INTRODUCTION
Dementia is a syndrome or group of symptoms characterized by a loss of intellectual abilities severe enough to impair social or occupational functioning. Symptoms may include: loss of memory, impairment of judgment and abstract thinking, disturbances of higher brain functions affecting language, perception, and complex sequences of action (American Psychological Association, DSM III 1980). While many disorders may produce symptoms, Alzheimer’s disease (AD) is the most common cause of dementia in the elderly (Jorm, 1987). Assessing the prevalence of AD in the United States, Evans et al. (1990) estimated that in 1980 2.88 million or 11.3% of persons 65 and older were affected with probable AD. Using statistical methods to make predictions for the prevalence of AD in the United States population from 1990 through 2050, Evans et al. (1990) projected an AD population of: 3.75 million in 1990, 4.51 million in 2000, 6.99 million in 2030, and 10.2 million in 2050, of people age 65 and older. Projected costs to society are staggering. Huang, Cartwright, and Hu (1988) estimated the prevalence of AD in 1985 to be at 3.66 million in the United States. Based on this estimate, they calculated the cost to society as a result of this disease to be approximately $ 88 billion. Symptoms of dementia and AD will reach epidemic proportions in the year 2010 and beyond as the baby-boom generation ages (Jorm, 1987). With this in mind, it is imperative that society seek out and research ways in which to intervene with this devastating disease. One treatment with significant potential benefits in the fight against AD is the use of dietary supplements. The 1990’s have seen a dramatic increase in the sales and use of such supplements. A specific area of interest is the usage of a compound or supplement as a cognition enhancer in the young, or as a possible safeguard and/or treatment for dementia and AD. Frequently, these compounds and supplements are referred to as “Smart Drugs”. John Morgenthaler and Ward Dean, M.D., authors of "Smart Drugs and Nutrients," contend that the creative use of smart drugs represents an idea whose time has come. Morgenthaler believes that the popularity of this type of dietary supplemention stems from the aging of that monolithic demographic group, the baby boomers."There`s a lot more interest in diseases like Alzheimer`s," he said. "It goes along with the aging population. Baby boomers are 30-plus and are now cognizant of the fact that they are aging. They are noticing their memory is not as sharp as it was. And in the proper tradition of the baby boomers, they are interested in using drugs to fix it" (Horvitz, 1997). While the use of drugs and dietary supplements to enhance cognition may seem outlandish to some, American pharmaceutical companies are currently developing more than 140 types of smart pills in their laboratories, making them one of the top ten classes of drugs being researched (The Economist February 1991).Acetyl-l-carnitine (ALCAR) is one such promising compound and supplement available in health and nutrition stores. Carnitine occurs naturally in the diet, and is particularly found in animal products. It can also be synthesized endogenously from two essential amino acids, lysine and methionine (Bowman, 1992). ALCAR is the acetylated form of L-carnitine, both of which occur naturally in the body and play a vital role in the transportation of fats into mitochondria, as well as assisting in the production of acetylcholine (ACh) (Fritz, 1963), a neurotransmitter implicated in the loss of cognitive functioning in AD patients (Jorm 1987). Studies have shown that a large deficit occurs in cholinergic transmission in AD leading to the suggestion that this may be the primary cause of the disease (Parnetti, 1995). ALCAR has been shown to increase levels of dopamine in aged rats, (Sershen et al. 1991), as well as serve as a precursor for acetylcholine (Carta, Calvani, Bravi, & Bhuachalla, 1990), which is thought to play a major role in the etiology of AD (Parnetti, 1995). Acetylcholine is the most widely dispersed neurotransmitter in the human brain, with its pathways being known as cholinergic (Fisk, 1981). Addressing the changes seen in choline acetyltransferase (CAT) and ACh synthesis in AD, Sims and Bowen (1983) reported that there is a large reduction in the activity of CAT in the brains of postmortem AD patients. Following their discussion on AD, Sims and Bowen (1983) furthermore state that CAT is one of the enzymes responsible for the production of the neurotransmitter ACh which is greatly reduced in AD patients. Thus, an attempt to enhance ACh concentrations in AD by administration of a precursor may be of benefit. White and Scates (1991) examined ALCAR as a