ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults: A Randomized Clinical Trial.

Importance: Older adults with lower intake and tissue levels of long-chain ω-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6) have more brain white matter lesions (WMLs), an association suggesting that small-vessel ischemic disease, a major contributor to the development of dementia, including Alzheimer disease, may be preventable through ω-3 treatment. Objective: To determine whether ω-3 treatment reduces WML accumulation in older adults without dementia harboring WMLs and with suboptimal ω-3 status. Design, Setting, and Participants: This quadruple-blinded, placebo-controlled, randomized clinical trial with treatment stratification by apolipoprotein E ε4 allele (APOE*E4) carrier status used linear mixed-effects models to estimate mean annual change between groups. The study was conducted at Oregon Health & Science University, a major academic medical center in the Pacific Northwest, from May 2014 to final participant visit in September 2019. Data analysis concluded in July 2022. Participants were adults without dementia aged 75 years and older with WMLs greater than or equal to 5 cm3 and plasma ω-3 PUFA less than 5.5 weight percentage of total. Intervention: Three-year treatment with 1.65 g of ω-3 PUFA (975 mg of EPA and 650 mg of DHA) vs a soybean oil placebo matched for taste, smell, and appearance. Main Outcomes and Measures: The primary outcome was annual WML progression measured using magnetic resonance imaging. Secondary outcomes included diffusion tensor imaging of fractional anisotropy (DTI-FA), representing neuronal integrity breakdown. Results: A total of 102 participants (62 women [60.8%]; mean age, 81 years [range, 75-96 years]) were equally randomized, 51 per treatment group. Although the ω-3 group had less annual WML accumulation than the placebo group, the difference was not statistically significant (1.19 cm3 [95% CI, 0.64-1.74 cm3] vs 1.34 cm3 [95% CI, 0.80-1.88 cm3]; P = .30). Similarly, the ω-3 group had less annual DTI-FA decline than the placebo group, but the difference was not statistically significant (-0.0014 mm2/s [95% CI, -0.0027 to 0.0002 mm2/s] vs -0.0027 mm2/s [95% CI, -0.0041 to -0.0014 mm2/s]; P = .07). Among APOE*E4 carriers, the annual DTI-FA decline was significantly lower in the group treated with ω-3 than the placebo group (-0.0016 mm2/s [95% CI, -0.0032 to 0.0020 mm2/s] vs -0.0047 mm2/s [95% CI, -0.0067 to -0.0025 mm2/s]; P = .04). Adverse events were similar between treatment groups. Conclusions and Relevance: In this 3-year randomized clinical trial, ω-3 treatment was safe and well-tolerated but failed to reach significant reductions in WML accumulation or neuronal integrity breakdown among all participants, which may be attributable to sample size limitations. However, neuronal integrity breakdown was reduced by ω-3 treatment in APOE*E4 carriers, suggesting that this treatment may be beneficial for this specific group. Trial Registration: ClinicalTrials.gov Identifier: NCT01953705.

Recovery of motor function is associated with rescue of glutamate biomarkers in the striatum and motor cortex following treatment with Mucuna pruriens in a murine model of Parkinsons disease.

There is growing interest in the use of natural products for the treatment of Parkinson's disease (PD). Mucuna pruriens has been used in the treatment of humans with PD. The goal of this study was to determine if daily oral treatment with an extract of Mucuna pruriens, starting after the MPTP-induced loss of nigrostriatal dopamine in male mice, would result in recovery/restoration of motor function, tyrosine hydroxylase (TH) protein expression in the nigrostriatal pathway, or glutamate biomarkers in both the striatum and motor cortex. Following MPTP administration, resulting in an 80 % loss of striatal TH, treatment with Mucuna pruriens failed to rescue either striatal TH or the dopamine transporter back to the control levels, but there was restoration of gait/motor function. There was an MPTP-induced loss of TH-labeled neurons in the substantia nigra pars compacta and in the number of striatal dendritic spines, both of which failed to be recovered following treatment with Mucuna pruriens. This Mucuna pruriens-induced locomotor recovery following MPTP was associated with restoration of two striatal glutamate transporter proteins, GLAST (EAAT1) and EAAC1 (EAAT3), and the vesicular glutamate transporter 2 (Vglut2) within the motor cortex. Post-MPTP treatment with Mucuna pruriens, results in locomotor improvement that is associated with recovery of striatal and motor cortex glutamate transporters but is independent of nigrostriatal TH restoration.

A Review of Oxylipins in Alzheimer's Disease and Related Dementias (ADRD): Potential Therapeutic Targets for the Modulation of Vascular Tone and Inflammation.

