Review and Commentary by Robert A. Anderson, MD
614 Daniels Drive NE East Wenatchee, Washington 98802 USA

Psychoneuroimmunoendocrinology is the term describing the unity of mental, neurological, hormonal and immune functions with its many potential applications. PNIE addresses the influence ofthe cognitive images of the mind (whatever its elusive definition) on the central nervous system and consequent interactions with the endocrine and immune systems. It encompasses several arenas, including but not limited to biofeedback and voluntary controls, the impacts of thought and belief on physiology, past and present effects of stress on mental, emotional and physical fimction, placebo effects, cumulative effects of social relationships on health and disease, and contiguous and remote impacts of "energy medicine" on one's own function and that of others. This column highlights the impact of cogent studies from these arenas on the understanding of holistic medicine in this new n Allennium.

Alzheimer's Disease and Cognitive Disorders

Stress and hippocampal function

Four,.12 and 18 month old rats were traine&for 6 months in a 2 way shuttle escape task inducing anxiety stress and elevated corticosteroid levels. After a recovery period of 3 weeks, under anesthetized conditions, hippocampal neurophysiological. aging markers were determined and brains then sectioned for determination of neuronal density in field CA1, a consistent marker for hippocampal aging. The two younger groups showed increased evidence of neurophysiological aging without neuronal loss (p=.005) and the older group showed no further age related physiological changes but exhibited significant neuronal cell loss (p<001). The aged stressed group showed significantly more decrease in hippocampal neuron density than controls (p<02). It appeared that a certain limit in physiological changes is reached, after which no further change is incurred; anatomical neuronal cellular loss, however, continued steadily. This suggests that 6 months of moderate daily stress accelerates functional as well as anatomical markers of hippocampal aging. If data are extrapolated to humans, chronic stress in the young and mid aged could alter neurophysiological mechanisms important for normal memory and cognition. In the aged, chronic stress may promote neurodegenerative changes.

Kerr DS et al. Chronic stress induced acceleration of electrophysiologic and morphometric biornarkers ofhippocampal aging. JNeurosci 1991 May; 11(5):1316 24.

COMMENT Greatly accelerated neuronal degeneration in Alzheimer's patients may occur in a subset of persons particularly susceptible to stress. Familial patterns have been shown with the presence of the E 4 allele of the apolipoprotein E genotype. This animal research published in 1991 has been followed with numerous human studies (see below) to demonstrate the neuronal loss that occurs with chronic stress and hyperadrenalcorticism. The mechanisms which operate to lead to neuronal damage are not all elucidated, but the evidence is sufficient to be able to emphasize the clinical importance of appropriate stress management practices for middle age and older adults, particularly those who may have a positive family history of Alzheimer's like dementia.

Memory loss in post traumatic stress disorder

This is a summary of animal and human research on neurological system effects of long term stress. High levels of glucocorticoids appear to destroy brain cells; animals with high levels of glucocorticoids suffer damage to the hippocampus, a gray matter brain area which is critically involved with memory and learning. An excessive level of stress in rodents leads to rapid hippocampal aging. Studies have also shown that Vietnam veterans with PTSD have an 8 20% reduction in hippocampal size. Depressed people as well have a markedly high level of glucocorticoids.

Sapolsky RM. Why stress is bad for your brain. Science 1996 Aug 9; 138(5276):749 50.

COMMENT. Therapists often wonder why treatment of PTSD is fraught with slow progress. Part of the answer to that puzzlement lies in this summary of the long term brain effects of stress and elevated corticosteroids. The hippocampus seems to be unusually susceptible to chronic elevated levels of corticosteroids, as emphasized in this review. This evidence allows therapists who bring to patients the tools to manage stress with lower levels of chronic adrenal hormones the right to lay claim on the primacy of what they are doing. Here is prevention in full flower. When patients learn to manage stressful situations while secreting lower levels of catecholamines and corticosteroids, they gain years to their lives and life to their years. Greater emphasis on acquisition of these skills is a legitimate goal in clinical practice and in medical education.

