Nutritional neuroscience is the scientific discipline that studies the effects various components of the diet such asminerals,vitamins,protein,carbohydrates, fats, dietary supplements,synthetic hormones, andfood additives have onneurochemistry,neurobiology,behavior, andcognition.
Research on nutritional mechanisms and their effect on the brain shows they are involved in almost every facet of neurological functioning, including alterations inneurogenesis,neurotrophic factors,neural pathways andneuroplasticity, throughout the life cycle.[2]
Relatively speaking, thebrain consumes an immense amount of energy in comparison to the rest of the body. The human brain is approximately 2% of the human body mass and uses 20–25% of the total energy expenditure.[3] Therefore, mechanisms involved in the transfer of energy from foods to neurons are likely to be fundamental to the control of brain function.[4] Insufficient intake of selected vitamins, or certain metabolic disorders, affectcognitive processes by disrupting the nutrient-dependent processes within the body that are associated with the management of energy in neurons, which can subsequently affect neurotransmission,synaptic plasticity, and cell survival.[4]
Deficiency or excess of essential minerals (e.g. iron, zinc, copper, and magnesium) can disrupt brain development and neurophysiology to affect behavior.[5] Furthermore, minerals have been implicated in the pathophysiology of neurodegenerative diseases including Alzheimer's dementia.[6][7]
Iron is essential for several critical metabolic enzymes and a deficiency of this mineral can disrupt brain development.[8] For, example chronic marginal iron affects dopamine metabolism and myelin fatty acid composition[9] and behavior in mice.[10] In rats a marginal iron deficiency that does not cause anemia disrupted axon growth in the auditory nerve affecting auditory brainstem latency without major changes in myelination.[11] Inrhesus macaques, prenatal iron deficiency disrupts emotional behavior[12] and polymorphisms that reduce the expression of monoamine oxidase interact with gestational iron deficiency to exacerbate the response to a stressful situation leading to increased aggressiveness.[13] Inexpensive and effective iron supplementation is an available preventive strategy recommended by the World Health Organization.[14] However, iron supplementation can exacerbate malaria infection. Therefore, individuals receiving iron supplementation in malaria-endemic areas must be carefully monitored.[15]
Zinc is essential for the structure and function of thousands of proteins critical for the function of every cell.[16] Zinc can also serve as a neurotransmitter in the brain,[17] thus a deficiency of this mineral can clearly disrupt development as well as neurophysiology. For example, zinc deficiency during early development impairs neurogenesis leading to memory impairments.[18][19] However, zinc deficiency later in life can disrupt appetite and cause depression-like behavior.[19][20] However, it is important to consider copper intake relative to zinc supplementation because excess zinc can disrupt copper absorption.[21]
Conservative estimates suggest that 25% of the world's population is at risk of zinc deficiency.[22]
Hypozincemia is usually a nutritional deficiency, but can also be associated withmalabsorption,diarrhea,acrodermatitis enteropathica,chronicliver disease, chronicrenal disease,sickle cell disease,diabetes,malignancy, pyroluria, and other chronicillnesses.[23][24] It can also occur afterbariatric surgery, heavy metal exposure[25][26] and tartrazine.[citation needed]
Zinc deficiency is typically the result of inadequate dietary intake of zinc, disease states that promote zinc losses, or physiological states that require increased zinc. Populations that consume primarily plant-based diets that are low in bioavailable zinc often have zinc deficiencies.[27][28] Diseases or conditions that involve intestinal malabsorption promote zinc losses. Fecal losses of zinc caused by diarrhea are one contributing factor,[29] often common indeveloping countries. Changes in intestinal tract absorbability and permeability due, in part, to viral, protozoal, and bacteria pathogens may also encourage fecal losses of zinc.[30] Physiological states that require increased zinc include periods of growth in infants and children as well as in mothers during pregnancy.[31]
Zinc deficiency may cause a decrease inappetite which can degenerate intoanorexia oranorexia nervosa.[32] Appetite disorders, in turn, causemalnutrition and, notably, inadequate zinc intake. Anorexia itself is a cause of zinc deficiency, thus leading to a vicious cycle: the worsening of anorexia worsens the zinc deficiency. A 1994 randomized, double-blind, placebo-controlled trial showed that zinc (14 mg per day) doubled the rate of body mass increase in the treatment of anorexia nervosa.[33]
Cognitive and motor function may also be impaired in zinc deficient children. Zinc deficiency can interfere with many organ systems especially when it occurs during a time of rapid growth and development when nutritional needs are high, such as during infancy.[34] Inanimal studies, rats who were deprived of zinc during early fetal development exhibited increased emotionality, poor memory, and abnormal response to stress which interfered with performance in learning situations.[35] Zinc deprivation in monkeys showed that zinc deficient animals were emotionally less mature, and also had cognitive deficits indicated by their difficulty in retaining previously learned problems and in learning new problems.[35] Human observational studies show weaker results. Low maternal zinc status has been associated with less attention during the neonatal period and worse motor functioning.[36] In some studies, supplementation has been associated with motor development in very lowbirth weight infants and more vigorous and functional activity in infants and toddlers.[36]
Plasma zinc level has been associated with many psychological disorders. However, the nature of this relationship remains unclear in most instances. An increasing amount of evidence suggests that zinc deficiency could play a causal role in the etiology of depression.[37] Indeed, zinc supplementation has been reported to improve measures of depression in randomized double blind placebo controlled trials.[38]
