chap. 1 EVIDENCE

From left to right: Dr. Richard Hansler, Mr. Vilnis Kubulins and Dr. Edward Carome.

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CHAPTER 1

What Is the Evidence That Improved Sleep and Maximizing Natural Melatonin Will Reduce the Risk of Alzheimer’s Disease?

Many studies of older animals and older humans find a decrease in the production of melatonin. Unfortunately most of these studies do not control light exposure, which we now know has a major impact. A 1999 well-controlled study at Harvard (PMID10569297) found no evidence of a drop in melatonin in 20 women and 14 men, aged 65 to 81 years. In any case, a prominent theory of Alzheimer’s disease is that there is a drop in melatonin production in old age and that this allows the formation of the plaques and nerve tangles in the brain that are the hallmark of Alzheimer’s disease.

There are a lot of technical terms in this chapter. Don’t let that bother you. My idea here is to let you know the studies have been done that support the concept that maximizing melatonin is a valid way to decrease your risk for dementia and Alzheimer’s disease. It isn’t necessary to understand all the details.

The existence of the early, familial form of Alzheimer’s disease experienced by some 5% of patients is evidence for the genetic nature of the early form of the disease. Mutations in the APP and tau genes result respectively in the amyloid plaques and neuron tangles. Since those born with mutations do not get the active disease until middle age, it suggests that additional mutations must be required.

One view of the disease is that the amyloid protein and the tau protein exist in many forms and that the presence of melatonin in the spinal fluid keeps them in soluble form, preventing the formation of the plaques and tangles that destroy the brain. Once the transition has occurred, melatonin is not able to reverse the process.

This is why maximizing melatonin in the early stages of the disease is vital and may prevent the disease. Melatonin should thus not be considered as a treatment once the harm is done but as a way of reducing the risk.

Animal Studies

Much of the evidence that melatonin is beneficial to the body and brain comes from animal experiments. Despite the large number of people who suffer with Alzheimer’s disease, there has been little research compared to other diseases. The earliest studies with small animals were aimed at finding causes of Alzheimer’s disease. Rabbits were exposed to aluminum and developed brain lesions that appeared similar to those in Alzheimer’s patients. This was in 1980, and some 40 additional studies were done in the next 10 years with uncertain results. In 2014 a paper (PMID24806729) was published entitled “Is the Aluminum Hypothesis Dead?” It states that almost no studies of aluminum and Alzheimer’s disease are still going on and the link between them is unlikely. The only reason I bring it up is that a 2015 study (PMID25891353) from Saudi Arabia found that melatonin prevented the damaging effects of aluminum in an animal model of Alzheimer’s that was produced by aluminum.

Most of the studies with small animals that show the benefit of melatonin regarding Alzheimer’s disease were done in the last 25 years. This is roughly the first time genetically modified animals became available that served as models of Alzheimer’s disease.

Transgenic mice (mice with modified genes) overproducing mutant APP genes develop pathology that is similar to that found in the human brain. Aβ (also written as Abeta, is the name for the substance in the brain involved in Alzheimer’s disease) accumulation into extracellular plaques occurs late in the animal’s life. Despite constant Aβ production, plaques only occur in mid to late adulthood in the majority of these animals. Notably, plaque formation is accelerated when the longer molecule Aβ42 is preferentially produced from APP, as this peptide is more prone to aggregation (collection into plaques) than Aβ40 and leads to earlier and more severe cognitive decline (loss of ability to think clearly).

A 2015 paper (PMID25988948) from Russia reported studies with OXYS rats that are a recognized model for sporadic Alzheimer’s disease (not the early genetic kind).

Our aim here was to evaluate, starting at the age of active progression of AD-like pathology in OXYS rats, the effects of long-term oral administration of melatonin on the structure of synapses and on neuronal and glial cells of the hippocampus. Melatonin significantly increased hippocampal synaptic density and the number of excitatory synapses, decreased the number of inhibitory synapses, and unregulated pre- and postsynaptic proteins (synapsin I and PSD-95, respectively). Furthermore, melatonin improved the ultrastructure of neuronal and glial cells and reduced glial density. Based on our past and present results, the repair of neuroplasticity by melatonin is a promising strategy against Alzheimer’s disease.

