Articles

Cognitive Function

Introduction

Cognitive function is the term used to describe a person’s state of consciousness (alertness and orientation), memory, attention span, and insight. A mental status examination (MSE) is a standard tool used by clinicians to measure a patient’s overall mental health. Evaluating a patient’s cognitive functions includes first of all, measuring the level of alertness and orientation.

Awareness and thinking are dependent on integrated and organized thoughts, subjective experiences, emotions, and mental processes, each of which resides, to a certain extent, in anatomically defined regions of the brain. Self-awareness requires that the organism senses this personal stream of thoughts and emotional experiences. The inability to maintain a coherent sequence of thoughts, accompanied usually by inattention and disorientation, is the best definition of confusion, a disorder of the content of consciousness. (1)

Alertness is a measure of a patient’s awareness of his or her environment and situation. Abnormal states range from confusion to lethargy, delirium, stupor, and at the end of the spectrum, coma. Similarly, orientation is a person’s ability to describe knowledge of person, place, and time. Simple questions may be asked, such as the patient’s name, where they live, the current date or day of the week, or season of the year to evaluate orientation. Disorientation is frequently associated with organic brain syndromes (e.g., dementia). (2)

Confusion is a behavioral state of reduced mental clarity, coherence, comprehension, and reasoning. (3) Inattention and disorientation are the main early signs; however, as an acute confusional state worsens, there is deterioration of memory, perception, comprehension, problem solving, language, praxis, visuospatial function, and various aspects of emotional behavior, each identified with particular regions of the brain.

Changes in a person’s state of consciousness such as confusion, lethargy, and delirium may be caused by many medical conditions including fever, ischemia, trauma, or brain diseases. It may also be caused by suppression of cerebral function from extrinsic factors such as drugs or toxins. Additional potential causes include internal metabolic derangements such as hypoglycemia, azotemia, hepatic failure, or hypercalcemia; and any brainstem lesion that can cause damage to the reticular activating system (RAS). However, if confusion is a feature of a dementing illness, it will become chronic in nature and will manifest as having an effect primarily on memory as opposed to acute confusion. Sometimes what was thought to be a confused state may be more clearly defined as a single cortical deficit in higher mental function such as impaired language comprehension, loss of memory, appreciation of space, in which case each is defined by the dominant behavioral change rather than characterizing the state as confusion.

The confused patient is usually subdued, and not inclined to speak, and is inactive physically. Psychiatrists will sometimes interchange the terms of confusion and delirium, while neurologists tend to keep the two separate, generally using the term delirium to describe a patient who is in an agitated, hypersympathotonic, hallucinatory state, most frequently caused by drug or alcohol withdrawal, or hallucinogenic drugs.

Memory helps to test a patient’s ability to recall both past and present information. Memory is generally considered the most common and the most important cognitive ability that is lost. Clinicians may test a patient’s memory by asking questions about the history of their present illness or a recent meal. Additionally, they may ask a patient to remember three unassociated words, such as a color, a person’s address, and an object, then, later in the interview, ask if the patient can recall what they were asked to remember. These are tests of present or short-term memory. Questions concerning family history, date of birth, and past factual information test a patient’s past (distant) memory. Delirium, dementias, amnesia, Korsakoff’s psychosis, and anxiety are conditions associated with an impaired memory. (4)

Dementias are neuropsychiatric disorders defined by widespread symptoms of memory loss and deficits in cognition and reasoning. (5) Dementia, sometimes considered to be synonymous with the lay term "senility", is not a part of the normal aging process, and reflects some underlying disease. A more simple definition of dementia is deterioration of cognitive abilities that impairs the previously successful performance of activities of daily living. (6) Accurate diagnosis of the underlying cause is essential for appropriate management, as well as an understanding of severity and prognosis.

The clinician also measures attention span and the ability to concentrate in evaluating cognitive function. This is most often accomplished by asking the patient to do a short series of problems such as sequentially subtracting seven from 100, or three from 30. Insight tests determine the patient’s ability to recognize the importance of their illness or situation. When indicated, the clinician may also wish to test higher levels of intelligence. These tests evaluate the patient’s command of language, fund of knowledge, abstract reasoning, and judgment.

