The Gary Null Show - 04.20.21

Study strengthens links between red meat and heart disease

Queen Mary University (UK), 15 April 2021

An observational study in nearly 20,000 individuals has found that greater intake of red and processed meat is associated with worse heart function. The research is presented at ESC Preventive Cardiology 2021, an online scientific congress of the European Society of Cardiology (ESC).1

"Previous studies have shown links between greater red meat consumption and increased risk of heart attacks or dying from heart disease," said study author Dr. Zahra Raisi-Estabragh of Queen Mary University of London, UK.2,3 "For the first time, we examined the relationships between meat consumption and imaging measures of heart health. This may help us to understand the mechanisms underlying the previously observed connections with cardiovascular disease."

The study included 19,408 participants of the UK Biobank.4 The researchers examined associations of self-reported intake of red and processed meat with heart anatomy and function.

Three types of heart measures were analysed. First, cardiovascular magnetic resonance (CMR) assessments of heart function used in clinical practice such as volume of the ventricles and measures of the pumping function of the ventricles. Second, novel CMR radiomics used in research to extract detailed information from heart images such as shape and texture (which indicates health of the heart muscle). Third, elasticity of the blood vessels (stretchy arteries are healthier).

The analysis was adjusted for other factors that might influence the relationship including age, sex, deprivation, education, smoking, alcohol, exercise, high blood pressure, high cholesterol, diabetes, and body mass index (BMI) as a measure of obesity.

The researchers found that greater intake of red and processed meat was associated with worse imaging measures of heart health, across all measures studied. Specifically, individuals with higher meat intake had smaller ventricles, poorer heart function, and stiffer arteries - all markers of worse cardiovascular health.

As a comparison, the researchers also tested the relationships between heart imaging measures and intake of oily fish, which has previously been linked with better heart health. They found that as the amount of oily fish consumption rose, heart function improved, and arteries were stretchier.

Dr. Raisi-Estabragh said: "The findings support prior observations linking red and processed meat consumption with heart disease and provide unique insights into links with heart and vascular structure and function."

The associations between imaging measures of heart health and meat intake were only partially explained by high blood pressure, high cholesterol, diabetes, and obesity.

"It has been suggested that these factors could be the reason for the observed relationship between meat and heart disease," said Dr. Raisi-Estabragh. "For example, it is possible that greater red meat intake leads to raised blood cholesterol and this in turn causes heart disease. Our study suggests that these four factors do play a role in the links between meat intake and heart health, but they are not the full story."

She noted that the study did not look into alternative mechanisms. But she said: "There is some evidence that red meat alters the gut microbiome, leading to higher levels of certain metabolites in the blood, which have in turn been linked to greater risk of heart disease."

Dr. Raisi-Estabragh said: "This was an observational study and causation cannot be assumed. But in general, it seems sensible to limit intake of red and processed meat for heart health reasons."

 

 

More Fruits and Veggies Improves Sleep for Young Adults

University of Michigan, April 15, 2021

Eating more fruits and vegetables can help young adults, especially young women, sleep better, a new study shows

Young adults who reported eating less than five servings of fruits and vegetables per day reported a high prevalence of chronic insomnia symptoms, with over one-third reporting difficulties with falling asleep or maintaining sleep at least three times per week for three months or longer.

Women who increased their fruit and vegetable intake by three or more servings over a three-month period were more than twice as likely to experience an improvement in these insomnia symptoms, according to the study in the Sleep Health Journal.

“We were very excited to see that a fairly simple dietary intervention, such as encouraging an increase in fruit and vegetable consumption, could make such an impact on sleep,” says lead author Erica Jansen, research assistant professor of nutritional sciences at the University of Michigan’s School of Public Health.

“We know from other literature that improving sleep improves overall quality of life and many other health outcomes, so the benefits likely extend beyond the sleep changes.”

Jansen and senior author Gwen Alexander, a researcher in the public health sciences department at Henry Ford Health System, and colleagues analyzed data of more than 1,400 participants compiled by Detroit-based Henry Ford and the more rural Geisinger Health System headquartered in Danville, Pennsylvania.

“From my health educator perspective, our study shows a link between dietary choices and improved sleep for young people who wish to improve their overall health and well-being,” Alexander says.

“Our study was unique in that it investigated an understudied population of generally healthy young adults. Future research designed for this population has great potential to lead to better health habits.”