The neurodegenerative syndrome of copper deficiency has been recognized for some time in ruminant animals, in which it is commonly known as "swayback".[39] The disease involves a nutritional deficiency in the trace elementcopper.[39] Copper is ubiquitous and daily requirement is low making acquired copper deficiency very rare. Copper deficiency can manifest in parallel with vitamin B12 and other nutritional deficiencies.[40] The most common cause of copper deficiency is a remote gastrointestinal surgery, such as gastric bypass surgery, due to malabsorption of copper, or zinc toxicity. On the other hand,Menkes disease is a genetic disorder of copper deficiency involving a wide variety of symptoms that is often fatal.[41]
Copper deficiency can cause a wide variety of neurological problems including,myelopathy, peripheralneuropathy, andoptic neuropathy.[39][42]
Affected individuals typically present difficulty walking (gait difficulty) caused bysensory ataxia (irregular muscle coordination) due todorsal column dysfunction[42] or degeneration of the spinal cord (myelopathy).[39][43] Patients with ataxic gait have problems balancing and display an unstable wide walk. They often feel tremors in their torso, causing side way jerks and lunges.[44]
In brain MRI, there is often an increasedT2 signalling at the posterior columns of the spinal cord in patients withmyelopathy caused by copper deficiency.[39][42][45] T2 signalling is often an indicator of some kind of neurodegeneration. There are some changes in the spinal cord MRI involving the thoracic cord, the cervical cord or sometimes both.[39][42] Copper deficiency myelopathy is often compared tosubacute combined degeneration (SCD).[43]Subacute combined degeneration is also a degeneration of the spinal cord, but insteadvitamin B12 deficiency is the cause of the spinal degeneration.[39] SCD also has the same high T2 signalling intensities in the posterior column as copper deficient patient in MRI imaging.[45]
Another common symptom of copper deficiency isperipheral neuropathy, which is numbness or tingling that can start in the extremities and can sometimes progress radially inward towards the torso.[42][46] In an Advances in Clinical Neuroscience & Rehabilitation (ACNR) published case report, a 69-year-old patient had progressively worsened neurological symptoms.[47] These symptoms included diminished upper limb reflexes with abnormal lower limb reflexes, sensation to light touch and pin prick was diminished above the waist, vibration sensation was lost in the sternum, and markedly reducedproprioception or sensation about the self's orientation.[47] Many people with the neurological effects of copper deficiency complain about very similar or identical symptoms as the patient.[39][46] This numbness and tingling poses danger for the elderly because it increases their risk of falling and injuring themselves. Peripheralneuropathy can become very disabling leaving some patients dependent on wheel chairs or walking canes for mobility if there is lack of correct diagnosis. Rarely can copper deficiency cause major disabling symptoms. The deficiency will have to be present for an extensive amount of time until such disabling conditions manifest.
Some patients with copper deficiency have shown signs of vision and color loss.[46] The vision is usually lost in the peripheral views of the eye.[46] The bilateral vision loss is usually very gradual.[46][48] Anoptical coherence tomography (OCT) shows some nerve fiber layer loss in most patients, suggesting the vision loss and color vision loss was secondary tooptic neuropathy or neurodegeneration.[46]
Copper toxicity can occur from excessive supplement use, eating acid foods cooked in uncoated copper cookware, exposure to excess copper in drinking water, or as the result of an inherited metabolic disorder in the case ofWilson's disease. A significant portion of the toxicity of copper comes from its ability to accept and donate single electrons as it changes oxidation state. This catalyzes the production of very reactive radical ions, such ashydroxyl radical in a manner similar toFenton chemistry.[49] This catalytic activity of copper is used by the enzymes with which it is associated, thus is only toxic when unsequestered and unmediated. This increase in unmediated reactive radicals is generally termedoxidative stress, and is an active area of research in a variety of diseases where copper may play an important but more subtle role than in acute toxicity.
Some of the effects of aging may be associated with excess copper.[50] In addition, studies have found that people with mental illnesses, such asschizophrenia, had heightened levels of copper in their systems. However, it is unknown at this stage whether the copper contributes to the mental illness, whether the body attempts to store more copper in response to the illness, or whether the high levels of copper are the result of the mental illness.[51]
Elevated free copper levels exist inAlzheimer's disease.[52] Copper and zinc are known to bind toamyloid beta proteins in Alzheimer's disease.[53]
Manganese is a component of someenzymes and stimulates the development and activity of other enzymes. Manganese superoxide dismutase (MnSOD) is the principalantioxidant inmitochondria. Several enzymes activated by manganese contribute to themetabolism ofcarbohydrates,amino acids, andcholesterol.[54]
Deficiency of manganese causes skeletal deformation in animals and inhibits the production ofcollagen in wound healing.[55] On the other hand, manganese toxicity is associated with neurological complications.[56]
Manganese poisoning is atoxic condition resulting from chronic exposure tomanganese and first identified in 1837 byJames Couper.[57]
Chronic exposure to excessive Mn levels can lead to a variety of psychiatric and motor disturbances, termedmanganism. Generally, exposure to ambient Mn air concentrations in excess of 5 mg Mn/m3 can lead to Mn-induced symptoms.[58]
In initial stages of manganism, neurological symptoms consist of reduced response speed, irritability, mood changes, and compulsive behaviors.[56] Upon protracted exposure symptoms are more prominent and resemble those ofidiopathicParkinson's disease, as which it is often misdiagnosed, although there are particular differences in both the symptoms (nature of tremors, for example), response to drugs such aslevodopa, and affected portion of thebasal ganglia. Symptoms are also similar toLou Gehrig's disease andmultiple sclerosis.