The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, (DSM-IV) provides a common language for mental health care practitioners to describe psychiatric disorders. (7) Common language is essential since there may be significant overlap in many diagnoses. The manual also provides the complete diagnosing criteria for each mental illness and the number of symptoms required to establish a diagnosis, as well as usual age of onset, clinical course, complications, predisposing factors, and prevalence. Another frequently used tool is the Mini-Mental Status Examination (MMSE), a 30-point series of test questions to measure cognitive function.

A discussion of cognitive function and the disorders that lead to loss of cognitive function includes a review of Alzheimer’s disease. Alzheimer’s disease is the most common cause of dementia, accounting for over 60 percent of all cases of late-life cognitive dysfunction. (8) Loss of memory is typically the patient’s presenting complaint. Minor memory loss, sometimes called age-associated memory impairment, is a common complaint associated with normal aging and is not a cause for concern. However, if minor memory loss affects social or occupational functioning, or is noticed by friends and coworkers, patients should be encouraged to visit a neurologist for formal evaluation. (9) Loss of memory as presented in patients with Alzheimer’s typically includes an inability to extract and use previously learned information, activity, and experience. Patients are generally disturbed with their inability to recall recent events, or with their disorientation with time.

Another cause of decreased cognition that should be mentioned is dementias that occur as the result of dietary deficiencies. (10) A lack of thiamine is known to produce Wernicke’s encephalopathy. Such a patient presents with malnutrition, confusion, ataxia, and diplopia. A severe lack of vitamin B12, folic acid or omega 3 fatty acids may cause, among other things, dementia due to damage to cerebral myelinated fibers. Deficiency of nicotinic acid (pellagra) and pyridoxine may cause spastic paraparesis, peripheral neuropathy, fatigue, irritability, and dementia. This syndrome has been seen in prisoner-of-war camps.

Toxicities known to produce dementias include narcotic poisoning, heavy metal intoxication, dialysis dementia (aluminum), and other organic toxins. Dementias associated with vitamin deficiencies or poisonings are potentially treatable.

Signs and Symptoms

[span class=alert]The following list does not insure the presence of this health condition. Please see the text and your healthcare professional for more information.[/span]

The most common symptom of decreased cognitive function is a loss of memory. While some memory loss occurs in the normal aging process, it is a gradual process and generally involves things like forgetting phone numbers, people’s names, or where objects have been placed. In dementia causing illnesses such as Alzheimer’s disease, the process continually worsens until the patient is unable to perform normal activities of daily living.

In the early stages, patients may seem inattentive or disoriented. Patients that become confused are generally subdued, not inclined to speak, and physically inactive. As the disease progresses, patients have increasing difficulty with memory, perception, comprehension, problem solving skills, language skills, praxis, visuospatial functions, and various aspects of emotional behavior. In the final stages of dementia producing illnesses, the patient may lose the ability to coordinate muscle movement for walking, control the bowel or bladder, and may lose the ability to chew or swallow.

General

    Memory loss Disorientation (impaired perception of time or direction, acquaintances, family, or self) Dysphasia (anomia, aphasia) Dyspraxia Impaired calculation Impaired judgment or problem solving skills Behavioral or emotional problems

Treatment Options

Conventional

There are two primary goals in the treatment of reduced cognitive function or dementia. The first is correction of any treatable underlying disorder. The second is to provide support and comfort to the patient and caregivers.

Treatment of underlying causes may include thyroid replacement in the hypothyroid patient, vitamin therapy for thiamine and B12 deficiency, antibiotics for opportunistic infections, ventricular shunting for normal-pressure hydrocephalus, and appropriate surgical, radiation, and/or chemotherapy for CNS neoplasms. (11) Removal of sedating or cognition-impairing drugs and medications is often beneficial.

Patients with dementias are often depressed as well. The antidepressants most often recommended that are low in cognitive side effects are selective serotonin reuptake inhibitors (SSRIs) and the tricyclic antidepressants lowest in anticholinergic activity (desipramine and nortriptyline). Medications that may reduce agitation and insomnia without worsening dementia include low-dose haloperidol, trazodone, buspirone, and propranolol.

The importance of non-drug behavioral therapy cannot be overemphasized. The goal is to make the patient’s life as uncomplicated, safe, and comfortable as possible. Education on the part of caregivers is essential.