Eligible young adults included those ages 21-30, who received any medical care at the centers and who reported eating less than five servings of fruits and vegetables per day. Researchers randomized the participants into one of three groups: one had an untailored web-based program to encourage higher fruits and vegetables consumption; the second had an age-targeted tailored web-based program; and the third group also included personalized e-coaching support.

Young adults who increased their fruit and vegetable consumption by at least three servings experienced modest improvements in sleep latency (time to fall asleep) and insomnia over a three-month period, compared to participants with no change or smaller increases in fruits and vegetable intake, although there were no differences in sleep duration.

Women who increased their fruit and vegetable intake by three or more servings reported a four-minute shorter time, on average, to fall asleep at follow-up, and twofold higher odds of improvement in insomnia symptoms.

“What is unique about our study is that we were able to see that as fruit and vegetable intake changed, insomnia-related sleep characteristics also changed,” Jansen says.

“We still cannot rule out that sleep characteristics changed first, which in turn caused a change in fruit and vegetable intake, but since the participants were part of a trial to increase fruit and vegetable intake, it is more likely the other way around. The participants were not told to change anything about their sleep habits.”

The researchers hope the findings will be incorporated into other sleep hygiene principles, which include things like maintaining a consistent bedtime and rise time, eliminating screens prior to going to bed, sleeping in a dark, cool environment, and not drinking caffeine or alcohol before bed.

Additional coauthors are from the University of South Carolina School of Medicine and the Henry Ford Health System.

 

 

Multivits, omega-3, probiotics, vitamin D may lessen risk of positive COVID-19 test

British Medical Journal, April 20, 2021

Taking multivitamins, omega-3, probiotics or vitamin D supplements may lessen the risk of testing positive for SARS-CoV-2, the virus responsible for COVID-19 infection—at least among women—indicates a large population study, published online in the journal BMJ Nutrition Prevention & Health.

But taking any of vitamin C, zinc, or garlic supplements wasn't associated with a lower risk of testing positive for the virus, the findings show.

There has been plenty of celebrity endorsement of the use of dietary supplements to both ward off and treat COVID-19 infection since the start of the pandemic, note the researchers.

In the UK alone, market share rose by 19.5% in the period leading up to the first national 'lockdown' on March 23 last year, with sales of vitamin C rising by 110% and those of multivits by 93%.

Similarly, zinc supplement sales rose by 415% in the first week of March, at the height of COVID-19 fears in the U.S..

Dietary supplements can help to support a healthy immune system, but whether specific supplements might be associated with a lower risk of catching SARS-CoV-2 isn't known.

In a bid to plug this knowledge gap, the researchers drew on adult users of the COVID-19 Symptom Study app to see if regular supplement users were less likely to test positive for SARS-CoV-2.

The app was launched in the UK, the US, and Sweden in March 2020 to capture self-reported information on the evolution of the pandemic.

Initially, it recorded the location, age and core health risk factors of its users. But as time went on, subscribers were asked to provide daily updates on a range of issues, including symptoms, coronavirus test results, and healthcare. People without obvious symptoms were also encouraged to use it.

For the purposes of this study, the researchers analysed information supplied by 372,720 UK subscribers to the app about their regular use of dietary supplements throughout May, June, and July 2020 during the first wave of the pandemic as well as any coronavirus swab test results.

Between May and July,175,652 UK subscribers regularly took dietary supplements;197,068 didn't. Around two thirds (67%) were women and over half were overweight (BMI of 27).

In all, 23,521 people tested positive for SARS-CoV-2 and 349,199 tested negative between May and July.

Taking probiotics, omega-3 fatty acids, multivits or vitamin D was associated with a lower risk of SARS-CoV-2 infection: by 14%, 12%, 13% and 9%, respectively, after accounting for potentially influential factors, including underlying conditions and usual diet.

No such effects were observed among those taking vitamin C, zinc, or garlic supplements.

And when the researchers looked specifically at sex, age and weight (BMI), the protective associations for probiotics, omega-3 fatty acids, multivits and vitamin D were observed only in women of all ages and weights. No such clear associations were seen in men.

Despite some differences, the same overall patterns were mirrored in both the US (45,757) and Swedish (27,373) subscribers.

The equivalent figures for the US and Sweden were a reduced risk of:18% and 37%, respectively for probiotics; 21% and 16%, respectively, for omega-3 fatty acids; 12% and 22%, respectively for multivits; and 24% and 19%, respectively, for vitamin D supplements.