possible precursor of ACh. Their study explored the conditions under which ALCAR can serve as an effective precursor of ACh. The results of this study found that synthesis of ACh from ALCAR was demonstrated in vitro by coupling choline acetyltransferase (ChAT) and carnitne acetyltransferase (CarAT). This finding supports the rationale that ALCAR may serve as a neuroprotective agent in AD through the promotion of ACh synthesis and release (Calvani, Carta, Caruso, Benedetti, and Ianuccelli 1991).Studies have found ALCAR to be a promising tool in the treatment of age related learning and memory deficits found in both elderly human and animal subjects. Ghirardi, Milano, Rammacci, and Angelucci (1988) examining the effects of ALCAR on aged rats in a simple discrimination learning task (i.e.. lever pressing in the presence of a discriminative stimulus for reinforcement), found that rats treated with ALCAR exhibited a higher capacity for learning this task than controls. Barnes et al. (1990) looked at ALCAR and its effects on spatial learning and memory in aged rats, using both simple and complex mazes. Results indicated that the aged ALCAR treated rats showed greater accuracy in locating the position of an escape box than did the aged control rats. Additionally, ALCAR tended to improve memory in tasks that required an event to be remembered across several days. Examining the effects of ALCAR on old rats displaying a notably reduced learning capability, Ghirardi et al. (1992) found that senescent ALCAR treated rats performed significantly better than controls and were reminiscent of the performances exhibited by young rats. The results of this study led the researchers to report that ALCAR might be regarded as an agent capable of preserving old animals from the loss of learning and memory associated with aging.Recent research suggests that ALCAR may slow the progression of dementia in both aged rats (Ghirardi, Giuliani, Caprioli, & Angelucci, 1992) and humans (Spagnoli et al. 1991). Thal, et al. (1996) found that probable AD patients with an early age of onset tended to decline more slowly in response to treatment with ALCAR than those in a placebo group. ALCAR has also been shown to be useful in the treatment of dysthymia in the elderly. Bella, Biondi, Raffaele, and Pennisi, (1990) found a reduction in depressive symptoms leading to a higher quality of life in response to short term treatment with ALCAR. Examining the effects of ALCAR on young healthy participants, Lino et al. (1990) found that ALCAR improved reaction times as well as decreased the number of errors in the participant’s responses.While numerous studies have been conducted on animal and human subjects with age-related learning and memory deficits, there appears to be a paucity of studies (only one located) examining the effects of ALCAR on cognition in young healthy human participants with no known cognitive deficits. The current research will respond to this lack of information and examine the effects of ALCAR on memory and cognition using healthy college age participants. METHODS
Participants Thirty-nine university students were recruited for this research. Fifteen volunteered their time without compensation, with the remaining 24 being offered extra credit in their psychology classes. Students were briefed on ALCAR, its origins, and potential beneficial effects. This research used a Solomon four group design (Solomon, 1949), with varying degrees of time commitment for each group (see appendix A). After a brief presentation and synopsis of group requirements, four separate sign-up sheets were passed around psychology classes allowing volunteers to choose their level of time commitment to this experiment.Materials Materials for this research consisted of ALCAR 500mg capsules and placebo, both prepared and donated by Vitamin Research Products Inc. Cognitive testing was facilitated by the Cognometer, a computer software program designed to measure and analyze the brain’s memory, information processing speed, and efficiency. The Cognometer was donated to this research by Cognitive Diagnostics Inc. Design and Procedure A Solomon four group design (Solomon, 1949) controlled for pre/post-test, practice, and history effects. Groups were comprised of 11-10-10 and 8 participants respectively,and were treated in the following manner: Group one received a pre-test, two weeks of treatment with ALCAR 1000mg daily in two divided doses, followed by a post-test two weeks to the day after beginning their treatment. Group two served as a control group treated in the exact manner as group one, only differing by placebo treatment. Group three was not subjected to pre-testing and received ALCAR 1000mg twice daily for a two-week period, with testing on day 