Manganism has become an active issue inworkplace safety as it has been the subject of numerousproduct liability lawsuits against manufacturers ofarc welding supplies. In these lawsuits, welders have accused the manufacturers of failing to provide adequate warning that their products could cause welding fumes to contain dangerously high manganese concentrations that could lead welders to develop manganism. Companies employing welders are also being sued, for what colloquially is known as "welders' disease". However, studies fail to show any link between employment as a welder and manganism (or other neurological problems).[59][60][61]
Manganism is also documented in reports of illicitmethcathinone manufacturing.[62] This is due to manganese being a byproduct of methcathinone synthesis ifpotassium permanganate is used as an oxidiser.[63] Symptoms include apathy, bradykinesia, gait disorder with postural instability, and spastic-hypokineticdysarthria. Another street drug sometimes contaminated with manganese is the so-called "Bazooka", prepared byfree-base methods fromcocaine using manganesecarbonate.[64]
Reports also mention such sources as contaminated drinking water,[65] and fuel additivemethylcyclopentadienyl manganese tricarbonyl (MMT),[66] which oncombustion becomes partially converted into manganesephosphates andsulfate that go airborne with the exhaust,[67][68] andmanganese ethylene-bis-dithiocarbamate (Maneb), a pesticide.[69]
Manganese may affectliver function, but the threshold of acute toxicity is very high. On the other hand, more than 95% of manganese is eliminated by biliary excretion. Any existing liver damage may slow this process, increasing its concentration in blood plasma.[70] The exactneurotoxic mechanism of manganese is uncertain but there are clues pointing at the interaction of manganese withiron,[71][72][73][74]zinc,[75]aluminum,[71][75] andcopper.[75] Based on a number of studies, disturbed ironmetabolism could underlie the neurotoxic action of manganese.[76]
It participates inFenton reactions and could thus induceoxidative damage, a hypothesis corroborated by the evidence from studies of affected welders.[77] A study of the exposed workers showed that they have significantly fewer children.[78] This may indicate that long-termaccumulation of manganese affectsfertility. Pregnant animals repeatedly receiving high doses of manganese bore malformed offspring significantly more often compared to controls.[79] Manganism mimics Schizophrenia.[80] It is found in large quantities in paint and steelmaking.
The current mainstay of manganism treatment islevodopa andchelation withEDTA. Both have limited and at best transient efficacy. Replenishing the deficit ofdopamine with levodopa has been shown to initially improveextrapyramidal symptoms,[81][82] but the response to treatment goes down after 2 or 3 years,[83] with worsening condition of the same patients noted even after 10 years since last exposure to manganese.[84] Enhanced excretion of manganese prompted bychelation therapy brings its blood levels down but the symptoms remain largely unchanged, raising questions about efficacy of this form of treatment.[85][86]
Increasedferroportin protein expression in human embryonic kidney (HEK293) cells is associated with decreased intracellular Mn concentration and attenuated cytotoxicity, characterized by the reversal of Mn-reducedglutamate uptake and diminishedlactate dehydrogenase (LDH) leakage.[58]
TheRed River Delta nearHanoi has high levels of manganese orarsenic in the water. Approximately 65 percent of the region's wells contain high levels of arsenic, manganese, selenium and barium.[87] This was also published in theProceedings of the National Academy of Sciences.
Magnesium is necessary for the function of many metabolic enzymes and also serves as a key regulator of calcium channels involved in neurotransmission (e.g. NMDA receptor).[88] Magnesium supplementation facilitates nerve regeneration after injury.[89] Although unpolished grains contain magnesium, phytic acid in grains can inhibit its absorption. Leafy greens are an excellent source of magnesium.[90]
Deficiency or excess intake of many vitamins can affect the brain contributing to developmental[91] and degenerative diseases.[92]
Vitamin A is an essentialnutrient for mammals which takes form in eitherretinol or theprovitaminbeta-Carotene. It helps regulation of cell division, cell function, genetic regulation, helps enhance the immune system, and is required for brain function, chemical balance, growth and development of thecentral nervous system and vision.[citation needed]
In an experiment byChongqing Medical University pregnant rats were either plentiful in vitamin A or were of avitamin A deficiency (VAD) due to their diet. The offspring of these rats were then tested in a water maze at 8 weeks old and it was found the VAD offspring had a harder time finishing the maze which helps show that these rats, even while having a deficiency fromin utero, have more problems with learning memory.[93] Young rats in a separate study by the same university also showed impairedlong-term potentiation in thehippocampus when they were VAD which shows neuronal impairment.[94] When the patient is VAD for too long, the effects of the damage to thehippocampus can be irreversible.[95]
Vitamin A affects spatial memory most of the time because the size of thenuclei in hippocampal neurons are reduced by approximately 70% when there is a deficiency which affects a person's abilities for higher cognitive function. In a study by theUniversity of Cagliari, Italy, VAD rats had more trouble learning aRadial arm maze than rats who had normal levels of thevitamin. The healthy rats were able to correctly solve the maze within the 15-day training period and other rats that were once deficient but had vitamin A restored to normal levels were also able to solve it. Here it was found that theretinoid receptors which help transport vitamin A were of normal function.[96]
Eating foods high in vitamin A or takingdietary supplements, retinol orretinal will prevent a deficiency. The foods highest in vitamin A are any pigmented fruits and vegetables and leafy green vegetables also providebeta-Carotene.[citation needed]There can be symptoms of fat loss and a reduction of any weight gain that would be considered normal for an individual,[96] especially developmental weight gains such as in infants which would occur if the infant was deprived of vitamin Ain utero and/or if it was deprivedpostnatal for an extensive period of time.[93] The deficiency can also cause conditions such asblindness or night blindness, also known asnyctalopia. Night blindness is due to the inability to regeneraterhodopsin in therods which is needed in dim light in order to see properly.[citation needed]A treatment of supplements ofretinoic acid which is a part of vitamin A can help replenish levels and help bring learning to normal,[97] but after 39 weeks this is ineffective even if the treatment is daily because it will not bring theretinoid hypo-signalling back to normal.[95]