This is an observational study, and as such, can't establish cause. The researchers also acknowledge several limitations, including that the study relied on self reported data and a self selected group. No information was collected on supplement doses or ingredients either.

But although the observed effects were modest, they were significant, note the researchers, who call for large clinical trials to inform evidence-based therapeutic recommendations.

"We know that a range of micronutrients, including vitamin D, are essential for a healthy functioning immune system. This, in turn, is key to prevention of, and recovery from, infections.

"But to date, there is little convincing evidence that taking nutritional supplements has any therapeutic value beyond maintaining the body's normal immune response," comments Professor Sumantra Ray, Executive Director, NNEdPro Global Centre for Nutrition and Health, which co-owns the journal.

"What's more, this study wasn't primarily designed to answer questions about the role of nutritional supplements in COVID-19. This is still an emerging area of research that warrants further rigorous study before firm conclusions can be drawn about whether specific nutritional supplements might lessen the risk of COVID-19 infection," he cautions.

 

Vitamin D deficiency may impair muscle function

Garvan Institute of Medical Research (Australia), April 16, 2021

Vitamin D deficiency may impair muscle function due to a reduction in energy production in the muscles, according to a mouse study published in the Journal of Endocrinology. Vitamin D deficient mice were found to have impaired muscle mitochondrial function, which may have implications for muscle function, performance and recovery. This may suggest that preventing vitamin D deficiency in older adults could help maintain better muscle strength and function and reduce age related muscle deterioration, but further studies are needed to confirm this. 

Vitamin D is a hormone well known to be important for maintaining bone health and preventing rickets and osteoporosis. In recent years, vitamin D deficiency has been reported to be as prevalent as 40% in European populations and linked to increased risk for several conditions, including COVID-19, cancer and diabetes. Although these studies report association rather than causation, the benefits of vitamin D supplementation are now a major subject of health debate. Multiple studies have also linked low vitamin D levels to poor muscle strength, particularly in older people. Skeletal muscle enables us to move voluntarily and perform everyday activities. It is essential that they have enough energy to power these movements. Specialised organs in cells, called mitochondria, convert nutrients in to energy to meet this demand. Previous studies indicate that impaired muscle strength in people with vitamin D deficiency may be linked to impaired muscle mitochondrial function. Determining the role of vitamin D in muscle performance of older people is also difficult, as they may suffer from a number of pre-existing health conditions that can also affect their vitamin D status. Therefore, previous studies have been unable to determine how vitamin D may directly affect muscle performance.

Dr Andrew Philp and his team at the Garvan Institute of Medical Research in Australia, and collaborating universities, used a mouse model to determine the effects of diet-induced vitamin D deficiency on skeletal muscle mitochondrial function in young, male mice. Mice were either fed a diet with normal quantities of vitamin D, or with no vitamin D to induce deficiency, for a period of 3 months. A typical vitamin D level for humans is 40-50 nmol.L-1, and acute vitamin D deficiency is diagnosed when levels drop below 12 nmol.L-1. On average, the mice in this study had vitamin D levels of 30 nmol.L1, with diet-induced vitamin D deficiency leading to levels of just 3 nmol.L-1. Although this level was more extreme than typically observed in people, it is still within the clinically-recognised range. Tissue and blood samples were collected monthly to quantify vitamin D and calcium concentrations and to assess markers of muscle mitochondrial function and number. After 3 months of diet-induced vitamin D deficiency skeletal muscle mitochondrial function was found to be impaired by up to 37%. This was not due to a reduced number of mitochondria or a reduction in muscle mass.

"Our results show there is a clear link between vitamin D deficiency and oxidative capacity in skeletal muscle. They suggest that vitamin D deficiency decreases mitochondrial function, as opposed to reducing the number of mitochondria in skeletal muscle." Dr Philp comments. "We are particularly interested to examine whether this reduction in mitochondrial function may be a cause of age related loss in skeletal muscle mass and function."

These findings suggest that vitamin D deficiency may impair mitochondrial function and reduce the amount of energy produced in the muscles, which may lead to poor muscle function. Therefore, preventing vitamin D deficiency in older people may help maintain muscle performance and reduce the risk of muscle related diseases, such as sarcopenia. However, further studies that investigate the direct effect of vitamin D deficiency on muscle function and strength are necessary to confirm this.