Nutritional Supplementation


Vitamin C

Vitamin C is an antioxidant that reduces free radical damage in the body. Several studies with elderly subjects indicate that individuals who ingest higher amounts of vitamin C have better cognitive function, which suggests that vitamin C may protect against cognitive decline. (12) , (13) , (14)

The relation between cognitive function and risk of death from stroke suggests that cerebrovascular disease is an important cause of declining cognitive function. The results of one study involving 921 men and women indicated that vitamin C status may be a determinant of cognitive function in elderly people through its protective effect against atherogenesis. Thus, individuals who ingest higher amounts of vitamin C intake may gain protection against both cerebrovascular disease and cognitive decline. (15)


Vitamin E

Vitamin E is another antioxidant nutrient that reportedly protects against subsequent development of dementia and poor cognitive functioning. (16) Part of this effect is probably due to the role that vitamin E plays in protecting against free radical damage to the vascular system.

In an analysis of data from the Third National Health and Nutrition Examination Survey, it was reported that the amount of vitamin E per unit serum cholesterol is associated with memory performance. These results are consistent with the growing body of evidence that implicates vascular disease and vascular disease risk factors in age-related cognitive decline and Alzheimer's disease. (17)

A placebo-controlled, clinical trial of vitamin E in patients with moderately advanced Alzheimer disease was conducted by the Alzheimer's Disease Cooperative Study. Subjects in the vitamin E group were treated with 2000 IU (1342 alpha-tocopherol equivalents) vitamin E/d. The results indicated that vitamin E may slow functional deterioration leading to nursing home placement. (18) A new clinical trial is planned that will examine whether vitamin E can delay or prevent a clinical diagnosis of Alzheimer disease in elderly persons with mild cognitive impairment.


Vitamin B12

Cognitive impairment is an important manifestation of vitamin B12 deficiency. Cognitive decline due to low levels of vitamin B12 is a greater problem in elderly individuals since cobalamin deficiency increases with advancing age. Some researchers suggest that the cut-off point of serum concentration should be raised, because many elderly people with "normal" serum vitamin B12 concentrations are metabolically deficient in vitamin B12 as determined by levels of homocysteine and methylmalonic acid. (19)

One study investigated the effects of vitamin B12 supplementation on the cognitive function of demented patients with documented cobalamin deficiency. Despite cobalamin replacement, 16 of 19 patients persisted in showing progressive decline during follow-up visits (3 to 24 months). The authors of this study suggest that the lack of response to vitamin B12 replacement in most cases seems to reflect the presence of associated irreversible dementia. However, an important finding was the fact that all of the patients who showed some improvement (determined by Mini-Mental State Examination values returned to normal) had mild dementia with a history of less than 2 years. This underscores the importance of screening elderly individuals for B12 deficiency. Vitamin B12 supplementation in elderly individuals with recent onset of mild mental status changes may result in cognitive improvement and help slow down the onset of irreversible dementia. (20)

Another study investigated whether cognitive functioning is affected in adolescents (aged 10-16 y) with marginal cobalamin status as a result of being fed a macrobiotic diet up to an average age of 6 years. Control subjects performed better on most psychological tests than did macrobiotic subjects with low or normal cobalamin status. A significant relationship between test scores and cobalamin deficiency was observed for a test measuring fluid intelligence, which was more pronounced within the subgroup of macrobiotic subjects. These results suggest that cobalamin deficiency, in the absence of hematologic signs, may lead to impaired cognitive performance in adolescents. (21)


Acetyl-L-Carnitine (ALC)

Acetyl-L-carnitine is a nutritional compound that is structurally similar to acetylcholine and acts as a cholinomimetic agent. (22) It provides potential protection against neurodegeneration, and also shows promise as an adjunct in the treatment of Alzheimer’s disease due to its ability to promote the synthesis and release of acetylcholine. (23)

Acetyl-L-carnitine also plays a role in facilitating mitochondrial energy production and in removing toxins from the mitochondria. A new line of thinking in terms of the pathology of Alzheimer’s disease suggests that abnormal cellular energy production leading to cellular death. Thus, researchers speculate that acetyl-L-carnitine’s beneficial effects in patients with Alzheimer’s disease are not only due to its ability to stimulate the production of acetylcholine, but also are due to its ability to promote energy production and proper cellular functioning within the mitochondria. (24)