Zinc is needed to maintain normal vitamin A levels inblood plasma.[citation needed] It also helps vitamin A becomemetabolized by theliver. However evidence suggests that when someone is deficient in both vitamin A and zinc, memory is more improved when just vitamin A is increased than when just zinc is increased. Of coursememory has the largest improvement when both are increased. When one of these nutrients is not balanced, the other is most likely to be affected because they rely on each other for proper functioning in learning.[98]
Vitamin B1, also known as thiamine, is acoenzyme essential for the metabolism ofcarbohydrates.[99] This vitamin is important for the facilitation of glucose use, thus ensuring the production of energy for the brain,[100] and normal functioning of the nervous system, muscles, and heart.[101]
Thiamine is found in all livingtissues,[102] and is uniformly distributed throughout mammalian nervous tissue, including the brain andspinal cord. Metabolism and coenzyme function of the vitamin suggest a distinctive function for thiamin within thenervous system.[103]
The brain retains its thiamine content in the face of a vitamin-deficient diet with great tenacity, as it is the last of all nervous tissues studied to become depleted. A 50% reduction of thiamine stores inrats becomes apparent after only 4 days of being put on a thiamine-deficient diet. However, polyneuritic signs do not begin to appear until about 4 or 5 weeks have passed.[103] Similar results have been found in human subjects.[102]
The body has only small stores of B1; accordingly, there is risk of deficiency if the level of intake is reduced only for a few weeks.[102] Thiamin deficiency during critical periods of early development can disrupts neurogenesis in animal models.[104] Lack of thiamin later in life causes the disease known as beriberi.[105] There are two forms ofberiberi: "wet", and "dry". Dry beriberi is also known as cerebral beriberi. Characteristics of wet beriberi include prominentedema andcardiac involvement, whereas dry beriberi is mainly characterized by apolyneuritis.[103]
In industrialized nations, thiamine deficiency is a clinically significant problem in individuals with chronic alcoholism or other disorders that interfere with normal ingestion of food.[106] Thiamine deficiency within developed nations tends to manifest asWernicke–Korsakoff syndrome.[105] Chronic alcoholism can disrupt thiamin absorption and thiamin deficiency contributes to neurodegeneration and memory loss in alcoholics known as Wernicke's encephalopathy.[107] Individuals with chronicalcoholism may fall short on minimumdaily requirements of thiamine in part due toanorexia, erratic eating habits, lack of available food, or a combination of any of these factors. Thiamine deficiency has been reported in up to 80% of alcoholic patients due to inadequate nutritional intake, reduced absorption, and impaired utilization of thiamine.[108] Alcohol, in combination with itsmetaboliteacetaldehyde, interacts with thiamine utilization at the molecular level during transport, diphosphorylation, and modification processes. For this reason, chronic alcoholics may have insufficient thiamine for maintenance of normal brain function, even with seemingly adequate dietary intake.[106]
Clinical signs of B1 deficiency include mental changes such as apathy, decrease inshort-term memory, confusion, and irritability.[105] Moderate deficiency in thiamine may reduce growth in young populations, in increase chronic illness in both young and middle-aged adults. In addition, moderate deficiency of thiamine may increase rates ofdepression,dementia, falls, andfractures in old age.[106]
The lingering symptoms of neuropathy associated with cerebral beriberi are known asKorsakoff's syndrome, or the chronic phase of Wernicke-Korsakoff's.[109] Wernicke encephalopathy is a neurological disorder resulting from a deficiency in thiamine, sharing the same predominant features of cerebral beriberi, as characterized by ocular abnormalities,ataxia of gait, a global state of confusion, and neuropathy.[106] The state of confusion associated with Wernicke's may consist of apathy, inattention, spatial disorientation, inability to concentrate, and mental sluggishness or restlessness.[99] Clinical diagnosis of Wernicke's disease cannot be made without evidence of ocular disturbance, yet these criteria may be too rigid.[110] Korsakoff's likely represents a variation in the clinical manifestation of Wernicke encephalopathy, as they both share similar pathological origin.[110]
Korsakoff's syndrome is often characterized byconfabulation, disorientation, and profoundamnesia.[109] Characteristics of the neuropathology are varied, but generally consist of bilaterally symmetrical midlinelesions ofbrainstem areas, including themammillary bodies,thalamus,periaqueductal region,hypothalamus, and thecerebellar vermis.[106][109]
Immediate treatment of Wernicke encephalopathy involves the administration ofintravenous thiamine, followed with long-term treatment and prevention of the disorder through oral thiamine supplements, alcoholabstinence, and a balanced diet.[99] Improvements in brain functioning of chronic alcoholics may occur with abstinence-related treatment, involving the discontinuation of alcohol consumption and improved nutrition.[106] Wernicke's encephalopathy is life-threatening if left untreated. However, a rapid reversal of symptoms may result from prompt administration of thiamine.[102]
Fortification of flour is practiced in some countries to replace the thiamine lost during processing. However, this method has been criticized for missing the target population of chronic alcoholics, who are most at risk for deficiency. Alternative solutions have suggested the fortification of alcoholic beverages with thiamine.[102]
Ingesting a diet rich in thiamine may stave off the adverse effects of deficiency. Foods providing rich sources of thiamine includeunrefined grain products, ready-to-eatcereals, meat (especially pork),dairy products, peanuts,legumes, fruits and eggs.[111]
Vitamin B3, also known as niacin, includes bothnicotinamide as well asnicotinic acid, both of which function in manybiological oxidization and reduction reactions within the body. These functions include thebiochemical degradation of carbohydrates,fats andproteins. Niacin is also involved in the synthesis offatty acids andcholesterol,[112] which are known mediators of brain biochemistry, and in effect, of cognitive function.[113]
Sufficient niacin intake is either obtained from diet, or synthesized from theamino acidtryptophan.[112]
Severe niacin deficiency typically manifests itself as the diseasepellagra.[112] Synthesis of B3 from tryptophan involvesvitamin B2 and B6, so deficiencies in either of these nutrients can lead to niacin deficiency. An excess ofleucine, anessential amino acid, in the diet can also interfere with tryptophan conversion and subsequently result in a B3 deficiency.[114]