 

A 2015 paper (PMID25401971) from Korea found that mice subjected to chronic exposure to D-galactose (a form of sugar) suffered memory loss, synaptic dysfunction, elevated reactive oxygen species (ROS), neuroinflammation, and neurodegeneration. The results of treatment with melatonin are described as follows:

Our behavioral (Morris water maze and Y-maze test) results revealed that chronic melatonin treatment alleviated D-galactose-induced memory impairment. Additionally, melatonin treatment reversed D-galactose-induced synaptic disorder via increasing the level of memory-related pre- and postsynaptic protein markers. We also determined that melatonin enhances memory function in the D-galactose-treated mice possibly via reduction of elevated ROS and receptor for advanced glycation end products…Taken together, our data suggest that melatonin could be a promising, safe, and endogenous compatible antioxidant candidate for age-related neurodegenerative diseases such as Alzheimer’s disease.

A very similar 2014 study (PMID24797165) in Taiwan found similar results. Researchers attributed the benefit to melatonin’s ability to reduce oxidative damage.

Sleep Deprivation

The early sign of deterioration of the brain is the loss of short-term memory. Older people like to joke about a “senior moment” when they can’t recall a name or a word for some common object. It is possible to simulate this effect by intentionally preventing sleep. In experiments in half a dozen different countries, short-term sleep deprivation in rats caused loss of both short- and long-term memory, activation of the neurons in the hippocampus, and chemical evidence of oxidative stress in blood samples. Melatonin reversed or prevented all of these effects of sleep-deprivation-induced memory problems.

Cultured Brain Cells and Melatonin

A 1997 study (PMID9030627) from the University of South Alabama is titled “Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide.”

“In this study we demonstrate that melatonin, a pineal hormone with recently established antioxidant properties, is remarkably effective in preventing death of cultured neuroblastoma (brain) cells as well as oxidative damage and intracellular Ca2+ increases induced by a cytotoxic fragment of Abeta.”

This is further evidence that maximizing natural melatonin by avoiding blue light in the hours before bedtime may help in preserving the brain. This will be discussed in chapter 3.

Dynamic Brain Function

A 2015 paper (PMID25739489) from the Universidad de Colima, Colombia, describes the dynamic nature of the part of the brain that provides memory as follows:

Adult neurogenesis (formation of new neurons) in the dentate gyrus (DG) in the hippocampus is a process that involves proliferation, differentiation, maturation, migration, and integration of young neurons in the granular layer of DG. These newborn neurons mature in three to four weeks and incorporate into neural circuits in the hippocampus. There, these new neurons play a role in cognitive functions, such as acquisition and retention of memory, which are consolidated during sleep periods.

It thus appears that sleep deprivation interferes with this consolidation process and melatonin restores or prevents the damaging effect of sleep deprivation.

Mild Cognitive Impairment

This initial phase of loss of cognitive ability is termed “mild cognitive impairment” (MCI). The Mayo Clinic website lists the following symptoms of MCI.

  • You forget things more often.
  • You forget important events, such as appointments or social engagements.
  • You lose your train of thought or the thread of conversations, books, or movies.
  • You feel increasingly overwhelmed by making decisions, planning steps to accomplish a task, or interpreting instructions.
  • You start to have trouble finding your way around familiar environments.
  • You become more impulsive or show increasingly poor judgment.Therapeutic Application of Melatonin in Mild Cognitive ImpairmentAuthor information
  • Cardinali DP1, Vigo DE, Olivar N, Vidal MF, Furio AM, Brusco LI.
  • If melatonin is capable of preventing memory impairment caused by sleep deprivation in rats, it is reasonable to ask if it would be beneficial in preventing or delaying MCI in humans. The following is the abstract from a 2012 paper (PMID23383398) from the Catholic University in Buenos Aires, Argentina.
  • 1Departamento de Docencia e Investigación, Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina Buenos Aires, Argentina.

Abstract

Mild cognitive impairment (MCI) is an etiologically heterogeneous syndrome defined by cognitive impairment in advance of dementia. We previously reported in a retrospective analysis that daily 3–9 mg of a fast-release melatonin preparation given p. o. (by mouth) at bedtime for up to 3 years significantly improved cognitive and emotional performance and daily sleep/wake cycle in MCI patients. In a follow-up of that study we now report data from another series of 96 MCI outpatients, 61 of whom had received daily 3–24 mg of a fast-release melatonin preparation p. o. at bedtime for 15 to 60 months. Melatonin was given in addition to the standard medication prescribed by the attending psychiatrist. Patients treated with melatonin exhibited significantly better performance in Mini-Mental State Examination and the cognitive subscale of the Alzheimer’s disease Assessment Scale. After application of a neuropsychological battery comprising a Mattis test, Digit-symbol test, Trail A and B tasks, and the Rey’s verbal test, better performance was found in melatonin-treated patients for every parameter tested. Abnormally high Beck Depression Inventory scores decreased in melatonin-treated patients, concomitantly with the improvement in the quality of sleep and wakefulness. The comparison of the medication profile in both groups of MCI patients indicated that 9.8% in the melatonin group received benzodiazepines (sleeping pills) vs. 62.8% in the nonmelatonin group. The results further support that melatonin can be a useful add-on drug for treating MCI in a clinic environment.