In a multicenter trial, 236 mildly impaired elderly patients were administered 1,500 mg of acetyl-L-carnitine daily for 150 days. The results indicated acetyl-L-carnitine treatment is effective against the outcomes of mental impairment in cognitive (in particular, for memory functioning and constructional thinking) and emotional-affective domains, while its effects on relational behavior are less consistent. (25)


Phosphatidylserine

Phosphatidylserine has been used to treat loss of memory and cognitive function in individuals with mild to moderate age-associated memory impairment. Phosphatidylserine is the most abundant phospholipid in the brain, and it plays critical roles in maintaining both the structure and functionality brain cells. Numerous studies have documented phosphatidylserine’s ability to improve memory, learning, concentration, word recall, and mood in middle-aged and elderly subjects with dementia or age-related cognitive decline. (26) , (27) , (28)


Docosahexaenoic Acid (DHA)

Docosahexaenoic acid is a member of the omega-3 family of fatty acids that is essential for proper growth and functional development of the brain in infants, and DHA is also required for maintenance of normal brain function in adults. The inclusion of plentiful DHA in the diet has been reported to improve learning ability, whereas deficiencies of DHA are associated with deficits in learning. Also, in adults, decreases in DHA in the brain are associated with cognitive decline during aging. (29)

In one study, infants receiving standard formulas were compared to a group of infants who received formulas supplemented with DHA for the first 17 weeks of their lives. Testing at 18 months of age revealed that the infants who had received formulas enhanced with DHA scored significantly higher in both cognitive and motor skills. (30) In Japan and many European countries, DHA is being added to infant formulas, but unfortunately, the United States is lagging behind in recognizing the importance of supplementing infant formulas with DHA to insure proper infant brain development. (31)


Zinc

Zinc is a trace metal that is present in the brain and contributes to its structure and function. A review of the scientific literature reveals limited evidence from animal and human studies suggesting that zinc deficiency may lead to delays in cognitive development. Although the mechanisms linking zinc deficiency with cognitive development are unclear, it appears that zinc deficiency may lead to deficits in children's neuropsychologic functioning, activity, or motor development, and thus interfere with cognitive performance. (32)


Iron

The prevalence of iron deficiency anemia (IDA) in industrialized countries has declined in recent decades, but there has been little change in the worldwide prevalence. IDA is currently estimated to affect more than 500 million people. Recent studies have indicated that anemia per se, the most common manifestation of iron deficiency, is less important from a public health standpoint than liabilities associated with tissue iron deficiency. Tissue iron deficiencies cause impairment in psychomotor development and cognitive function in infants and preschoolers, a deficit in work performance in adults, and an increase in the frequency of low birth weight, prematurity, and perinatal mortality in pregnancy. (33)


Iodine

It has been known for some time that iodine deficiency during pregnancy leads to poor cognitive function in the offspring. More recently, it has been determined that iodine-deficient school-age children perform worse than euthyroid children on reading and spelling and other general cognitive factors. (34)


Choline, Phosphatidyl Choline

Acetylcholine (Ach) is the primary neurotransmitter involved in memory and thought processes. Both choline and phosphatidyl choline (PC) can be used as nutritional precursors for the production of acetylcholine. However, studies using these acetylcholine precursors to improve cognitive function in patients with Alzheimer’s disease have had only limited success. (35) This may be due to the fact that too many of the cholinergic neurons have been destroyed before treatment is initiated.

Significant cognitive gains have been recorded using a combination of choline and a drug named piracetam. Piracetam is a cognitive enhancing drug with little known side effects that is available in over 85 countries throughout the world, but it has still not been approved by the FDA for use in the United States (however, many people order piracetam from overseas mail order companies). Based on results from animal experiments, (36) a group of researchers decided to test the effects of combined choline/piracetam therapy in patients suffering from Alzheimer’s disease. Subjects were treated for seven days with 9 gm of choline and 4.8 grams of piracetam per day, administered in three equally divided doses. All participants made some cognitive gains. However, during the evaluation period, it became apparent that approximately 30% of the patients had achieved dramatic clinical improvements—far greater than what had been observed with either choline or piracetam alone. For example, scores on one test showed a mean improvement of 70% in verbal memory retrieval. Based on these results, the lead author suggested that there may be a subgroup of patients suffering from Alzheimer’s disease that can gain substantial cognitive enhancement from the combination of choline and piracetam. (37)