Whilst this study indicates that vitamin D deficiency can alter mitochondrial function in skeletal muscle, Dr Philp and his team were unable to determine precisely how this process occurred. Therefore, their future work aims to establish how vitamin D deficiency alters mitochondrial control and function in skeletal muscle.

 

 

Psychedelic experience may not be required for psilocybin's antidepressant-like benefits

So-called 'magic mushroom' drug seems to work through multiple brain mechanisms for its different effects

University of Maryland School of Medicine, April 16, 2021

University of Maryland School of Medicine (UMSOM) researchers have shown that psilocybin--the active chemical in "magic mushrooms"-- still works its antidepressant-like actions, at least in mice, even when the psychedelic experience is blocked. The new findings suggest that psychedelic drugs work in multiple ways in the brain and it may be possible to deliver the fast-acting antidepressant therapeutic benefit without requiring daylong guided therapy sessions. A version of the drug without, or with less of, the psychedelic effects could loosen restrictions on who could receive the therapy, and lower costs, making the benefits of psilocybin more available to more people in need.

In all clinical trials performed to date, the person treated with psilocybin remains under the care of a guide, who keeps the person calm and reassures them during their daylong experience. This can include hallucinations, altered perception of time and space, and intense emotional and spiritual encounters. 

Researchers in the field have long attributed psilocybin's effectiveness to the intense psychedelic experience. 

"We do not understand the mechanisms that underlie the antidepressant actions of psilocybin and the role that the profound psychedelic experience during these sessions plays in the therapeutic benefits," says Scott Thompson, Ph.D., Professor and Chair, Department of Physiology at UMSOM and senior author of the study. "The psychedelic experience is incredibly powerful and can be life-changing, but that could be too much for some people or not appropriate." 

Several barriers prevent the wide-spread use of psychedelic compounds. For example, there is fear that the psychedelic experience may promote psychosis in people who are predisposed to severe mental disorders, like bipolar disorder and schizophrenia, so the clinical therapy sessions performed to-date have been limited to a highly selected screened group without a family history of these disorders. 

Dr. Thompson adds that there may also be an equity issue because not everyone can take several days off work to prepare and engage in the experience. The costs of staffing a facility with at least one trained guide per treated person per day and a private space may also be prohibitive to all but a few. He says it is conceivable that a depression treatment derived from psilocybin could be developed without the psychedelic effects so people can take it safely at home without requiring a full day in a care facility.

For their study, led by UMSOM MD/PhD student Natalie Hesselgrave, the team used a mouse model of depression in which mice were stressed for several hours a day over 2-3 weeks. Because researchers cannot measure mouse moods, they measure their ability to work for rewards, such as choosing to drink sugar water over plain water. People suffering from depression lose the feeling of pleasure for rewarding events. Similarly, stressed mice no longer preferred sugar water over plain water. However, 24 hours after a dose of psilocybin, the stressed mice regained their preference for the sugar water, demonstrating that the drug restored the mice's pleasure response. 

Psilocybin exerts its effects in people by binding to and turning on receptors for the chemical messenger serotonin. One of these receptors, the serotonin 2A receptor, is known to be responsible for the psychedelic response. To see if the psychedelic effects of psilocybin were needed for the anti-depressive benefits, the researchers treated the stressed mice with psilocybin together with a drug, ketanserin, which binds to the serotonin 2A receptor and keeps it from being turned on. The researchers found that the stressed mice regained their preference for the sugar water in response to psilocybin, even without the activation of the psychedelic receptor.

"These findings show that activation of the receptor causing the psychedelic effect isn't absolutely required for the antidepressant benefits, at least in mice," says Dr. Thompson, "but the same experiment needs to be performed in depressed human subjects." He says his team plans to investigate which of the 13 other serotonin receptors are the ones responsible for the antidepressant actions.

"This new study has interesting implications, and shows that more basic research is needed in animals to reveal the mechanisms for how these drugs work, so that treatments for these devastating disorders can be developed" says Albert E. Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, University of Maryland Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine.

 

Tea compound promotes formation of osteoblasts under inflammatory environment and increases bone mass

First Affiliated Hospital of Soochow University (China), April 7, 2021

 

According to news originating from Suzhou, People’s Republic of China, the research stated, “Postmenopausal osteoporosis is a disease of bone mass reduction and structural changes due to estrogen deficiency, which can eventually lead to increased pain and fracture risk.”