There is now a convincing body of evidence from observational studies that the majority of modifiable Alzheimer's disease and related dementia (ADRD) risk factors are vascular in nature. In addition, the co-existence of cerebrovascular disease with AD is more common than AD alone, and conditions resulting in brain ischemia likely promote detrimental effects of AD pathology. Oxylipins are a class of bioactive lipid mediators derived from the oxidation of long-chain polyunsaturated fatty acids (PUFAs) which act as modulators of both vascular tone and inflammation. In vascular cognitive impairment (VCI), there is emerging evidence that oxylipins may have both protective and detrimental effects on brain structure, cognitive performance, and disease progression. In this review, we focus on oxylipin relationships with vascular and inflammatory risk factors in human studies and animal models pertinent to ADRD. In addition, we discuss future research directions with the potential to impact the trajectory of ADRD risk and disease progression.

Qualitative analysis of the Meals, Mindfulness, & Moving Forward (M3 ) lifestyle programme: Cultivating a 'safe space' to start on a 'new path' for youth with early episode psychosis.

AIM: The Meals, Mindfulness, & Moving Forward (M3 ) programme included nutrition education, hands-on cooking classes, mindfulness meditation practice, physical activities and facilitated group sharing. M3 was designed as a supplement to standard care for youths (age 15-25 years) with first-episode psychosis (FEP) who were clients of coordinated specialty care teams. M3 's primary aim was feasibility by demonstrating high programme attendance; secondary aims included cardiometabolic measures. Data collection included quantitative and qualitative outcomes. The aim of the qualitative study was to understand participants' and study partners' experiences during the programme and to understand programme elements that were helpful for young people to sustain healthy lifestyle choices 6 weeks post-programme. METHODS: During the last programme session, we conducted two focus groups, one with participants (n = 13) and one with their study partners (n = 11); 6 weeks post-intervention, individual semi-structured interviews were conducted with 11 participants. All interviews were audio recorded and transcribed; grounded theory methods guided thematic analysis. RESULTS: Main themes from the focus groups included appreciation for a 'non-stigmatizing' environment providing participants and study partners with a sense of 'dignity' that enabled a 'new path'. Six weeks post-intervention, participants reported continued use of mindfulness practice to stay grounded and assist with making healthful lifestyle changes. However, many were unsure of how to sustain these changes long-term. CONCLUSION: The results suggest that young people with FEP value a non-stigmatizing space that allows for social engagement and facilitates healthy behaviours. Short-term, M3 participants reported behaviour change but wanted on-going support to sustain healthy behaviours.

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.

Natural Product Target Network Reveals Potential for Cancer Combination Therapies.

A body of research demonstrates examples of in vitro and in vivo synergy between natural products and anti-neoplastic drugs for some cancers. However, the underlying biological mechanisms are still elusive. To better understand biological entities targeted by natural products and therefore provide rational evidence for future novel combination therapies for cancer treatment, we assess the targetable space of natural products using public domain compound-target information. When considering pathways from the Reactome database targeted by natural products, we found an increase in coverage of 61% (725 pathways), relative to pathways covered by FDA approved cancer drugs collected in the Cancer Targetome, a resource for evidence-based drug-target interactions. Not only is the coverage of pathways targeted by compounds increased when we include natural products, but coverage of targets within those pathways is also increased. Furthermore, we examined the distribution of cancer driver genes across pathways to assess relevance of natural products to critical cancer therapeutic space. We found 24 pathways enriched for cancer drivers that had no available cancer drug interactions at a potentially clinically relevant binding affinity threshold of < 100nM that had at least one natural product interaction at that same binding threshold. Assessment of network context highlighted the fact that natural products show target family groupings both distinct from and in common with cancer drugs, strengthening the complementary potential for natural products in the cancer therapeutic space. In conclusion, our study provides a foundation for developing novel cancer treatment with the combination of drugs and natural products.

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.

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.

Impact of mindfulness-based stress reduction for people with multiple sclerosis at 8 weeks and 12 months: A randomized clinical trial.

BACKGROUND: Mindfulness training is often used as a therapeutic intervention to manage stress and enhance emotional well-being, yet trials for multiple sclerosis (MS) are limited and few have used an active control. OBJECTIVE: Assess the feasibility of mindfulness-based stress reduction (MBSR) for people with MS and evaluate the efficacy of MBSR compared to an education control. METHODS: We conducted a single-blind, randomized trial of MBSR versus education control among 62 adults with MS. Primary outcomes were measures of feasibility. Secondary outcomes included perceived stress, anxiety, depression, fatigue, pain, resilience, and the Paced Auditory Serial Addition Test, assessed at baseline, 8 weeks, and 12 months. Mean scores for secondary outcome measures were compared between groups at each time point and within groups across time by analyses of covariance or paired t-tests, respectively. RESULTS: Successful recruitment and retention demonstrated feasibility. Improvements in several secondary outcomes were observed among both MBSR and control groups. However, differences between the groups were not statistically significant at either 8 weeks or 12 months. CONCLUSION: Emotional well-being improved with both MBSR and education. Spontaneous improvement cannot be ruled out as an explanation for findings and additional studies that evaluate the impact of mindfulness training to improve emotional health are warranted.