Herbal Supplementation


Ginkgo

Ginkgo is among the oldest living species on earth and has been used extensively as a medicinal agent worldwide for centuries, and is the most frequently prescribed medicinal herb in Europe. The most dramatic benefits are reported in improving circulation in the elderly. (38) , (39) This can lead to enhanced memory, delaying the onset of Alzheimer's (40) and reducing senile dementia, (41) tinnitus, (42) and vertigo. (43) Ginkgo’s memory-enhancing effects are reported in younger populations as well. The main active components of ginkgo are the flavoglycosides. These compounds act as strong free radical scavengers or antioxidants. (44) Ginkgo is also reported to inhibit platelet activating factor (PAF) which could reduce the adhesive nature of platelets possibly through competitive binding. Ginkgo may foster vasodilation by stimulating endothelium releasing factor and prostacyclin. (45) It may also stimulate venous tone and improves the clearance of homotoxins during ischemic episodes. (46) Gingko reportedly acts as a tonic for the circulatory system. It may increase cerebral brain flow and, therefore, improve delivery of nutrients to the brain, enhancing elimination of the byproducts of cell metabolism and oxygenating the tissues. (47) Ginkgo may normalize acetylcholine receptors and, therefore, improve cholinergic function. (48)


Bacopa

Bacopa or water hyssop, is a plant used since approximately the sixth century A.D. in the traditional Ayurvedic Medical System of India as an extract with cognition-enhancing benefits. Termed "Brahmi" in the Hindu language sanskrit, bacopa is the foremost tonic for the nervous system in Ayurvedic medicine. It has been traditionally used for epilepsy, mental illness and to improve memory and mental capacities. (49) The saponin compounds (bacosides) are attributed with the capability to enhance nerve impulse transmission and thereby strengthen memory and general cognition. Bacopa was reported to increase learning ability in laboratory animals. (50) Clinically, bacopa has been reported to be a useful agent for improving intellectual behavior in children; in adults, bacopa has been reported to be effective in reducing anxiety levels, thereby allowing improved brain functioning in terms of memory enhancement and elevated mental performance. (51)

Bacopa is also reported beneficial in children. Traditionally it was used to anoint newborns with the hope of improving their intelligence, to "open the gate of Brahma" (Brahma being "creator" in the Hindu culture). Bacopa is still given in India to school age children for improving intellectual behavior. A single-blind trial in India was conducted to study the effects of bacopa on children (ages 6-8) and learning behavior. (52) Maze learning improved, as did immediate memory and perception and the reaction/performance times.


Panax Ginseng (Asian)

Asian ginseng is one of the most frequently purchased herbal supplement in the United States. Historically, it has been used for a variety of health benefits, especially for its adaptogenic and tonic effects for people fatigued or under stress. (53) Asian ginseng, or panax ginseng, is an adaptogen. It has a non-specific action on the functions of the body which increases its ability to cope with various stressors. These include physiologic, emotional and endogenic (external) toxins, thus reducing susceptibility to illness.

The chief constituents responsible for the activity of panax ginseng are the ginsenosides. There are over 20 saponin triterpenes in ginseng. The triterpenoid structure is similar to that of steroid hormones. It is thought that ginsenosides act at hormone receptor sites, especially in the hypothalamus and pituitary glands, stimulating secretion of adrenocorticotropic hormone (ACTH). (54) , (55) ACTH stimulates the production of adrenal hormones and other factors, leading to balance and regulation of the hypothalamic/adrenal axis which may have been influenced by stress.

The triterpenoidal saponins claimed to be responsible for much of the bio-activity of ginseng are chemically categorized as either diols or triols. The diols, or Rb-1 groups, are reported to have an ability to improve stamina and learning capacity, as well as sedative and blood pressure-lowering properties. American ginseng (Panax quinquifolius) contains more diols than panax, and may be more suitable for individuals who are coffee drinkers, overweight, on prescription drugs or with insomnia. The triols, or Rg-1 groups, reportedly raise blood pressure slightly in some instances and are mild central nervous system stimulants. Asian ginseng (Panax ginseng) contains more triols and may be more suitable for individuals who are non-hypertensive, athletes, fatigued or with high stress jobs.