Our news correspondents obtained a quote from the research from First Affiliated Hospital of Soochow University: “Chronic inflammatory microenvironment leading to the decreased activation of osteoblasts and inhibition of bone formation is an important pathological factor that leads to osteoporosis. Theaflavin-3,3’-digallate (TFDG) is an extract of black tea, which has potential anti-inflammatory and antiviral effects. In our study, we found that TFDG significantly increased the bone mass of ovariectomized (OVX) mice by micro-CT analysis. Compared with OVX mice, TFDG reduced the release of proinflammatory cytokines and increased the expression of osteogenic markers in vivo. In vitro experiments demonstrated that TFDG could promote the formation of osteoblasts in inflammatory environment and enhance their mineralization ability. In this process, TFDG activated MAPK, Wnt/b-Catenin and BMP/Smad signaling pathways inhibited by TNF-a, and then promoted the transcription of osteogenic related factors including Runx2 and Osterix, promoting the differentiation and maturation of osteoblasts eventually.”

According to the news reporters, the research concluded: “In general, our study confirmed that TFDG was able to promote osteoblast differentiation under inflammatory environment, enhance its mineralization ability, and ultimately increase bone mass in ovariectomized mice. These results suggested that TFDG might have the potential to be a more effective treatment of postmenopausal osteoporosis.”

 

 

Patients who are overweight or obese at risk of more severe COVID-19

 

Murdoch Children's Research Institute and University of Queensland, April 16, 2021

 

Patients who are overweight or obese have more severe COVID-19 and are highly likely to require invasive respiratory support, according to a new international study. 

The research, led by the Murdoch Children's Research Institute (MCRI) and The University of Queensland and published in Diabetes Care, found obese or overweight patients are at high risk for having worse COVID-19 outcomes. They are also more likely to require oxygen and invasive mechanical ventilation compared to those with a healthy weight. 

MCRI researcher Dr Danielle Longmore said the findings, which highlighted the relationship between obesity and increased COVID-19 disease burden, showed the need to urgently introduce strategies to address the complex socio-economic drivers of obesity, and public policy measures such as restrictions on junk food advertising. 

"Although taking steps to address obesity in the short-term is unlikely to have an immediate impact in the COVID-19 pandemic, it will likely reduce the disease burden in future viral pandemics and reduce risks of complications like heart disease and stroke," she said.

The study looked at hospitalised SARS-CoV-2 patients from 18 hospitals in 11 countries including China, America, Italy, South Africa and The Netherlands. 

Among the 7244 patients aged 18 years and over, 34.8 per cent were overweight and 30.8 per cent were obese. 

COVID-19 patients with obesity were more likely to require oxygen and had a 73 per cent greater chance of needing invasive mechanical ventilation. Similar but more modest results were seen in overweight patients. No link was found between being overweight or obese and dying in hospital from COVID-19. 

Cardiovascular and pre-existing respiratory diseases were associated with increased odds of in-hospital deaths but not a greater risk for needing oxygen and mechanical ventilation. For patients with pre-existing diabetes, there was increased odds of needing invasive respiratory support, but no additionally increase in risk in those with obesity and diabetes. 

Men were at an increased risk of severe COVID-19 outcomes and needing invasive mechanical ventilation. In those aged over 65 years, there was an increased chance of requiring oxygen and higher rates of in-hospital deaths.

The University of Queensland's Dr Kirsty Short, who co-led the research, said almost 40 per cent of the global population was overweight or obese. 

"Obesity is associated with numerous poor health outcomes, including increased risk of cardiometabolic and respiratory disease and more severe viral disease including influenza, dengue and SARS-CoV-1," she said. 

Dr Short said while previous reports indicated that obesity was an important risk factor in the severity of COVID-19, almost all this data had been collected from single sites and many regions were not represented. Moreover, there was a limited amount of evidence available about the effects of being overweight or obese on COVID-19 severity. 

"Given the large scale of this study we have conclusively shown that being overweight or obese are independent risk factors for worse outcomes in adults hospitalised with COVID-19," she said.

MCRI Professor David Burgner, who co-led the research, said the data would help inform immunisation prioritisation for higher-risk groups.

"At the moment, the World Health Organization has not had enough high-quality data to include being overweight or obese as a risk factor for severe COVID-19 disease. Our study should help inform decisions about which higher-risk groups should be vaccinated as a priority," he said.