Pellagra is most common to populations within developing countries in whichcorn is the dietarystaple. The disease has virtually disappeared from industrialized countries, yet still appears in India and parts of China and Africa.[112] This is in part due to the bound form of niacin that unprocessed corn contains, which is not readily absorbed into the human body. The processes involved in making corntortillas, can release the bound niacin into a more absorbable form. Pellagra is not problematic in countries which traditionally prepare their corn in this way, but is a problem in other countries where unprocessed corn is main source of caloric intake.[115]
Though pellagra predominantly occurs indeveloping countries, sporadic cases of pellagra may be observed within industrialized nations, primarily in chronic alcoholics and patients living with functional absorption complications.[114]
Pellagra is classically characterized by four 4 "D's": diarrhea,dermatitis, dementia, and death.[114] Neuropsychiatric manifestations of pellagra include headache, irritability, poor concentration, anxiety, hallucinations, stupor, apathy, psychomotor unrest, photophobia, tremor, ataxia, spastic paresis, fatigue, and depression. Symptoms of fatigue and insomnia may progress to encephalopathy characterized by confusion, memory loss, and psychosis.[114]
Those affected by pellagra may undergo pathological alterations in the nervous system. Findings may includedemylenation and degeneration of various affected parts of the brain, spinal cord, and peripheralnerves.[116]
Prognosis of deficiency is excellent with treatment. Without, pellagra will gradually progress and lead to death within 4–5 years, often a result ofmalnutrition from prolonged diarrhea, or complications as caused by concurrent infections or neurological symptoms. Symptoms of pellagra can be cured withexogenous administration of nicotinic acid or nicotinamide.[114]
Flushing occurs in many patients treated therapeutically with nicotinic acid,[117] and as a result, nicotinamide holds more clinical value as it is not associated with the same uncomfortable flushing. The adult dose of nicotinamide is 100 mg taken orally every 6 hours until resolution of major acute symptoms, followed with oral administration of 50 mg every 8–12 hours until skin lesions heal. For children, treatment involves oral ingestion of 10–15 mg of nicotinamide, depending on weight, every 6 hours until signs and symptoms are resolved. Severe cases require 1 gram every 3–4 hours, administeredparenterally.[114]
Oral nicotinamide has been promoted as an over-the-counter drug for the treatment ofAlzheimer's dementia. Conversely, no clinically significant effect has been found for the drug, as nicotinamide administration has not been found to promote memory functions in patients with mild to moderate dementia of either Alzheimer's, vascular, or fronto-temporal types. This evidence suggests that nicotinamide may treat dementia as related to pellagra, but administration does not effectively treat other types of dementia.[118]
The best method of prevention is to eat foods rich in B3. Generally, this involves the intake of a protein-rich diet. Foods that contain high concentrations of niacin in the free form include beans and organ meat, as well as enriched grain and cereal products.[112] While niacin is present in corn and other grains, thebioavailability of the nutrient is much less than it is in protein-rich sources. Different methods of processing corn may result in a higher degree of bioavailability of the vitamin.[115]
Though treatment with niacin does little to alter the effects of Alzheimer's dementia, niacin intake from foods is inversely associated with the disease.[119]
Folate deficiency can disrupt neurulation and neurogenesis. Maternal folic acid intake around the time of conception prevents neural tube defects.[120] Furthermore, folic acid intake was recently associated with incidence of autism.[121] Enriched white flour is fortified with folic acid in the United States and many other countries. However the European Union does not have mandatory folic acid fortification. Although the protective effects of folic acid are well documented, there remains legitimate concern that fortification could lead to toxic levels in a subset of the population. For example, elevated levels of folic acid can interact with vitamin B12 deficiency to cause neurodegeneration.[122] Furthermore, folic acid and iron can interact to exacerbate malaria.[123]
Folic acid is the most oxidized and stable form of folate, and can also be referred to as vitamin B9. It rarely occurs naturally in foods, but it is the form used in vitamin supplements as well as fortified food products.[124]
Folate coenzymes are involved in numerous conversion processes within the body, including DNA synthesis and amino acid interconversions.[124] Folate and vitamin B12 play a vital role in the synthesis ofS-adenosylmethionine, which is of key importance in the maintenance and repairment of all cells, including neurons.[125] In addition, folate has been linked to the maintenance of adequate brain levels of cofactors necessary for chemicals reactions that lead to the synthesis of serotonin and catecholamine neurotransmitters.[124]
Folate has a major, but indirect role in activities which help to direct gene expression andcell proliferation. These activities occur at a greatly increased rate duringpregnancy, and depend on adequate levels of folate withinblood plasma.[126]
Concentrations of blood plasma folate andhomocysteine concentrations are inversely related, such that an increase in dietary folate decreases homocysteine concentration. Thus, dietary intake of folate is a major determinant of homocysteine levels within the body.[127]
Autoantibodies againstfolate receptor alpha have been found in up to 75% of children with autism.[128]
Folate deficiency most commonly arises from insufficient folate intake from the diet, but may also stem from inefficient absorption or metabolic utilization of folate, usually a result of genetic variation.[129] The relationship between folate and B12 is so interdependent that deficiency in either vitamin can result inmegaloblastic anemia, characterized by organic mental change.[130]
The process of neural tube transformation into structures that will eventually develop into the central nervous system is known asneurulation, the success of which is dependent on the presence of folate within the body. This process begins in the human approximately 21 days afterconception, and is completed by 28 days. Thus, a woman may not even be aware of her pregnancy by the time the process of neurulation is complete, potentially causing severe consequences in the development of the fetus.[124]
Functional problems in the absorption and utilization of vitamins may also play a role in folate deficiencies within the elderly.[125]
