuritis. OBJECTIVE: To determine whether lipoic acid is neuroprotective in acute optic neuritis. METHODS: A single-center, double-blind, randomized, placebo controlled, 24-week trial. Intervention included 6 weeks of once daily lipoic acid (1200 mg) or placebo within 14 days of acute optic neuritis diagnosis. The primary outcome was the mean difference in affected eye retinal nerve fiber layer (RNFL) thickness from baseline to 24 weeks. RESULTS: We enrolled 31 subjects (placebo n=16; lipoic acid n=15; average age 38.6 years (standard deviation (SD) 10.3)). Affected eye mean global RNFL thickness (µm) in the lipoic acid group decreased from 108.47 (SD 26.11) at baseline to 79.31 (SD 19.26) at 24 weeks. The affected eye RNFL in the placebo group decreased from 103.67 (SD 18.04) at baseline to 84.43 (SD 20.94) at 24 weeks. Unaffected eye RNFL thickness did not significantly change in either group over 24 weeks. CONCLUSION: Six weeks of oral lipoic acid supplementation after acute optic neuritis is safe and well tolerated; however, because of insufficient recruitment, we could not conclude that lipoic acid treatment was neuroprotective in acute optic neuritis.

Randomized Trial of Marine n-3 Polyunsaturated Fatty Acids for the Prevention of Cerebral Small Vessel Disease and Inflammation in Aging (PUFA Trial): Rationale, Design and Baseline Results.

Vascular risk factors for age-related cognitive decline are significant, and their management may ultimately prove the most successful strategy for reducing risk and sustaining cognitive health. This randomized, double-blinded, placebo-controlled trial with parallel group allocation to either marine n-3 polyunsaturated fatty acids (n-3 PUFA) or soybean oil placebo assesses the effects on the total volume of accumulation in cerebral white matter hyperintensities (WMH), a potentially modifiable neurovascular component of age-related cognitive decline. Total WMH accumulation over 3 years is the primary endpoint. The safety and efficacy of n-3 PUFA is evaluated in older adults with significant WMH and suboptimum plasma n-3 PUFA as inclusion criteria. One hundred and two non-demented older adults were enrolled with a mean age of 81.1 (±4.4) years, WMH of 19.4 (±16.1) cm³, and a plasma n-3 PUFA of 86.64 (±29.21) µg/mL. 61% were female, 28% were apolipoprotein E epsilon 4 carriers, and the mean mini-mental state exam (MMSE) was 27.9 (±1.7). This trial provides an initial evaluation of n-3 PUFA effects on WMH, a reproducible and valid risk biomarker for cognitive decline, as well as on inflammatory biomarkers thought to play a role in WMH accumulation. We present the baseline results and operational experience of enriching a study population on advanced age, blood n-3 PUFA, and magnetic resonance imaging (MRI) derived WMH with biomarker outcomes (WMH, inflammation markers) in a dementia prevention paradigm.

Local effects of acupuncture on the median and ulnar nerves in patients with carpal tunnel syndrome: a pilot mechanistic study protocol.

BACKGROUND: While acupuncture's mechanism of action is not fully understood, there is consensus that the nervous system plays a key role in processing its effects. This research is based on the structural theory of acupuncture, which aims to correlate the location of acupuncture points to peripheral nerves, spinal segments, and spinal plexuses. This mechanistic study explores the close anatomical association between the Pericardium meridian/median nerve and the Heart meridian/ulnar nerve in an attempt to produce electrophysiologic data measuring acupuncture's direct, nerve-specific effect on the underlying nerves. Specifically, the purpose of this research is to use nerve conduction studies (NCSs) and quantitative sensory testing (QST) to assess for any local, nerve-specific effect of three acupuncture modalities on two anatomically distinct nerves in the forearm - the median and ulnar nerves - in subjects with carpal tunnel syndrome (CTS). The choice of CTS as an injured nerve model allows for comparisons between the response in an injured nerve (median) to that of a healthy one (ulnar). METHODS: Subjects with mild to moderate CTS will be randomized to three intervention groups: manual acupuncture and low- and high-frequency electroacupuncture. Each subject will receive two treatments, 1 week apart, to points in the forearm, which overlay the median nerve (Pericardium meridian) or the ulnar nerve (Heart meridian). Acupuncture will be administered in random order to minimize learning effects in sensory testing. During Week 1, baseline NCS and QST (vibration and cold detection thresholds) will be obtained in both nerve territories, followed by acupuncture and post-acupuncture NCS and QST measurements in both nerve territories. During Week 2, repeat baseline QST and NCS measurements will be obtained, followed by acupuncture to points overlying the nerve not treated in Week 1, followed by post-acupuncture NCS and QST measurements in both nerve distributions. DISCUSSION: This works aims to capture and characterize the local effects of acupuncture on an underlying nerve and compare them to those on a neighboring nerve. Quantifying acupuncture's effects using physiologic parameters and discrete values could standardize treatment regimens and help assess their therapeutic effect. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03036657 . Registered on 30 January 2017. Retrospectively registered.