"Idea density"

Findings from the Nun Study indicate that low linguistic ability in early life has a strong association with dementia and premature death in late life. In this study, the relationship of linguistic ability in early life to the neuropathology of Alzheimer's disease and cerebrovascular disease was studied in a subset of 74 participants in the Nun Study for whom handwritten autobiographies completed some time between the ages of 19 and 37 (mean = 23 years) had been collected. An average of 62 years after writing the autobiographies, when the participants were 78 to 97 years old, they,died and their brains were removed for neuropathological studies. IAnguistic ability in early life was measured by the idea (proposition) density of the autobiographies, i.e., a standard measure of the content of ideas in text samples. Idea density scores from early life had strong inverse correlations with the severity of Alzheimer's disease pathology in the neocortex: Correlations between idea density scores and neurofibrillary tangle counts were (0.59 for the frontal lobe, (0.48 for the temporal lobe, and (0.49 for the parietal lobe (p < 0.0001). Idea density scores were unrelated to the severity of atherosclerosis of the major arteries at the base of the brain and to the presence of lacunar and large brain infarcts.

Snowdon DA et al. Linguistic ability in early life and the neuropathology ofAlzheimer's disease and cerebrovascular disease. Findings from the Nun Study. Ann N Y Acad Sci 2000 Apr; 903:34 38.

COMMENT: The "Nun studies" have appeared to connect the "idea density"theory with remote risk of later Alzheimer's like dementia. Low linguistic ability in early life may well reflect suboptimal neurological and cognitive development, which may increase susceptibility to the development of Alzheimer's disease pathology in late life. There is therefore some possibility that a greater reservoir of dendritic connections might take longer to disappear in old age. But until we know for sure, why not encourage children and juveniles to develop the largest fund of ideas, concepts, thoughts, and images possible. It makes for a much more interesting life, one would think. Isn't that what we expect our schools to help us do challenge children to develop a great depth of ideas in all fields of human interest?

Activity in mid life

This case control study involved 193 persons with possible or probable Alzheimer s dementia (AD) and 358 healthy controls. Information was obtained from spouses, friends and neighbors regarding the activities in which patients had been involved (including hours per month) in their 20s, 30s, 40s and 50s. Information on controls was obtained from the subjects and their spouses. Information was also obtained on possible confounding factors including smoking history, education, family history, medical history, medicine use, and diet; 26 potential non vocational activities were identified, and grouped in to intellectual, passive, and physical categories. End points of diversity, intensityand percentage intensity were developed and applied to each subject. Diversity meant the total number of activities. Intensity meant the sum total of monthly hours involved. Percentage intensity meant the total monthly hours involved in each activity divided by the total for all activities. AD subjects had a mean attained education level of 13 years versus 15.3 years of education for healthy controls (p<0.001). [Greater idea density?] Controls reported a mean of 16 activities compared to AD cases at 12.9 (p<0.001) after controlling for all variables. The OR for AD was 3.85 for those with activity totals below the mean (p<0.001). Controls also participated in a greater diversity of passive, intellectual and physical activities compared to AD cases (p<0.001). The OR for AD in low passive diversity was 2.51 (p<0.001); for low intellectual diversity 2.43 (p<0.001) and low physical diversity 2.67 (p<0.001). Intensity of activities was non significantly lower for AD patients vs. controls after controlling for variables. Holding other variables constant, a low percentage of intellectual activities in middle adulthood was a significant predictor of AD (p<0.05). Again controlling for variables, increases in the percentage of intellectual activities from young to middle age adulthood predicted a significantly lower risk for AD. Diversity and intensity of intellectual activities were reduced in AD patients v. controls. Friedland RP et al. Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control group members. Proc Natl Acad Sci USA 2001 Mar 31; 98(6):3440 45.