Ginsenosides reportedly stimulate RNA, protein synthesis and cholesterol production in the liver. (56) They may also stimulate the production of precursors to adrenal hormones. Ginsenosides may increase hepatic rough endoplasmic reticulum and have carbohydrate-sparing and stamina-increasing activity in muscle tissues. They are also claimed to increase enzyme activity and fatty acid production.

Other components of panax ginseng, including glycans and adenosine, reportedly exhibit the ability to lower blood sugar in diabetic mice and yet have no effect on normally functioning lab animals. (57) Studies report that panax ginseng lowers cortisol levels in diabetics, having a positive benefit with regard to insulin regulation. In non-diabetic subjects, panax ginseng elevates cortisol levels - showing the "adaptogenic" effect of panax.

Panax ginseng may offer some positive benefits as a general tonic for improved stamina and overall health, especially for stressful conditions, fatigue, concentration, and recovery from illness.


Vinpocetine

The lesser periwinkle (Vinca minor) is a native of many parts of Europe, growing in woods and thickets. Isolated chemical constituents have been used in cancer therapy, as the chemotherapeutic drugs vincristine and vinblastine. Vinpocetine is chemically related to, and derived from vincamine, an alkaloid found in the periwinkle plant. Vinpocetine was introduced into clinical practice in Europe more than two decades ago for the treatment of cerebrovascular disorders and related symptoms. (58) , (59) , (60) , (61)

Early experiments with vinpocetine indicated five main pharmacological and biochemical actions: (62) (1) selective enhancement of the brain circulation and oxygen utilization without significant alteration in parameters of systemic circulation, (2) increased tolerance of the brain toward hypoxia and ischemia, (3) anticonvulsant activity, (4) inhibitory effect on phosphodiesterase (PDE) enzyme and (5) improvement of rheological properties of the blood and inhibition of aggregation of thrombocytes. Evidence has been obtained that neuroprotective action vinpocetine is related to the inhibition of operation of voltage dependent neuronal Na(+)-channels, indirect inhibition of some molecular cascades initiated by the rise of intracellular Ca(2+)-levels and, to a lesser extent, inhibition of adenosine reuptake. (63) Vinpocetine has been shown to be a selective inhibitor of Ca(2+)-calmodulin dependent cGMP-PDE. (64) It is assumed that this inhibition enhances intracellular a GMP levels in the vascular smooth muscle leading to reduced resistance of cerebral vessels and increase of cerebral flow. This effect might also beneficially contribute to the neuroprotective action. (65) , (66) The antioxidant effect of vinpocetine might contribute to the protective role exerted by the drug in reducing neuronal damage in pathological situations. (67)

Vinpoceptine has anticonvulsant action, possibly linked to its neuronal protective capacity and/or its modulation of several chemical transmitter systems. (68) , (69) In these respects vinpocetine resembles adenosine, thought to be a major endogenous anticonvulsant and cerebral protectant; Vinpocetine happens to be an effective adenosine re-uptake inhibitor. It increases cerebral metabolism and raises ATP levels in nerve cells, perhaps also raising neuronal excitability more directly by modulating cellular enzymatic control systems. (70) , (71)


Huperzine A

Huperzine A is an extract from a club moss (Huperzia serrata) that has been used for centuries in Chinese folk medicine for conditions such as blood loss, fever, as a diuretic and for irregular menstruation. (72) Modern science, especially in China, has focused on huperzine’s potential benefit in memory and learning, along with patients with Alzheimer's disease and dementia. (73) Huperzine A acts as an acetylcholinesterase inhibitor similar to, and potentially even more effectively than pharmaceutical agents such as tacrine. (74) , (75) , (76) The inhibition is reversible, selective and with a long duration of action. (77) Acetylcholine is involved in memory and learning, and by inhibiting the enzyme that breaks it down, more acetylcholine becomes available to stimulate neurons. With this pharmacology, huperzine A is a potential agent in treating Alzheimer's disease, a condition where there's a relative shortage of acetylcholine. (78) , (79)

Huperzine A has exhibited memory-enhancing activities in a broad range of animal cognitive model with effects similar to and potentially even more effective than the pharmaceutical acetylcholinesterase inhibitors such as tacrine. (80) , (81) Data indicates that huperzine A binds to the enzyme acylation site in the active site gorge but interferes slightly with the binding of peripheral site ligands. (82) Laboratory animals studies have reported improvement in impaired learning and memory. (83) , (84) Several human studies have been done over the past few years with huperzine A both in China and the United States. (85) , (86) , (87)

Clinical Lab Assessment

Some of the following laboratory testing can provide information necessary for diagnosis and treatment. In addition, the tests listed may also give insight to functional metabolism and functional nutrient status in the body.