Meals, Mindfulness, & Moving Forward: A feasibility study to a multi-modal lifestyle approach in early psychosis.

AIM: The primary aim was to demonstrate adherence to a novel 6-week lifestyle intervention program ("Meals, Mindfulness, & Moving Forward" [M3 ]) designed to help improve lifestyle practices of youth with a history of at least 1 psychotic episode. METHODS: M3 used a non-equivalent control group design involving clients from a community early intervention program. Seventeen individuals in the active M3 program and 16 controls were assessed for secondary outcomes at baseline, 6-weeks, and 12-weeks (6 weeks post-intervention) on cardiometabolic and symptomatic outcomes. RESULTS: The program met its primary aim with 88% (15/17) of participants meeting adherence criteria. Compared with the controls, M3 participants showed significant improvement in positive psychotic symptoms (P = .002). CONCLUSION: This pilot study showed that young people involved in a community early intervention program adhered to an activity-based lifestyle program which included mindfulness meditation, yoga and nutrition education, warranting further evaluation with a larger sample size.

A randomized, controlled pilot study of the effects of vitamin D supplementation on balance in Parkinson's disease: Does age matter?

OBJECTIVES: To explore if short term, high dose vitamin D supplementation is safe and improves balance in persons with Parkinson's disease (PD). METHODS: A pilot randomized, double-blind intervention trial to measure the effects of 16 weeks of high dose vitamin D (10,000 IU/day) on balance as well as other motor and non-motor features of PD. We measured balance, gait, strength, falls, cognition, mood, PD severity, and quality of life before and after 16 weeks of high dose vitamin D supplementation or placebo. All participants also received 1000 mg calcium once daily. RESULTS: Fifty-one randomized participants completed sixteen weeks of high dose vitamin D supplementation or placebo. The intervention resulted in a rise in serum concentrations of vitamin D (25-OH) (30.2 ng/ml to 61.1 ng/ml) and was well tolerated with no serious adverse events. Serum vitamin D (25-OH) levels rose steadily and did not suggest a leveling off at the end of the 16 weeks. There was not an improvement in the primary endpoint, balance as measured by the Sensory Organization Test (p = 0.43). A post hoc analysis examining treatment effects in younger (ages 52-66) versus older (ages 67-86) participants found a significant improvement in the SOT of 10.6 points in the younger half of the cohort (p = 0.012). CONCLUSIONS: Short term, high dose vitamin D supplementation appears safe in persons with PD, but did not significantly improve balance as measured with the Sensory Organization Test in this pilot study population. A post hoc analysis suggests that vitamin D may have potential for improving balance in a younger population with PD. High dose vitamin D supplementation in PD needs further study especially in light of new research suggesting that mega doses and even moderate doses (as low as 4000IU a day) may increase falls in an older populations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01119131.

The Case for Local Needling in Successful Randomized Controlled Trials of Peripheral Neuropathy: A Follow-Up Systematic Review.

Objectives: This work follows-up on a systematic review, published in 2017, of acupuncture for the treatment of mono- and polyneuropathy and associated symptoms. Previously reviewed trials of acupuncture for neuropathy primarily used acupuncture points in close proximity to underlying nerves. Further exploration of point selection for the treatment of each neuropathic condition is needed to assess the anatomical relationships between acupuncture points and peripheral nerves with respect to the treatment of neuropathy. Methods: The 13 randomized controlled trials included in the original review studied acupuncture for neuropathy caused by diabetes, Bell's palsy, carpal tunnel syndrome (CTS), human immunodeficiency virus (HIV), and idiopathic causes. The present review reexamines all acupuncture points used, focusing on specific neuropathic condition treated. Anatomical diagrams are presented to highlight acupuncture points underlying the nerves' anatomical relationships. Each selected acupuncture point is reviewed in detail, including its Traditional Chinese Medicine theory-based function, the point's indications for use, and the peripheral nerve most closely associated with it. Results: In Bell's palsy, the majority of selected acupuncture points were associated with the ipsilateral facial nerve. In CTS, the majority of the selected acupuncture points were closely associated with the median nerve and its branches. In polyneuropathy caused by diabetes, HIV, or idiopathic causes, most selected acupuncture points were in close proximity to peripheral nerves. Conclusions: All reviewed trials of acupuncture for neuropathy and neuropathic pain use acupuncture points that are closely associated with the peripheral nerves treated. Local needling is crucial for successful treatment of peripheral neuropathy.

Centella asiatica attenuates Aß-induced neurodegenerative spine loss and dendritic simplification.