Association Between Pain and Mindfulness in Multiple Sclerosis: A Cross-sectional Survey.

BACKGROUND: Chronic pain is a common symptom in people with multiple sclerosis (MS) and often requires a multimodal approach to care. The practice of mindfulness has been shown to decrease the experience of pain in other conditions, yet little is known about the relationship between mindfulness and pain in people with MS. The objective of this study was to evaluate the association between pain interference and trait mindfulness in people with MS. METHODS: In this cross-sectional survey, 132 people with any type of MS completed the Patient-Reported Outcomes Measurement Information System Pain Interference scale and the Five Facet Mindfulness Questionnaire. Linear regression was used to test the association between pain and mindfulness while adjusting for demographic and MS-related characteristics. RESULTS: The relationship between pain and mindfulness was clinically meaningful and highly significant (t = -5.52, P < .0001). For every 18-point increase in mindfulness scores, pain interference scores are expected to decrease by 3.96 (95% CI, -2.52 to -5.40) points (ß = -0.22, P < .0001). The adjusted model, including age, type of MS, the interaction between mindfulness and age, and the interaction between mindfulness and MS type, explains 26% of the variability in pain interference scores (R2 = 0.26). CONCLUSIONS: These results suggest a clinically significant association between mindfulness and pain interference in MS and support further exploration of mindfulness-based interventions in the management of MS-related pain.

Analysis of Levodopa Content in Commercial Mucuna pruriens Products Using High-Performance Liquid Chromatography with Fluorescence Detection.

OBJECTIVES: Mucuna pruriens (MP) seeds contain levodopa (up to 2% by weight) and have been used in traditional Indian medicine to treat an illness named "Kampavata," now understood to be Parkinson's disease (PD). Studies have shown MP to be beneficial, and even superior, to levodopa alone in treating PD symptoms. Commercial products containing MP are readily available from online and retail sources to patients and physicians. Products often contain extracts of MP seeds, with significantly higher levodopa content than the seeds. However, MP products have limited regulatory controls with respect to quality and content of active ingredient. The aim of this study was to apply a quantitative method to determine levodopa content in readily available MP products that might be used by patients or in research studies. DESIGN: Levodopa present in six commercial MP products was quantified by solvent extraction followed by reversed-phase high-performance liquid chromatography (HPLC) coupled to fluorescence detection (FD). Certificates of analysis (COA) were obtained, from manufacturers of MP products, to assess the existence and implementation of specifications for levodopa content. RESULTS: HPLC-FD analysis revealed that the levodopa content of the six commercial MP products varied from 6% to 141% of individual label claims. No product contained levodopa within normal pharmacopeial limits of 90%-110% label claim. The maximum daily dose of levodopa delivered by the products varied from 14.4 to 720 mg/day. COAs were inconsistent in specifications for and verification of levodopa content. CONCLUSIONS: The commercial products tested varied widely in levodopa content, sometimes deviating widely from the label claim. These deficiencies could impact efficacy and safety of MP products used by PD patients and compromise the results of scientific studies on MP products. The HPLC-FD method described in this study could be utilized by both manufacturers and scientific researchers to verify levodopa content of MP products.

Wellness and multiple sclerosis: The National MS Society establishes a Wellness Research Working Group and research priorities.

BACKGROUND: People with multiple sclerosis (MS) have identified "wellness" and associated behaviors as a high priority based on "social media listening" undertaken by the National MS Society (i.e. the Society). OBJECTIVE: The Society recently convened a group that consisted of researchers with experience in MS and wellness-related research, Society staff members, and an individual with MS for developing recommendations regarding a wellness research agenda. METHOD: The members of the group engaged in focal reviews and discussions involving the state of science within three approaches for promoting wellness in MS, namely diet, exercise, and emotional wellness. RESULTS: That process informed a group-mediated activity for developing and prioritizing research goals for wellness in MS. This served as a background for articulating the mission and objectives of the Society's Wellness Research Working Group. CONCLUSION: The primary mission of the Wellness Research Working Group is the provision of scientific evidence supporting the application of lifestyle, behavioral, and psychosocial approaches for promoting optimal health of mind, body, and spirit (i.e. wellness) in people with MS as well as managing the disease and its consequences.

Associations between Serum Omega-3 Fatty Acid Levels and Cognitive Functions among Community-Dwelling Octogenarians in Okinawa, Japan: The KOCOA Study.