14 of the treatment. Group four was tested once only and received no treatment whatsoever. All students signed a waiver/consent form agreeing to participate as well as release the university and the experimenter from any liability with respect to the treatment or testing. Groups one through three received a written synopsis describing ALCAR and summarizing past research on its effects. Group assignment was strictly based on scheduling. Sign up sheets for each group were passed around psychology classes with available pre/post-test dates and times listed. Students were able to choose dates and times that fit their academic schedule. All participants were tested using the Cognometer tests number eight, six, and four, which are summarized directly from the Cognometer user manual as follows. Test eight measures delayed memory by the recognition of recently presented stimuli (with a span of up to several minutes in duration). By presenting a variety of stimuli items (e.g. words, pictures, faces, and paralogs) over a period of five minutes, and asking the participant to respond with either yes or no as to whether the current image has been displayed previously, test eight measures depth of memory as indicated by the length of time the presented stimuli can be carried in the participants short term memory (Reynolds, 1998). Test six examines immediate memory capacity and recall speed via recognition of just-presented stimuli. Participants were presented with either a set of symbols or letters which were immediately followed by a smaller number of the same item (i.e. symbols or letters). Participants were then asked to respond with a right or left mouse click indicating a yes or no as to whether the second presentation contained one or more of the items in the first presentation. Test six is interactive, increasing the amount of items presented with correct responses, until a memory threshold is reached. (Reynolds, 1998). Test four measures working memory speed and efficiency. “Test four is a complex cognitive choice test that measures long-term memory retrieval with working memory ‘executive’ inhibitory activity randomly called on (activated) via a rule altering cue” (Reynolds, 1998). Test four presents the participant with a word and picture combination, asking them to respond either yes or no with a right or left mouse click, as to whether the pair match. Intermittently throughout the test, a rule-altering cue will sound, signaling the participant to reverse their answer. Reynolds (1998), believes that this may be the most sensitive single measure of global cognitive status and subtle changes in status. Participants were tested in an enclosed office free of distractions. The experimenter gave each person written as well as verbal instructions for testing protocol. Prior to the actual recorded test, the Cognometer was set to demonstration mode and the students were asked to read the instructions on the computer screen and go through the tutorial. An abbreviated version of the actual test followed. This procedure was used to insure that all participants had a concrete understanding of each task. After completing the demonstration run, the experimenter would set the Cognometer to testing mode; enter the person’s name, date of birth, and instruct the participant to again do the brief tutorial to reacquaint themselves with each test. After completing the test, participants were given a written reminder of their re-test date (groups one and two). Post-testing of groups one and two required only a review of the tutorial in testing mode prior to the recorded test. RESULTS AND DISCUSSION
ResultsStatistical analyses found no significant effect for pre-test influence on post-test scores. The results of a t test and ANOVA indicated that ALCAR had no significant effects on memory or cognition. However, an examination of combined group means (i.e. combining of treatment and control groups post-test / treatment scores) found a definite trend for the treatment group to out-perform the controls on 83% of the dependent measures. A two-way sign analysis of this trend suggests a significant finding with p < .05. DiscussionThe idea that we may be able to enhance our cognitive abilities through dietary supplementation is fascinating. While past research examining the effects of ALCAR on memory and cognition have suggested this, the results of the current trial were non-significant. A possible reason for the lack of a desired effect may have been due to the short length of the treatment period and small sample size. Previous research on the elderly has suggested a treatment period of at least six months. The shortest treatment period found in the literature reporting significant results with the elderly suffering from