 

Neuroprotective Herbs for the Management of Alzheimer’s Disease

University of Central Florida and University of California, Los Angeles

 

Background—Alzheimer’s disease (AD) is a multifactorial, progressive, neurodegenerative disease that is characterized by memory loss, personality changes, and a decline in cognitive function. While the exact cause of AD is still unclear, recent studies point to lifestyle, diet, environmental, and genetic factors as contributors to disease progression. The pharmaceutical approaches developed to date do not alter disease progression. More than two hundred promising drug candidates have failed clinical trials in the past decade, suggesting that the disease and its causes may be highly complex. Medicinal plants and herbal remedies are now gaining more interest as complementary and alternative interventions and are a valuable source for developing drug candidates for AD. Indeed, several scientific studies have described the use of various medicinal plants and their principal phytochemicals for the treatment of AD. This article reviews a subset of herbs for their anti-inflammatory, antioxidant, and cognitive-enhancing effects. Methods—This article systematically reviews recent studies that have investigated the role of neuroprotective herbs and their bioactive compounds for dementia associated with Alzheimer’s disease and pre-Alzheimer’s disease. PubMed Central, Scopus, and Google Scholar databases of articles were collected, and abstracts were reviewed for relevance to the subject matter. Conclusions—Medicinal plants have great potential as part of an overall program in the prevention and treatment of cognitive decline associated with AD. It is hoped that these medicinal plants can be used in drug discovery programs for identifying safe and efficacious small molecules for AD.

 

1.1. Ashwagandha (Withania somnifera)

Ashwagandha, commonly called Indian ginseng or winter cherry, is one of the most prominent herbs prescribed as a brain rejuvenator for AD. It is prescribed to increase energy, improve overall health and longevity, and as a nerve tonic [86]. Ashwagandha has been shown to possess antioxidant activity, free radical scavenging activity, as well as an ability to support a healthy immune system [87]. Ashwagandha contains several bioactive compounds of great interest, such as ergostane-type steroidal lactones, including withanolides A-Y, dehydrowithanolide-R, withasomniferin-A, withasomidienone, withasomniferols A-C, withaferin A, withanone, and others. Other constituents include the phytosterols sitoindosides VII-X and beta-sitosterol and alkaloids [86,88].

A subset of these components has been shown to scavenge free radicals generated during the initiation and progression of AD. Molecular modeling studies showed that withanamides A and C uniquely bind to the active motif of Aβ25-35 and prevent fibril formation. Furthermore, these compounds protected PC-12 cells and rat neuronal cells from β-amyloid-induced cell death [89,90,91]. Treatment with the methanol extract of ashwagandha triggered neurite outgrowth in a dose- and time-dependent manner in human neuroblastoma cells [29], and, in another study involving cultured rat cortical neurons, treatment with Aβ peptide induced axonal and dendritic atrophy and loss of pre-and postsynaptic stimuli [92]. Subsequent treatment with withanolide A induced significant regeneration of both axons and dendrites and restored the pre- and post-synapses in the cultured cortical neurons.

In vivo, withanolide A inhibited Aβ(25–35)-induced degeneration of axons, dendrites, and synapses in the cerebral cortex and hippocampus and also restored Aβ-peptide-induced memory deficits in mice [93]. The in vivo ameliorative effects were maintained even after the discontinuation of the drug administration. Aqueous extracts of ashwagandha increased acetylcholine (ACh) content and choline acetyl transferase activity in rats, which might partly explain the cognition-enhancing and memory-improving effects [29,94,95]. Treatment with the root extract caused the upregulation of the low-density lipoprotein receptor-related protein, which enhanced the Aβ clearance and reversed the AD pathology in middle-aged and old APP/PS1 mice [96].

Oral administration of a semi-purified extract of ashwagandha reversed behavioral deficits and blocked the accumulation of Aβ peptides in an APP/PS1 mouse model of AD. This therapeutic effect of ashwagandha was mediated by the liver low-density lipoprotein receptor-related protein [96]. Using an AD model of Drosophila melanogaster, researchers noted that treatment with ashwagandha mitigated Aβ toxicity and also promoted longevity [97]. Despite the extensive literature on the therapeutic effects of ashwagandha, there are limited data on its clinical use for cognitive impairment [98].