BACKGROUND: Epidemiological studies have found frequent consumption of fatty fish is protective against cognitive decline. However, the association between circulating omega-3 polyunsaturated fatty acid (PUFA) levels and cognitive functions among the oldest old is not well known. OBJECTIVE: To examine the association between serum PUFA levels and cognitive function among community-dwelling, non-demented elderly aged over 80 years old. METHODS: The data came from the Keys to Optimal Cognitive Aging (KOCOA) study; an ongoing cohort of relatively healthy volunteers aged over 80 years old, living in Okinawa, Japan. One hundred eighty five participants (mean age 84.1±3.4 years) assessed in 2011 who were free from frank dementia (defined as Clinical Dementia Rating <1.0) were used for the current cross-sectional study. We examined whether serum omega-3 PUFAs (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), arachidonic acid (AA), EPA/AA ratio, DHA/AA ratio, and DHA+EPA are associated with (1) age and (2) global cognitive function (Japanese MMSE) and executive function (Verbal Fluency Letter). Data was analyzed univariately by t-test and multivariately by cumulative logistic regression models controlling for age, gender, years of education, obesity, hypertension, diabetes, and dyslipidemia. RESULTS: Serum DHA levels decreased with increasing age (p = 0.04). Higher global cognitive function was associated with higher levels of serum EPA (p = 0.03) and DHA + EPA (p = 0.03) after controlling for confounders. CONCLUSIONS: Higher serum EPA and DHA + EPA levels were independently associated with better scores on global cognitive function among the oldest old, free from dementia. Longitudinal follow-up studies are warranted.

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.

Managing psychological stress in the multiple sclerosis medical visit: Patient perspectives and unmet needs.

Psychological stress can negatively impact multiple sclerosis. To further understand how stress is addressed in the multiple sclerosis medical visit, 34 people with multiple sclerosis participated in focus groups. Transcripts were analyzed by inductive thematic analysis. The majority of participants did not discuss stress with their provider, citing barriers to communication such as lack of time, poor coordination between specialties, physician reliance on pharmaceutical prescription, and patient lack of self-advocacy. Participants recommended several ways to better manage psychological well-being in the clinical setting. These findings provide a foundation for future studies aimed at minimizing the detrimental effect of stress in multiple sclerosis.

Perceived stress in multiple sclerosis: the potential role of mindfulness in health and well-being.

Stressful life events are associated with worsening neurological symptoms and decreased quality of life in multiple sclerosis (MS). Mindful consciousness can alter the impact of stressful events and has potential to improve health outcomes in MS. This study evaluated the relationship between trait mindfulness and perceived stress, coping, and resilience in people with MS. Quality of life was assessed as a secondary outcome. One hundred nineteen people with confirmed MS completed the Five-Facet Mindfulness Questionnaire, Perceived Stress Scale, Brief Coping Orientation for Problem Experiences, Connor-Davidson Resilience Scale, and Medical Outcome Study Short Form-36. Greater trait mindfulness was significantly associated with decreased psychological stress, better coping skills, increased resilience, and higher quality of life. After investigators controlled for confounders, mindfulness accounted for 25% of the variation in perceived stress scores and 44% of the variation in resilience scores. Results support further investigation of mindfulness training to enhance psychological resilience and improve well-being for those living with MS.

Reducing survey burden: feasibility and validity of PROMIS measures in multiple sclerosis.

BACKGROUND: Patient-reported outcomes are important for clinical research and care, yet administering and scoring the questionnaires requires considerable effort and time. The Patient Reported Outcomes Measurement Information System (PROMIS) could considerably reduce administrative obstacles and lessen survey burden for participants. OBJECTIVE: Assess the feasibility and validity of PROMIS, compared to commonly-used legacy measures for multiple sclerosis (MS). METHODS: In this cross-sectional survey, 133 participants with confirmed MS completed legacy surveys and PROMIS Computerized Adaptive Tests (CATs) for depression, anxiety, pain, fatigue and physical function. We conducted a multi-trait, multi-method analysis and verified results with confirmatory factor analysis. RESULTS: The correlations between PROMIS and the corresponding legacy measures were large (0.67 to 0.87). The multi-trait, multi-method criteria were generally well met, providing good evidence of the validity of PROMIS measures. PROMIS surveys asked fewer questions and required substantially less time to complete than the legacy scales. CONCLUSIONS: Our results provide evidence of the construct validity of PROMIS for use with MS patients. Several aspects of the PROMIS CATs made them an important resource, including: (a) less time was required to complete them; (b) missing data was reduced; and (c) the automatic scoring referenced the general population. Our findings support the use of PROMIS in MS research and may have broader implications for clinical care, as well.