Robust Daily Rhythm

Having a robust circadian rhythm by establishing a regular schedule of rising and going to bed may also be beneficial in delaying or preventing MCI.

A 2014 paper (PMID24100124) from the University of Sydney, Australia, entitled “Circadian Misalignment and Sleep Disruption in Mild Cognitive Impairment,” found the following:

Patients with MCI had advanced timing of their melatonin secretion onset relative to controls, but the levels of melatonin secreted did not differ between groups. The MCI group also had greater wake after sleep onset and increased rapid eye movement sleep latency. There were differential associations between dim light melatonin onset and cognition between the two groups, with earlier dim light melatonin onset being associated with poorer memory performance in MCI patients.

Conclusion:

Circadian misalignment and sleep disruption are evident in patients with MCI, and are consistent with changes observed in Alzheimer’s disease. Such findings could be a marker for disease trajectory, and may even be implicated in disease pathogenesis.

A 2011 paper (PMID22162057) from the California Pacific Medical Center Research Institute, San Francisco, California, found the same result and reported it as follows:

After 4.9 years of follow-up, 195 (15%) women had developed dementia and 302 (24%) had developed MCI. Older women with decreased activity rhythms had a higher likelihood of developing dementia or MCI when comparing those in the lowest quartiles of amplitude (odds ratio [OR] = 1.57; 95% CI, 1.09-2.25) or rhythm robustness (OR = 1.57; 95% CI, 1.10-2.26) to women in the highest quartiles. An increased risk of dementia or MCI (OR = 1.83; 95% CI, 1.29-2.61) was found for women whose timing of peak activity occurred later in the day (after 3:51p.m.) when compared to those with average timing (1:34 p.m.–3:51 p.m.).

INTERPRETATION:

Older, healthy women with decreased circadian activity rhythm amplitude and robustness and delayed rhythms have increased odds of developing dementia and MCI. If confirmed, future studies should examine whether interventions (physical activity, bright light exposure) that influence activity rhythms will reduce the risk of cognitive deterioration in the elderly.

Moderate Exercise

A 2015 paper (PMID25147086) from the National Center for Geriatrics and Gerontology, Aichi, Japan, reports that moderate exercise (measured with an accelerometer) for two weeks makes a measurable (by MRI) increase in the hippocampal volume and a measurable (by standardized tests) improvement in memory of 310 elderly people with MCI. While no mention is made of melatonin in this paper, other studies have shown that vigorous exercise increases the flow of melatonin during the night.

A 2015 US paper (PMID26305648) is titled “Effect of 24-Month Physical Activity Intervention vs. Health Education on Cognitive Outcomes in Sedentary Older Adults: The LIFE Randomized Trial.”

Abstract

IMPORTANCE:

Epidemiological evidence suggests that physical activity benefits cognition, but results from randomized trials are limited and mixed.

OBJECTIVE:

To determine whether a 24-month physical activity program results in better cognitive function, lower risk of mild cognitive impairment (MCI) or dementia, or both, compared with a health education program.

DESIGN, SETTING, AND PARTICIPANTS:

A randomized clinical trial, the Lifestyle Interventions and Independence for Elders (LIFE) study, enrolled 1,635 community-living participants at 8 US centers from February 2010 until December 2011. Participants were sedentary adults aged 70 to 89 years who were at risk for mobility disability but able to walk 400 m [meters].

INTERVENTIONS:

A structured, moderate-intensity physical activity program (n = 818) that included walking, resistance training, and flexibility exercises or a health education program (n = 817) of educational workshops and upper-extremity stretching.

MAIN OUTCOMES AND MEASURES:

Prespecified secondary outcomes of the LIFE study included cognitive function measured by the Digit Symbol Coding (DSC) task subtest of the Wechsler Adult Intelligence Scale (score range: 0-133; higher scores indicate better function) and the revised Hopkins Verbal Learning Test (HVLT-R; 12-item word list recall task) assessed in 1,476 participants (90.3%). Tertiary outcomes included global and executive cognitive function and incident MCI or dementia at 24 months.