In a prospective, randomized, double-blind, placebo-controlled pilot study involving 50 subjects with mild cognitive impairment, subjects were treated with either ashwagandha root extract (300 mg twice daily) or placebo for eight weeks. After eight weeks of study, the ashwagandha treatment group demonstrated significant improvements in both immediate and general memory tests compared to the placebo group. Furthermore, the treatment group showed significant improvement in executive function, sustained attention, and information-processing speed [99]. These studies lend credence to ashwagandha’s role in enhancing memory and improving executive function in people with SCI or MCI.

1.2. Brahmi (Bacopa monnieri)

Brahmi, or Bacopa monnieri (Bm), is a perennial creeper medicinal plant found in the damp and marshy wetlands of Southern and Eastern India, Australia, Europe, Africa, Asia, and North and South America. In the Ayurvedic system of medicine, Bm is recommended for mental stress, memory loss, epilepsy, insomnia, and asthma [34,36]. The bioactive phytochemicals present in this plant include saponins, bacopasides III, IV, V, bacosides A and B, bacosaponins A, B, C, D, E, and F, alkaloids, sterols, betulic acid, polyphenols, and sulfhydryl compounds, which may be responsible for the neuroprotective roles of the plant. Both in vitro and in vivo studies show that these phytochemicals have an antioxidant and free radical scavenging action by blocking lipid peroxidation in several areas of the brain [36,100,101,102]. Bm acts by reducing divalent metals, scavenging reactive oxygen species, decreasing the formation of lipid peroxides, and inhibiting lipoxygenase activity [103].

Numerous studies have also shown Bm’s role in memory and intellect [33,56,100,104,105,106]. To determine the neuroprotective effect of Bm in a rat model of AD, researchers tested an alcoholic extract of Bm at doses of 20, 40, and 80 mg/kg for a period of 2 weeks before and 1 week after the intracerebroventricular (icv) administration of ethylcholine aziridinium ion (AF64A). Spatial memory was tested using the Morris water maze (MWM), and the cholinergic neuron density was determined using histological techniques. The researchers showed that Bm extract improved the escape latency time in the MWM test and blocked the reduction of cholinergic neuron densities [35]. Another group reported the reversal of colchicine-induced cognitive deficits by a standardized extract of Bm. In addition to reversing colchicine-triggered cognitive impairment, the Bm extract also attenuated colchicine-induced oxidative damage by decreasing the protein carbonyl levels and restoring the activities of the antioxidant enzymes [107].

Most of the studies exploring the cognitive-enhancing effects of Bm in humans focused on normal, aged individuals. In a double-blind, randomized, placebo-controlled trial on 35 individuals aged above 55 years, subjects received either 125 mg of Bm extract or a placebo twice a day for a period of 12 weeks, followed by a placebo period of another four weeks. Subjects underwent a battery of memory tests, including general information, orientation, mental control, logical memory, digit forward, digit backward, visual reproduction, and paired association learning. Subjects were scored on each sub-test, and total memory score was calculated by adding the score of all subtests. A significant improvement was observed in mental control, logical memory, and paired association learning in Bm-treated patients compared to the placebo group at 8 and 12 weeks after initiation of the trial [37]. The results suggested the use of Bm in the treatment of age-associated memory impairment.

Ten subjects were given 500 mg of Sideritis extract, 320 mg Bm extract, or a combination using a crossover design. Sideritis extract is rich in a variety of flavonoids and has been shown to improve cognition in animal models of AD [108]. The Attention d2 Test is a neuropsychological measure of selective and sustained attention and visual scanning speed. Assessment tests revealed that Sideritis extract combined with a low-dose Bm extract resulted in improvement in the d2 concentration test score [109]. A similar effect of Bm alone was observed only after repetitive dosing, suggesting that the long-term memory effects seen with repetitive dosing of Bm may be a promising therapeutic option for subjects suffering from MCI [109].

In another prospective, non-comparative, multicenter trial involving 104 subjects who suffered from MCI, Bm extract in combination with astaxanthin, phosphatidylserine, and vitamin E was given for 60 days. The tested combination formula was well tolerated. Cognitive and mnemonic performance was assessed with validated instruments including Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Clock-Drawing Test (CDT) that can assess the risk of MCI progression to AD. Researchers noted significant improvements in ADAS-cog and CDT scores [110]. The observed sixty-day improvements in ADAS-cog and CDT were statistically significant as compared with baseline values. Memory is affected by several factors, including focus and attention, neurotransmitters, hormones, trophic factors, cyclic AMP, ion channels, protein transcription, synapse formation, and nutrients. Some of these processes can be modulated by Bm extract alone or in combination with other compounds.