The link between levels of folate and altered mental function is not large, but is sufficient to suggest a causal association.[124] Deficiency in folate can cause an elevation of homocysteine within the blood,[127] as the clearance of homocysteine requires enzymatic action dependent on folate, and to a lesser extent, vitamins B6 and B12. Elevated homocysteine has been associated with increased risk ofvascular events, as well as dementia.[132]
Differences lie in the presentation of megaloblastic anemia induced by either folate or B12 deficiency. Megaloblastic anemia related to deficiency in B12 generally results in peripheral neuropathy, whereas folate-related anemia often results in affective, or mood disorders.[130][133] Neurological effects are not often associated with folate-related megaloblastic anemia, although demyelinating disorders may eventually present.[130] In one study, mood disturbances were recorded for the majority of patients presenting with megaloblastic anemia in the absence of B12 deficiency.[124] In addition, folate concentrations within blood plasma have been found to be lower in patients with both unipolar and bipolar depressive disorders when compared with control groups. In addition, depressive groups with low folate concentrations responded less well to standardantidepressant therapy than did those with normal levels within plasma.[124] However, replication of these findings are less robust.[134]
The role of folic acid during pregnancy is vital to normal development of the nervous system in the fetus. A deficiency in folate levels of a pregnant woman could potentially result inneural tube disorder, a debilitating condition in which the tubes of the central nervous system do not fuse entirely.[126] NTDs are not to be confused withspina bifida, which does not involve neural elements.[124] Neural tube defects can present in a number of ways as a result of the improper closure at various points of the neural tube. The clinical spectrum of the disorder includesencephalocele, craniorachischisis, andanencephaly. In addition, these defects can also be classified as open, if neural tissue is exposed or covered only by membrane, or can be classified as closed, if the tissue is covered by normal skin.[131]
Intake of the vitamin has been linked to deficits inlearning and memory, particularly within the elderly population.[124] Elderly people deficient in folate may present with deficits in free recall and recognition, which suggests that levels of folate may be related to efficacy of episodic memory.[135]
Because neurulation may be completed before pregnancy is recognized, it is recommended that women capable of becoming pregnant take about 400μg of folic acid from fortified foods, supplements, or a combination of the two in order to reduce the risk of neural tube defects.[124] These major anomalies in the nervous system can be reduced by 85% with systematic folate supplementation occurring before the onset of pregnancy.[126]
The incidence of Alzheimer's and other cognitive diseases has been loosely connected to deficiencies in folate. It is recommended for the elderly to consume folate through food, fortified or not, and supplements in order to reduce risk of developing the disease.[136]Good sources of folate includeliver, ready-to-eat breakfast cereals, beans, asparagus, spinach, broccoli, and orange juice.[137]
Choline is an important methyl donor involved in one-carbon metabolism that also becomes incorporated into phospholipids and the neurotransmitter acetylcholine. Because of its role in cellular synthesis, choline is an important nutrient during the prenatal and early postnatal development of offspring as it contributes heavily to the development of the brain. A study found that rats that were given supplements of choline in utero or in the weeks following birth had superior memories. The changes appeared to be a result of physical changes to thehippocampus, the area of the brain responsible for memory.[138][139] Furthermore, choline can reduce some of the deleterious effects of folate deficiency on neurogenesis.[140]
While choline during development is important, adult levels of choline are also important. Choline has been shown to increase the synthesis and release of acetylcholine from neurons,[141] which in turn increases memory. Adouble-blind study was conducted using normal college students (no neurological disorders). Results showed that twenty-fivegrams ofphosphatidylcholine (another form of choline) created a significant improvement inexplicit memory, measured by aserial learning task, however this improvement may be attributed to the improvement of slow learners.[142] Another study found that a single ten-gram oral dose of choline, given to normal volunteers (again, without neurological disorders) significantly decreased the number of trials needed to master a serial-learning word test. This increase in memory is particularly beneficial to memory loss experienced by old age. A study conducted on rats who, like humans, had an age-related loss of memory were tested on how choline affected memory. The results showed that rats who had a chronic low-choline diet showed greater memory loss then their same-age control counterparts, while rats who had choline-enriched diets showed a diminished memory loss compared to both the choline-low diet and control rat groups. Furthermore, young rats who were choline-deficient performed as poorly on memory tasks as older rats while older rats that were given choline supplements performed as well as three-month-old rats.[143]
Despite the wide range of foods that choline is found in, studies have shown that the mean choline intake of men, women and children are below theAdequate Intake levels.[144] It is important to note that not enough choline is naturally produced by the body, so diet is an important factor. People who consume a large quantity of alcohol may be at an increased risk for choline deficiency.Sex and age also plays a role, withpremenopausal females being less sensitive to choline deficiency than either males orpostmenopausal females.[143] This has been theorized to be a result of premenopausal women having an increased ability to synthesize choline in some form, which has been confirmed in studies on rats.[145] In such instances of deficiency, choline supplements or (if able) dietary changes may be beneficial. Good sources of choline include liver, milk, eggs and peanuts.[146] There is further evidence to suggest that choline supplements can be used to treat people who have neurological disorders as well we memory defects.[143][144] Oral doses ofCDP-choline (another form of choline) given toelderly subjects with memory deficits, but without dementia, for four weeks showed improved memory in free recall tasks, but not in recognition tests.[147] In a second study, patients with early Alzheimer-type dementia were treated with twenty-give gram doses of phosphatidylcholine every day for six months. Slightly improvements were shown in memory tests compared to the placebo control group. Other studies conducted did not find any such improvement.