RESULTS:

At 24 months, DSC task and HVLT-R scores (adjusted for clinic site, sex, and baseline values) were not different between groups. The mean DSC task scores were 46.26 points for the physical activity group vs. 46.28 for the health education group (mean difference, -0.01 points [95% CI, -0.80 to 0.77 points], P = .97). The mean HVLT-R delayed recall scores were 7.22 for the physical activity group vs. 7.25 for the health education group (mean difference, -0.03 words [95% CI, -0.29 to 0.24 words], P = .84). No differences for any other cognitive or composite measures were observed. Participants in the physical activity group who were 80 years or older (n = 307) and those with poorer baseline physical performance (n = 328) had better changes in executive function composite scores compared with the health education group (P = .01 for interaction for both comparisons). Incident MCI or dementia occurred in 98 participants (13.2%) in the physical activity group and 91 participants (12.1%) in the health education group (odds ratio, 1.08 [95% CI, 0.80 to 1.46]).

CONCLUSIONS AND RELEVANCE:

Among sedentary older adults, a 24-month moderate-intensity physical activity program compared with a health education program did not result in improvements in global or domain-specific cognitive function.

This large study found no benefit of moderate exercise in preserving mental abilities compared to studying health education. Equal numbers of individuals in the two groups were diagnosed with MCI or dementia during the two years. This is disappointing since one would think that getting more blood to the brain through exercise would help preserve its function. Apparently not. (Hopefully those who exercised experienced some improvements in physical health.) This disappointing outcome points up how uniquely powerful is the maximizing of melatonin production by avoiding blue light in the hours before bedtime.

Is Melatonin Beneficial?

A definitive 2015 paper (PMID26052727) from Japan helps answer the question whether having more melatonin in the blood (and brain) helps reduce the incidence of MCI and depression. Researchers measured melatonin concentration in first morning urine for 1,105 individuals with an average age of 72 years and did measures of MCI and depression. They summarized the results as follows: “Significant associations of higher physiological (natural) melatonin levels with lower prevalence of cognitive impairment and depressed mood were revealed in a large general elderly population. The association between physiological melatonin levels and cognitive function was independent of depressive symptoms.”

This is a clear answer to the question,”Does melatonin help?” The answer is “Yes!”

Melatonin is produced by the pineal gland during the night. A good question is “What is protecting the brain during the day?” A good answer might be “Melatonin and other antioxidants derived from the diet.” This may be why it is important to eat those brightly colored fruits and a variety of nuts throughout the day, starting with breakfast. In what few studies there are on how diet affects the incidence of MCI, the main conclusion is that a poor diet may increase the incidence.

A 2015 paper (PMID25223887) from Japan studied the melatonin concentration in first morning urine for 518 older people. After correcting for variables researchers found women had an 18% lower melatonin concentration than the men. There are about twice as many women than men with Alzheimer’s disease. One is tempted to draw a conclusion, but it is certainly not warranted, scientifically.

Prevent Pesticide Damage

A 2014 study (PMID24733834) from India looked at the damage to cognitive function caused by a pesticide (Propoxur) and the effect of melatonin (MEL). Researchers concluded: “Treatment with MEL attenuated the effect of propoxur on oxidative stress. The results of the present study thus show that MEL has the potential to attenuate cognitive dysfunction and oxidative stress induced by toxicants like propoxur in the brain.”

Prevent Damage Due to Lack of Oxygen

A 2013 paper (PMID24399008) from Romania reported on the effect in rats of exposure to low atmospheric pressure. The lack of oxygen (hypoxia) causes cognitive and other damage that is reduced by having melatonin (MEL) in the blood. Researchers sum up their results as follows:

The most important morphological changes were observed in Group 2 (no MEL): increased cellularity, loss of pericellular haloes, shrunken neurons with scanty cytoplasm and hyperchromatic, pyknotic or absent nuclei; reactive gliosis, edema, and blood-brain barrier alterations could also be observed in some areas. MEL treatment significantly diminished all these effects. Our results suggest that melatonin is a neuroprotective antioxidant both in normoxia and hypobaric hypoxia that can prevent and counteract the deleterious effects of oxidative stress (neuronal death, reactive astrogliosis, memory impairment, and cognitive dysfunctions). Dietary supplements containing melatonin might be useful neuroprotective agents for the therapy of hypoxia-induced consequences.