The medicinal plant Centella asiatica has long been used to improve memory and cognitive function. We have previously shown that a water extract from the plant (CAW) is neuroprotective against the deleterious cognitive effects of amyloid-ß (Aß) exposure in a mouse model of Alzheimer's disease, and improves learning and memory in healthy aged mice as well. This study explores the physiological underpinnings of those effects by examining how CAW, as well as chemical compounds found within the extract, modulate synaptic health in Aß-exposed neurons. Hippocampal neurons from amyloid precursor protein over-expressing Tg2576 mice and their wild-type (WT) littermates were used to investigate the effect of CAW and various compounds found within the extract on Aß-induced dendritic simplification and synaptic loss. CAW enhanced arborization and spine densities in WT neurons and prevented the diminished outgrowth of dendrites and loss of spines caused by Aß exposure in Tg2576 neurons. Triterpene compounds present in CAW were found to similarly improve arborization although they did not affect spine density. In contrast caffeoylquinic acid (CQA) compounds from CAW were able to modulate both of these endpoints, although there was specificity as to which CQAs mediated which effect. These data suggest that CAW, and several of the compounds found therein, can improve dendritic arborization and synaptic differentiation in the context of Aß exposure which may underlie the cognitive improvement observed in response to the extract in vivo. Additionally, since CAW, and its constituent compounds, also improved these endpoints in WT neurons, these results may point to a broader therapeutic utility of the extract beyond Alzheimer's disease.

Acupuncture for the Treatment of Peripheral Neuropathy: A Systematic Review and Meta-Analysis.

OBJECTIVES: Neuropathy and its associated pain pose great therapeutic challenges. While there has been a recent surge in acupuncture use and research, little remains known about its effects on nerve function. This review aims to assess the efficacy of acupuncture in the treatment of neuropathy of various etiologies. METHODS: The Medline, AMED, Cochrane, Scopus, CINAHL, and clintrials.gov databases were systematically searched from inception to July 2015. Randomized controlled trials (RCTs) assessing acupuncture's efficacy for poly- and mononeuropathy were reviewed. Parallel and crossover RCTs focused on acupuncture's efficacy were reviewed and screened for eligibility. The Scale for Assessing Scientific Quality of Investigations in Complementary and Alternative Medicine was used to assess RCT quality. RCTs with score of >9 and active control treatments such as sham acupuncture or medical therapy were included. RESULTS: Fifteen studies were included: 13 original RCTs, a long-term follow-up, and a re-analysis of a prior RCT. The selected RCTs studied acupuncture for neuropathy caused by diabetes, Bell's palsy, carpal tunnel syndrome, human immunodeficiency virus (HIV), and idiopathic conditions. Acupuncture regimens, control conditions, and outcome measures differed among studies, and various methodological issues were identified. Still, the majority of RCTs showed benefit for acupuncture over control in the treatment of diabetic neuropathy, Bell's palsy, and carpal tunnel syndrome. Acupuncture is probably effective in the treatment of HIV-related neuropathy, and there is insufficient evidence for its benefits in idiopathic neuropathy. Acupuncture appears to improve nerve conduction study parameters in both sensory and motor nerves. Meta-analyses were conducted on all diabetic neuropathy and Bell's palsy individual subject data (six RCTs; a total of 680 subjects) using a summary estimate random effects model, which showed combined odds ratio of 4.23 (95% confidence interval 2.3-7.8; p < 0.001) favoring acupuncture over control for neuropathic symptoms. CONCLUSIONS: Acupuncture is beneficial in some peripheral neuropathies, but more rigorously designed studies using sham-acupuncture control are needed to characterize its effect and optimal use better.

Omega-3 Fatty Acids for Depression in Multiple Sclerosis: A Randomized Pilot Study.

UNLABELLED: Multiple sclerosis is the most common chronic disabling disease in the central nervous system in young to middle aged adults. Depression is common in multiple sclerosis (MS) affecting between 50­60% of patients. Pilot studies in unipolar depression report an improvement in depression when omega-3 fatty acids are given with antidepressants. The objective of this study was to investigate whether omega-3 fatty acid supplementation, as an augmentation therapy, improves treatment-resistant major depressive disorder (MDD) in people with MS. We performed a randomized, double-blind, placebo-controlled pilot study of omega-3 fatty acids at six grams per day over three months. The primary outcome was a 50% or greater improvement on the Montgomery-Asberg Depression Rating Scale (MADRS). Thirty-nine participants were randomized and thirty-one completed the 3-month intervention. Improvement on MADRS between groups was not significantly different at the 3-month end point with 47.4% in the omega-3 fatty acid group and 45.5% in the placebo group showing 50% or greater improvement (p = 0.30). Omega-3 fatty acids as an augmentation therapy for treatment-resistant depression in MS was not significantly different than placebo in this pilot trial. Omega-3 fatty acid supplementation at the dose given was well-tolerated over 3 months. TRIAL REGISTRATION: ClinicalTrials.gov NCT00122954.