COMMENT: Inactivity might be a risk factor for Alzheimer's dementia or inactivity might be a reflection of extremely early subclinical harbingers ofAD. The distribution of positive findings through all four decades makes the latter possibility less likely. The theme continues: challenge in midlife with greater diversity of intellectual activities and indeed activities of any sort reduces risk for Alzheimer's dementia. In the following study, challenge during the retirement years also scored as important in reducing risk. So, in all three age ranges, challenge, including stimulation of all sorts but most importantly in the intellectual realm, scores very high on the essentials list.

Leisure activity

Of 1,772 non demented subjects over the age of 65, 207 became demented in 3 year followup. The risk of dementia was decreased 38% in subjects with 13 high leisure activities (RR, 0.62; 95% CI 0.46 0.83) categorized as intellectual, physical or social. The association of high leisure with decreased RR of dementia was present even after adjustment for baseline cognitive performance, health limitations interfering with desired leisure activities, cerebrovascular disease, and depression were considered.

Scarmeas N et al. Influence of leisure activity on the incidence ofAlzheimer's disease. Neurology 2001 Dee 26; 57(12):2236 42.

COMMENT' The data suggest that engagement in leisure activities. may reduce the risk of incident dementia, possibly by providing a reserve that delays the onset of clinical manifestations of the disease. Here is another why not. A reasonable observer would probably conclude that increased leisure activities would be more fun anyway. I suppose it would depend on the personality characteristics of the subject involved. I recently was told by a patient that his 80 some year old father occupied himself by watching the weather channel all the time! So there you are, the exception to the conclusion of this research. The right amount of stimulation and challenge would seem to be beneficial in reducing risk of dementia.

Managing Alzheimer's

Assisted walking and walking combined with conversation were compared to a conversation only intervention in nursing home residents with Alzheimer's disease; 65 subjects randomly assigned to treatment group were tested at baseline and end of treatment. Subjects'mean Mini Mental State Examination score was 10.83; mean age was 87. Treatment was given for 30 minutes three times a week for 16 weeks. Subjects in the assisted walking group declined 20.9% in fimetional mobility; the conversation group declined 18.8%. The combined walking and conversation treatment group declined only 2.5%. These differences in outcome were significant and appear to have been affected by differences in treatment fidelity. Subjects in the conversation treatment group completed 90% of intended treatment compared with 75% in the combined group and only 57% in the assisted walking group.

Failure to treat was due to subject refusal and physical illness. The conversation component of the combined walking and conversation treatment intervention appears to have improved compliance with the intervention, thereby improving treatment outcome. Results indicate that assisted walking with conversation can contribute to maintenance of functional mobility in institutionalized populations with Alzheimer disease. Staff assigned to this task should be prepared to use effective communication strategies to gain acceptance of the intervention.

Tappen RM et al. Effect of a combined walking and conversation intervention on functional mobility of nursing home residents with Alzheimer disease. Alzheimer Dis Assoc Disord 2000 Oct Dee; 14(4):196 201

COMMENT: Here we are again. Several options have a bearing on the outcome of a given disease. I was taught in medical training, totally erroneously, that there is usually a single cause for each single problem. Combination treatment with physical movement and conversation two different types of challenges had a better outcome and better compliance than either separately. The conversation influence may relate as well to research that shows that social isolation is a significant promoter of faster deterioration in several disease entities. The socially isolated would seem to have less opportunity to be stimulated by conversation. Perhaps we could also infer, based on other work, that conversation and walking would help in prevention as well as treatment ofAlzheimer'slike dementia.

Robert Anderson is a retired family physician. In mid career, his practice took on a more holistic nature as decades passed.

He has authored five major books, Stress Power! (1978), Wellness Medicine (1987), 7he Complete Self Care Guide to Holistic Medicine (1999) (co author), The Scientiftc Basis for Holistic Medicine, (5th edition) available from American Health Press,, and Clinician's Guide to Holistic Medicine (McGraw Hill, 2001).

Anderson is serving as the founding president of the American Board of Holistic Medicine, is a past president of the American Holistic Medical Association, former Assistant Clinical Professor of Family Medicine at the University of Washington, and currently Adjunct Instructor in Family Medicine at Bastyr University.

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