Benefit of Melatonin in Diet

A 2012 paper (PMID22334085) from Italy entitled “Effects of a Diet Integration with an Oily Emulsion of DHA-Phospholipids Containing Melatonin and Tryptophan in Elderly Patients Suffering from Mild Cognitive Impairment” reported improvement in a large number of measures of cognitive performance in 25 adults, average age 86 years, after only 12 weeks on the enriched diet. Although the number of subjects was small, it was a double-blind, placebo-controlled study, so it very likely shows a simple, inexpensive way of improving the mental condition of elderly people.

Brain Training

The following is quoted from Scientific American.

If you’ve spent more than about 5 minutes surfing the web, listening to the radio, or watching TV in the past few years, you will know that cognitive training—better known as “brain training”—is one of the hottest new trends in self-improvement. Lumosity, which offers web-based tasks designed to improve cognitive abilities such as memory and attention, boasts 50 million subscribers and advertises on National Public Radio. Cogmed claims to be “a computer-based solution for attention problems caused by poor working memory,” and BrainHQ will help you “make the most of your unique brain.” The promise of all of these products, implied or explicit, is that brain training can make you smarter—and make your life better.

Yet, according to a statement released by the Stanford University Center on Longevity and the Berlin Max Planck Institute for Human Development, there is no solid scientific evidence to back up this promise. Signed by 70 of the world’s leading cognitive psychologists and neuroscientists, the statement minces no words:

“The strong consensus of this group is that the scientific literature does not support claims that the use of software-based ‘brain games’ alters neural functioning in ways that improve general cognitive performance in everyday life, or prevent cognitive slowing and brain disease.”

The statement also cautions that although some brain training companies “present lists of credentialed scientific consultants and keep registries of scientific studies pertinent to cognitive training…the cited research is [often] only tangentially related to the scientific claims of the company, and to the games they sell.”

This is bad news for the brain training industry, but it isn’t surprising. Little more than a decade ago, the consensus in psychology was that a person’s intelligence, though not fixed like height, isn’t easily increased. This consensus reflected a long history of failure. Psychologists had been trying to come up with ways to increase intelligence for more than a century, with little success. The consistent finding from this research was that when people practice some task, they get better on that task, and maybe on very similar tasks, but not on other tasks. Play a videogame and you’ll get better at that videogame, and maybe at very similar videogames, the research said, but you won’t get better at real-world tasks like doing your job, driving a car, or filling out your tax return.

A 2014 study (PMID25444575) from Australia is titled “The Study of Mental and Resistance Training (SMART) Study—Resistance Training and/or Cognitive Training in Mild Cognitive Impairment: A Randomized, Double-Blind, Double-Sham Controlled Trial.”

The training is described as “high intensity progressive resistance training vs. seated calisthenics and active or sham cognitive training (computerized, multidomain cognitive training vs. watching videos/quizzes).” Primary outcomes were global cognitive function (Alzheimer’s Disease Assessment Scale-cognitive subscale; ADAS-Cog) and functional independence (Bayer Activities of Daily Living).

The resistance training significantly improved the primary outcomes over 18 months. Cognitive training only attenuated decline in Memory Domain at six months. One hundred adults with MCI [70.1 (6.7) years; 68% women] were enrolled and analyzed.

From MCI to Alzheimer’s Disease

A very interesting 2014 paper (PMID25101236) from Johns Hopkins University presented the results of MRI brain scans made over many years in which researchers looked at measureable change in three medial temporal lobe regions, the amygdala, entorhinal cortex (ERC), and hippocampus. The subjects were symptom free at the start but later became symptomatic with preclinical Alzheimer’s disease. They found that the rate of change of the brain volume increased significantly 10 years before the start of symptoms in the case of the ERC, two to four years prior to symptoms for the hippocampus, and three years prior to symptoms for the amygdala. They conclude, “Understanding the order in which changes in the brain occur during preclinical AD may assist in the design of intervention trials aimed at slowing the evolution of the disease.”

Doing these kinds of measurements of the changes in the brain would make it possible to determine whether maximizing melatonin by avoiding blue light in the evening would delay or prevent MCI and Alzheimer’s disease. It seems the federal government would be the only likely source for funding for such a study.

I have said above that once plaques and tangles have developed in the brain, it is too late for melatonin to have any benefit. A 1998 study (PMID9885996) from Argentina refutes this. One of two identical twins with Alzheimer’s disease was treated with six milligrams of melatonin daily. Both twins received thioridizine daily because of behavioral and sleep problems. After 36 months the melatonin-treated twin showed milder memory impairment, improved sleep, and reduced sundowning (agitation near sunset) and could be taken off the thioridizine.