Adrenal Function Profiles

Aging impacts the HPA axis through reduced responsiveness to glucocorticoid feedback inhibition. (88) Stress activates the HPA axis and has impact on the immune system, particularly through the adrenal hormones. In assessing the HPA axis, adrenal functional abnormalities are relatively simple to identify and address (e.g. when compared to hypothalamic dysregulation or pituitary imbalance).

Thyroid Profile

Aging is associated with the appearance of thyroid autoantibodies and subclinical hypothyroidism in elderly subjects with positive serum thyroid autoantibodies is prevalent. Thyroid autoantibodies are rare in healthy centenarians and in other highly selected aged populations, while they are frequently observed in unselected or hospitalized elderly. (89) Thyroid nodules do occur with increasing frequency in the elderly. (90) Early detection of subclinical hypothyroid function may enable a postponement of some symptoms of aging, such as loss of cognitive function.

Organic Acids

Certain biochemical intermediates reflect sufficiency of nutrient cofactors (vitamins of the B complex, magnesium, some amino acids, and many others) that are important in carbohydrate, neurotransmitter and fatty acid metabolism, among other vital functions. Stress response can deplete enzymes dependent on these cofactors for synthesis. Chronic stress may also interfere with proper digestion and result in increased allergic response (91) and imbalanced gastrointestinal flora. Deficiencies of biotin, (92) , (93) folic acid (94) , vitamins B1, (95) B2, (96) B6, (97) B12, (98) , (99) and C (100) have all been implicated in depression. Organic acids analysis is a cost-effective means of evaluating functional vitamin status for these nutrients through measurement of biochemical intermediates in urine. Organic acids analysis provides information relevant to the energy production cycle – a critical aspect of aging processes. (101) Sensitive assessment of B12 status is particularly important in the elderly. (102) Methylmalonic acid, an organic acid metabolite, is a reasonable sensitive marker for assessing functional levels of B12. A subset of organic acids, the dysbiosis markers, may provide useful information regarding gastrointestinal pathogens that can contribute to compromise of neurologic function resulting in loss of cognitive clarity. Animal studies demonstrate the reduction in intestinal function in aging populations, which may compromise nutritional sufficiency, (103) thus assessment of digestive function is reasonable even in the absence of symptomatology.

Cortisol

Increases in free plasma cortisol are associated with aging. (104) Low cortisol values are associated with various degenerative diseases that may advance the aging process. Plasma or salivary cortisol measurements may be used as markers in the evaluation of the aging process. Imbalances in the cortisol release rhythm may affect cognitive function.

Dehydroepiandrosterone (DHEA)

DHEA may have significance in the aging process. (105) Serum or saliva provides useful monitors of these values.

Fatty Acids

Dietary polyunsaturated fatty acids (PUFA) are primarily composed of w-3 and w-6 fatty acids. PUFA are vital in the production of eicosanoids – components involved in regulating inflammatory response, blood vessel leakage, lipid accumulation, immune cell response and optimal control of virtually every body tissue. (106)

Clinical Notes

Lead: Researchers studied toddlers with low-level lead exposure to determine whether adverse developmental effects were evident. The study sample consisted of a cohort of 68 children aged 12 to 36 months who had blood lead levels lower than 25 microg/dL on a routine screening in a large urban public hospital clinic. Children with blood lead levels between 10 and 24.9 microg/dL had a mean Mental Developmental Index (Bayley Scales of Infant Development, Second Edition) score that was 6.3 points lower than that of children with blood lead levels between 0 and 9.9 microg/dL. After adjusting for confounders, the difference was 6.2 points. The results of this study indicate that low level lead exposure in young children causes a reduction in cognitive performance. (107)

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