dementia is eight-weeks (Sano et al 1992). Furthermore, the only trial found by this author to examine the effects of ALCAR on cognition in the young, reported a treatment period of four-weeks (Lino et al. 1990). Although the results of this study were non-significant, the trend for the treatment group to out- perform the controls on the majority of the dependent measures prompts this researcher to speculate about methodological criteria that may have played a role in the lack of desired effect. While a larger sample with a longer treatment period would have been desirable, financial restrictions and time constraints did not allow for this. Future research in this area should consider a treatment period of no less than four-weeks, with periodic testing (e.g. weekly) to allow the researcher to follow and document any change on the dependent criteria. REFERENCES
References American Psychiatric Association, (1980). Diagnostic and statistics manual of mental disorders, 3rd ed. DSM-III. Division of Public Affairs, American Psychiatric Assoc., Washington, DC. Barnes, C. A., Markowska, A. L., Ingram, D. K., Kametani, H., Spangler, E. L., Lemken, V. J., & Olton, D. S. (1990). Acetyl-l-Carnitine 2: Effects on Learning and Memory Performance of Aged Rats in Simple and Complex Mazes. Neurobiology of Aging, 11, 499-506. Bella, R., Biondi, R., Raffaele, R., & Pennisi, G. (1990). Effect of acetyl-l-carnitine on geriatric patients suffering from dysthymic disorders. International Journal of Clinical Pharmacological Research, 6, 355-360.Calvani, M., Carta, A., Caruso, G., Benedetti, N., & Ianuccelli, M. (1991). Action of acetyl-l-carnitine in neurodegeneration and Alzheimer’s disease. Annals New York Academy of Sciences, 483-486. Evans, D. A. (1990). Estimated prevalence of Alzheimer’s disease in the United States. The Milbank Quarterly, 68 ( 2), 267-289. Fritz, I. B. (1963). Carnitine and its role in fatty acid metabolism. Adv. Lipid Research, 1, 285-334 Ghirardi, O., Milano, S., Ramacci, T., & Angelucci, L. (1988). Effect of acetyl-l-carnitine chronic treatment on discrimination models in aged rats. Physiology and Behavior, 44, 769-773. Ghirardi, O., Milano, S., Ramacci, T., & Angelucci, L. (1989). Long-term acetyl-l carnitine preserves spatial learning in the senescent rat. NeuroPsychopharmacological and Biological Psychiatry, 13, 237-245. Ghirardi, O., Giuliani, A., Caprioli, A., M. T., Ramacci, & Angelucci, L. (1992). Spatial Memory in Aged Rats: Population Heterogeneity and Effect of Levocarnitine Acetyl. Journal of Neuroscience Research, 31 375-379.Ghirardi, O., Giuliani, A., Caprioli, A., Milano, S., Giuliani, A,. Ramacci, M. T., & Angelucci, L. (1992). Active avoidance learning in old rats chronically treated with levocarnitine acetyl. Physiology and Behavior 52, 185-187.Huang, L.F., Cartwright, W. S., & Hu, T.W. (1988). The Economic Costs of Senile Dementia in the United States, 1985. Public Health Reports 103, 3-7.Jorm, A.F. (1987) A Guide to the Understanding of Alzheimer’s Disease and Related Disorders. New York University Press, Washington Square New York. Parnetti, L. (1995). Clinical Pharmacokinetics of Drugs for Alzheimer’s Disease. Clinical Pharmacokinetic, 29, (2), 111-128.Reynolds, J. (1998). Cognometer User ManuelSershen, H., Harsing, L. G., Bana-Shwartz, M., Hashim, A., Ramacci, M. T., & Lajtha, A. (1991). Effect of Acetyl-l-Carnitine on the Dopaminergic System in Aging Brain. Journal of Neuroscience Research 30, 555-559. Sims, N. R., & Bowen, D. M. (1983). Changes in choline acetyltransferase and in acetylcholine synthesis. In B. Reisberg (Ed. ), Alzheimer’s disease (pp. 88-91). New York: The Free Press.Spagnoli, A., et al. (1991). Long term acetyl-l-carnitine treatment in Alzheimer’s disease. Neurology, 41, 1726-1732. Thal, L.J., et al., (1996). A 1-Year Multicenter Placebo-Controlled Study of Acetyl-L-Carnitine in Patients with Alzheimer’s Disease. Neurology 47, 705-710.Ward, D., Morgenthaler, J., & Fowkes, S. (1993) Smart Drugs II The Next Generation. Health Freedom Publications, Petaluma Ca. White, H.L., & Scates, P. (1990). Acetyl-L-carnitine as a precursor of acetylcholine. Neurochemical Research, 15 (6), 597-601. The psychology department of Hamline University would like to thank Cognitive Diagnostics and Vitamin Research Products Inc. for their donations in support of this research. APPENDIX 1
Appendix A Solomon Four Group Design Group One, Eleven ParticipantsPre-test, two-week TX/ALCAR, Post-test Group Two, Ten ParticipantsPre-test, two-week TX/placebo, Post-test Group Three, Ten ParticipantsTwo-week TX/ALCAR, Post-TX-test Group Four, Eight ParticipantsNo TX, test only CONTACT INFORMATION
For copies of SPSS printouts or graphs, please contact: Derek Rohdedrohde01@msn.com |