Also known as cobalamin, B12 is an essential vitamin necessary for normalblood formation. It is also important for the maintenance of neurological function and psychiatric health.[148] The absorption of B12 into the body requires adequate amounts ofintrinsic factor, theglycoprotein produced in theparietal cells of the stomach lining. A functioningsmall intestine is also necessary for the proper metabolism of the vitamin, as absorption occurs within theileum.[148]
B12 is produced in the digestive tracts of all animals, including humans.[149] Thus, animal-origin food is the only natural food source of vitamin B12[150] However, synthesis of B12 occurs in thelarge intestine, which is past the point of absorption that occurs within the small intestine. As such, vitamin B12 must be obtained through diet.[149]
Unlike other B vitamins which are not stored in the body, B12 is stored in theliver. Because of this, it may take 5–10 years before a sudden dietary B12 deficiency will become apparent in a previously healthy adult.[151] B12 deficiency, also known as hypocobalaminemia, often results from complications involving absorption into the body.[152]
B12 deficiency is often associated withpernicious anemia, as it is the most common cause. Pernicious anemia results from anautoimmune disorder which destroys the cells that produceintrinsic factor within the stomach lining, thereby hindering B12 absorption. B12 absorption is important for the subsequent absorption of iron, thus, people with pernicious anemia often present with typical symptoms ofanemia, such as pale skin, dizziness, and fatigue.[153]
Among those at highest risk for B12 deficiency are the elderly population, as 10-15% of people aged 60+ may present with some form of hypocobalaminemia. High rates of deficiency in the elderly commonly results from the decrease of functional absorption of B12, as production of intrinsic factor declines with age. However, pernicious anemia is the most common cause of B12 deficiency in North American and European populations.[150]
Those affected by variousgastrointestinal diseases may also be at risk for deficiency as a result of malabsorption. These diseases may affect production of intrinsic factor in the stomach, or of pancreaticbile. Diseases that involve disorders of the small intestine, such as celiac disease,Crohn's disease andileitis, may also reduce B12 absorption. For example, people with celiac disease may damage the microvilli within their small intestines through the consumption of gluten, thereby inhibiting absorption of B12 as well as other nutrients.[152]
A diet low in B12, whether voluntary or not, can also cause symptoms of hypocobalaminemia. Many rich sources of B12 come from animal meats and by-products. Populations in developing countries may not have access to these foods on a consistent basis, and as a result may become deficient in B12.[154] In addition,vegans, and to a lesser extentvegetarians, are at risk for consuming a diet low in cobalamin as they voluntarily abstain from animal sources of B12.[152] A combination of these two scenarios may increase prevalence of cobalamin deficit. For instance, B12 deficiency is problematic in India, where the majority of the population is vegetarian and the scarcity of meat consumption is common for omnivores as well.[154]
An assortment of neurological effects can be observed in 75-90% of individuals of any age with clinically observable B12 deficiency. Cobalamin deficiency manifestations are apparent in the abnormalities of the spinal cord, peripheral nerves, optic nerves, andcerebrum. These abnormalities involve a progressive degeneration ofmyelin,[155] and may be expressed behaviourally through reports of sensory disturbances in the extremities, or motor disturbances, such as gait ataxia. Combined myelopathy and neuropathy are prevalent within a large percentage of cases. Cognitive changes may range from loss of concentration to memory loss, disorientation, and dementia. All of these symptoms may present with or without additional mood changes.[150] Mental symptoms are extremely variable, and include mild disorders of mood, mental slowness, and memory defect. Memory defect encompasses symptoms ofconfusion, severe agitation and depression,delusions and paranoid behaviour, visual and auditoryhallucinations,urinary andfecal incontinence in the absence of overt spinal lesions, dysphasia, violent maniacal behaviour, and epilepsy. It has been suggested that mental symptoms could be related to a decrease in cerebral metabolism, as caused by the state of deficiency.[155] All of these symptoms may present with or without additional mood changes.[150]
Mild to moderate cases of pernicious anemia may show symptoms of bleedinggums,headache, poorconcentration, shortness of breath, and weakness. In severe cases of pernicious anemia, individuals may present with various cognitive problems such as dementia, and memory loss.[153]
It is not always easy to determine whether B12 deficiency is present, especially within older adults.[152] Patients may present with violent behaviour or more subtle personality changes. They may also present with vague complaints, such as fatigue or memory loss, that may be attributed to normative aging processes. Cognitive symptoms may mimic behaviour in Alzheimer's and other dementias as well.[150] Tests must be run on individuals presenting with such signs to confirm or negate cobalamin deficiency within the blood.[153]
Patients deficient in B12 despite normal absorption functionality may be treated through oral administration of at least 6 mg of the vitamin in pill form. Patients who have irreversible causes of deficiency, such as pernicious anemia or old age, will need lifelong treatment with pharmacological doses of B12. Strategy for treatment is dependent on the patient's level of deficiency as well as their level of cognitive functioning.[152] Treatment for those with severe deficiency involves 1000 mg of B12 administeredintramuscularly daily for one week, weekly for one month, then monthly for the rest of the patient's life. Daily oral supplementation of B12 mega-doses may be sufficient in reliable patients, but it is imperative that the supplementation be continued on a lifelong basis as relapse may occur otherwise.[153]
The progression of neurological manifestations of cobalamin deficiency is generally gradual. As a result, early diagnosis is important or else irreversible damage may occur.[148] Patients who become demented usually show little to no cognitive improvement with the administration of B12.[153]
A deficiency in folate may produce anemia similar to the anemia resulting from B12 deficiency. There is risk that folic acid administered to those with B12 deficiency may mask anemic symptoms without solving the issue at hand. In this case, patients would still be at risk for neurological deficits associated with B12 deficiency-related anemia, which are not associated with anemia related to folate deficiency.[129]
In addition to meeting intake requirements through food consumption, supplementation of diet with vitamin B12 is seen as a viable preventive measure for deficiency. It has been recommended for the elderly to supplement 50 mcg a day in order to prevent deficit from occurring.[153]
Animal protein products are a good source of B12, particularly organ meats such askidney or liver. Other good sources are fish, eggs, and dairy products.[149] It is suggested that vegans, who consume no animal meat or by-products, supplement their diet with B12. While there are foods fortified with B12 available, some may be mislabelled in an attempt to boost their nutritional claims. Products of fermentation, such as algae extracts and sea vegetables, may be labelled as sources of B12, but actually contain B12analogues which compete for the absorption of the nutrient itself.[154] In order to get adequate amounts of the vitamin, orally administered pills or fortified foods such as cereals and soy milk, are recommended for vegans.[156]
Vitamin D is an essential regulator of the vitamin D receptor that controls gene transcription during development. The vitamin D receptor is strongly expressed in the substantia nigra.[157] Accordingly, vitamin D deficiency can disrupt neurogenesis leading to altered dopamine signaling and increased exploratory behavior in rats.[158][159] This is considered a rodent model of the schizophrenia phenotype and vitamin D deficiency has been proposed as an explanation for the increased incidence of schizophrenia among children that were conceived during winter months. A Finnish study found that vitamin D supplement use is associated with reduced risk of schizophrenia.[160]
Vitamin D deficiency may also have downstream effects onneurosteriod synthesis. Vitamin D supplementation appears to increase both free and total testosterone levels in healthy men, with serum vitamin D levels between 70-80 nmol/L having been shown to maximize testosterone production in overweight men.[161][162]5a-Androstanediol, a metabolite of testosterone, is a potentpositive allosteric modulator of theGABAA receptor.[163] The synthesis of 5a-Androstanediol is generally correlated with that of testosterone production.[164]
Fatty acids are necessary for the synthesis of cell membranes neurotransmitters and other signaling molecules. While excessive fat intake can be harmful, deficiency of essential fatty acids can disrupt neurodevelopment and synaptic plasticity.[165]
Consuming large amounts of saturated fat can negatively affect the brain. Eating foods with saturated fats elevates the level of cholesterol and triglycerides in the body. Studies have shown that high levels of triglycerides strongly link with mood problems such as depression, hostility and aggression. This may occur because high triglyceride levels decrease the amount of oxygen that blood can carry to the brain.[166] The American Heart Association recommends that people consume no more than 16g of saturated fat daily. Common sources of saturated fat are meat and dairy products.