Sleep and Brain Volume

A 2012 study (PMID22197742) is titled “Sleep Duration during Weekdays Affects Hippocampal Gray Matter Volume in Healthy Children.”

The study states, “We found that the regional gray matter volume of the bilateral hippocampal body was significantly positively correlated with sleep duration during weekdays after adjusting for age, sex, and intracranial volume. Our results indicated that sleep duration affects (increases) the hippocampal regional gray matter volume of healthy children.”

One question we may want to ask is whether it is the sleep that does this or it is the increased amount of melatonin associated with the longer hours sleeping, or maybe it is both. In any case this is more reason to give high priority to sleep.

A 2014 study (PMID24554058) from Spain examined other sources of melatonin within the body.

With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. Melatonin is present in essentially all biological fluids, including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk.

One might tend to think that the wide distribution of melatonin throughout the body diminishes the significance of the pineal-produced melatonin. The fact that it is the nightly flow of the pineal melatonin that controls not only the body temperature and many other circadian-rhythm-controlled processes but also the seasonal effects in many animals would suggest it is the pineal hormone that is the most significant for sleep and mental health. The direct connection between the pineal gland and the brain and the high concentration of melatonin in the spinal fluid suggest the melatonin produced in other parts of the body may not be important regarding MCI and Alzheimer’s disease.

Direct Path Pineal Gland to Brain

A 2014 study (PMID24553808) from the University of Texas describes the direct path from the pineal gland to the brain by way of the third ventricle.

Melatonin concentrations in the CSF (spinal fluid) are not only much higher than in the blood, also, there is a rapid nocturnal rise at darkness onset and precipitous decline of melatonin levels at the time of lights on. Because melatonin is a potent free radical scavenger and antioxidant, we surmise that the elevated CSF levels are necessary to combat the massive free radical damage that the brain would normally endure because of its high utilization of oxygen, the parent molecule of many toxic oxygen metabolites, i.e., free radicals. Additionally, the precise rhythm of CSF melatonin provides the master circadian clock, the suprachiasmatic nucleus, with highly accurate chronobiotic information regarding the duration of the dark period. We predict that the discharge of melatonin directly into the 3V is aided by a number of epithalamic structures that have heretofore been overlooked; these include interpinealocyte canaliculi and evaginations of the posterodorsal 3V that directly abut the pineal. Moreover, the presence of tanycytes in the pineal recess and/or a discontinuous ependymal lining in the pineal recess allows melatonin ready access to the CSF. From the ventricles melatonin enters the brain by diffusion and by transport through tanycytes. Melatonin-rich CSF also circulates through the aqueduct and eventually into the subarachnoid space. From the subarachnoid space surrounding the brain, melatonin penetrates into the deepest portions of the neural tissue via the Virchow-Robin perivascular spaces from where it diffuses into the neural parenchyma. Because of the high level of pineal-derived melatonin in the CSF, all portions of the brain are better shielded from oxidative stress resulting from toxic oxygen derivatives.

Despite the large number of unfamiliar names of the parts of the brain, the quotation conveys the important message that the direct path from the pineal gland to every part of the brain not only protects it from damage by free radicals but provides accurate information about the duration of the dark period. Because of electric lighting, we are providing essentially false information to the brain and body. It should not be a surprise that this has detrimental consequences.

The importance of this direct path from the pineal gland to the brain cannot be overstated. In most of the studies cited above, melatonin was taken by mouth and had to find its way to the brain via the intestines and bloodstream. A benefit was still observed. Think how much bigger an effect one would see if the experiments had produced a 30% increase in melatonin injected directly into the brain. This would be possible by having the subjects in the study put on orange glasses three hours before bedtime. You don’t have to be in a study to claim this benefit for yourself, tonight. You will learn how orange glasses can confer this great benefit in Chapter 3.

Another possible benefit of the direct path from the pineal gland to the brain is that melatonin is not the only hormone being produced in this gland. In the 1990s the husband-and-wife research team of Bartsch and Bartech (PMID11133007) found that the hormones, other than melatonin, produced in the pineal gland were even more effective breast cancer fighters (antioxidants) than melatonin. Possibly the same may hold for the benefit to the brain. Again, it would seem that preserving the natural pineal production by avoiding blue light in the hours before a regular bedtime is the most effective way to avoid MCI, dementia, and Alzheimer’s disease.

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