The abovementioned study design is similar to our therapeutic program for people with SCI and MCI, where Bm is administered in combination with other nutraceuticals and cogniceuticals [15,111].

1.3. Cat’s Claw (Uncaria tomentosa)

Cat’s claw (CC) is a tropical vine with hooked thorns that resemble the claws of a cat and is mainly recommended for its potential role in the treatment of AD and pre-AD. It is found mainly in the Amazon rainforest and other areas of South and Central America. This medicinal plant contains oxindole alkaloids, polyphenols (flavonoids, proanthocyanidins, and tannins), glycosides, pentacyclic alkaloids, and sterols [38,39]. CC is known for its immune-modulating and anti-inflammatory effects and for its role as a free radical scavenger. Based on in vitro studies, the anti-inflammatory effect of CC is attributed to its ability to inhibit iNOS gene expression, nitrate formation, cell death, PGE2 production, and the activation of NF-κB and TNF-α [45].

Using a transgenic mouse model of Alzheimer’s disease, a significant reduction in the Aβ load (by 59%) and plaque number (by 78%) in the hippocampus and cortex was observed after treating 8-month-old mice with the CC extract for 14 days [44]. CC extract also caused a significant reduction in astrocytosis and microgliosis, and it improved hippocampus-dependent memory. Some of the components in the CC extract crossed the blood–brain barrier (BBB) and entered the brain parenchyma following intravenous injection [44].

Pre-clinical studies suggest that CC extract inhibits the formation of plaques and tangles, reduces astrocytosis and microgliosis and improves memory in mouse models of AD [43,44]. CC extract not only prevented the formation and aggregation of Aβ fibrils and tau protein paired helical filaments, but it also facilitated the disaggregation of preformed fibrils and tau protein tangles [43,44]. While proanthocyanidin B2 was identified as the primary phytochemical with plaque-and tangle-dissolving activity, other polyphenols present in the CC extract also possess plaque-reducing activity [44].

Based on pre-clinical studies, Cat’s claw may be effective for memory loss and cognitive decline associated with AD, although no studies have been carried out in humans.

1.4. Ginkgo Biloba

Ginkgo biloba (Gb) has been in the spotlight primarily for its potential role in treating AD. Gb also appears promising as a therapeutic agent for several other chronic and acute forms of diseases. The main pharmacologically active groups of compounds are flavonoids and terpenoids. Almost all clinical studies use Gb extract that contains a combination of flavonoid glycosides, terpene lactones, and ginkgolic acids [50]. Gb extract has shown beneficial effects in treating Alzheimer’s, cardiovascular diseases, cancer, tinnitus, and other age-associated conditions [49,50]. The suggested mechanisms of the Gb extract are its antioxidant effect, anti-platelet activating factor activity for vascular diseases, inhibition of β-amyloid peptide aggregation in AD, and decreased expression of peripheral benzodiazepine receptor for stress alleviation [48,49,50].

Gb is popular as a treatment for early-stage AD and vascular dementia. Gb extract reverses β-amyloid and NO-induced toxicity in vitro and reduces apoptosis both in vitro and in vivo [112,113,114]. Treatment with Gb extract enhanced memory retention in young and old rats and improved short-term memory in mice [49,115].

Several studies indicate that ginkgo delays the progression of AD and is as effective as the cholinesterase inhibitors for treating AD. A modest improvement in cognitive function was observed in AD subjects in various randomized, double-blind, placebo-controlled trials [116,117,118]. Gb extract also improves ADLs among AD individuals and is preferred over other AD medications because of its negligible adverse effects [119,120].

1.5. Gotu Kola (Centella asiatica)

Considered both a nutraceutical and cogniceutical, Gotu kola (Gk) is a staple in Chinese, Indonesian, and Ayurvedic medicine [57]. This medicinal plant is used to strengthen the brain, heal skin issues, and promote liver and kidney health. Gk is considered a rejuvenating herb for nerve and brain cells as it is believed to promote intelligence and improve memory [54,55,56,57]. In vitro studies using various Gk plant derivatives (asiaticosides, asiatic acid, madecassoside, and madasiatic acid) showed that these compounds were capable of blocking H2O