There are two kinds of essential fatty acids that people must consume (omega-3 and omega-6). Many academics recommend a balanced amount of omega-3s and omega-6s. However, some estimate that Americans consume twenty times more omega-6s than omega-3s. There is a theory that an imbalance of essential fatty acids may lead to mental disorders such as depression, hyperactivity and schizophrenia, but it still lacking evidences. An omega-3 deficient diet increases omega-6 levels in the brain disrupting endocannabinoid signaling in the prefrontal cortex and nucleus accumbens contributing to anxiety and depression-like behaviors in mice.[165]Sources of omega-3 include flax seeds, chia seeds, walnuts, sea vegetables, green leafy vegetables, and cold water fish. Sources of omega-6 include walnuts, hazelnuts; sunflower, safflower, corn, and sesame oils.[167]
While cholesterol is essential for membranes and steroid hormones, excess cholesterol affects blood flow impairing cognitive function in vascular dementia.[168]
Studies have shown that learning and memory improve after consuming carbohydrates. There are two kinds of carbohydrates people consume: simple and complex. Simple carbohydrates are often found in processed foods and release sugar into the bloodstream quickly after consumption. Complex carbohydrates are digested more slowly and therefore cause sugar to be released into the bloodstream more slowly.[169] Good sources of complex carbohydrates are whole-grain breads, pasta, brown rice, oatmeal, and potatoes. It is recommended that people consume more complex carbohydrates because consuming complex carbohydrates will cause the level of sugar in the bloodstream to be more stable, which will cause less stress hormones to be released. Consuming simple carbohydrates may cause the levels of sugar in the bloodstream to rise and fall, which can cause mood swings.[170]
The ketone body beta-hydroxybutyrate is a fuel source for the brain during times of fasting when blood glucose levels fall. Although the mechanism is not understood, it is well established that eating a diet low in carbohydrates can be therapeutic for children with epilepsy.[171] This is likely a result of ketone bodies providing an alternative fuel source to glucose for neuronal function. Furthermore, a ketogenic diet can be beneficial for dementia patients.[172]Medium-chain triglycerides can stimulate ketone synthesis[173] and coconut oil is a rich source of medium chain triglycerides that several anecdotal reports suggest can improve cognitive function in Alzheimer's type dementia patients.[174][175]
When protein is consumed, it is broken down into amino acids. These amino acids are used to produce many things like neurotransmitters, enzymes, hormones, and chromosomes. Proteins known as complete proteins contain all eight of the essential amino acids. Meat, cheese, eggs, and yogurt are all examples of complete proteins. Incomplete proteins contain only some of the eight essential amino acids and it is recommended that people consume a combination of these proteins. Examples of incomplete proteins include nuts, seeds, legumes, and grains.[176] When animals are fed a diet deficient in essential amino acids, uncharged tRNAs accumulate in the anterior piriform cortex signaling diet rejection [105]. The body normally interconverts amino acids to maintain homeostasis, but muscle protein can be catabolized to release amino acids during conditions of amino acid deficiency. Disruption of amino acid metabolism can affect brain development and neurophysiology to affect behavior. For example, fetal protein deficiency decreases the number of neurons in the CA1 region of the hippocampus.[177]
Glutamate is aproteinogenic amino acid and neurotransmitter, though it is perhaps publicly best known in itssodiumsalt form:monosodium glutamate (MSG). It is also aflavor on its own, producing theumami or savory flavor found in manyfermented foods such ascheese. As an amino acid it acts as a source of fuel for various cellular functions and as a neurotransmitter. Glutamate operates as anexcitatory neurotransmitter and is released when a nerve impulse excites a glutamate producing cell. This in turn binds to neurons with glutamate receptors, stimulating them.
Glutamate is a nutrient that is extremely difficult to be deficient in, as, being an amino acid, it is found in every food that contains protein. Additionally it is found, as previously mentioned, in fermented foods and in foods containing monosodium glutamate. As such, good sources of glutamate include meat, fish, dairy products and awide array of other foods. Glutamate is also absorbed extremely efficiently by the intestines.[178] However, there are instances of glutamate deficiency occurring, but only in cases where genetic disorders are present. One such example isGlutamate formiminotransferase deficiency and can cause either minor or profound physical and intellectual disabilities, depending on the severity of the condition. This disorder is extremely rare however, as only twenty people have so far been identified with this condition.[179] Glutamate, while critically important in the body also acts as anexcitotoxin in high concentrations not normally found outside of laboratory conditions,[180] although it can occur followingbrain injury orspinal cord injury.[181]
L-Phenylalanine is biologically converted into L-tyrosine, another one of the DNA-encoded amino acids, and beta-phenethylamine.[182] L-tyrosine in turn is converted into L-DOPA, which is further converted into dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). The latter three are known as the catecholamines. Phenethylamine is further converted into N-methylphenethylamine.[183] Phenylalanine uses the same active transport channel as tryptophan to cross the blood–brain barrier, and, in large quantities, interferes with the production of serotonin.[184]
Toxic levels of phenylalanine accumulate in the brains of patients withphenylketonuria leading to severe brain damage and intellectual disability. To prevent brain damage, these individuals can restrict dietary phenylalanine intake by avoiding protein and supplementing their diet with essential amino acids.[185]
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