RETROGENESIS

Retrogenesis is the reversal of normal developmental biologic processes during the course of disease. The retrogenic process has been described clearly for the brain diseases known as the dementias. The most common form of dementia is Alzheimer’s disease (AD), and retrogenesis has been demonstrated in striking detail in this common disorder of the elderly.

It is well established that normal human growth and development is marked by a series of landmarks. The most evident landmarks of human development are known as functional landmarks, representing the time course of acquisition of normal abilities. These functional landmarks are illustrated in Table 1. They begin with the ability of infants to hold up their heads independently, and proceed to the acquisition of the capacity to smile, to sit up, to walk, to speak, to toilet independently, to bathe, to dress, to manage money, and to hold a job. Studies have shown that the loss of these abilities in AD progresses in precisely the reverse order.

When the course of Alzheimer’s disease differs markedly from the retrogenic functional pattern, the differences are often the result of other illnesses or conditions, which add to the disability of an AD patient. For example, arthritis or a hip fracture can cause an elderly person with AD to prematurely lose the ability to walk. This excess disability may add to the AD patient’s functional downhill course.

Interestingly, not only does the order of functional losses in AD mirror that of normal human development, but, to some extent, the course of functional losses in AD mirrors the course of the acquisition of the same functions until the final, seventh stage of AD, which corresponds to infancy. For example, the average Alzheimer’s patient regresses from the loss of ability to select clothing properly (in the beginning of functional stage 5) to double incontinence (in functional stage 6e) over approximately the same three to four year interval as a child develops from the acquisition of fecal continence at about two to three years of age to the acquisition of the ability to pick out clothing independently at about five to seven years of age. Similarly, just as the ability to dress and bathe independently are acquired at about the same time in normal child development, these abilities are lost at almost the same time in the degenerative course of AD.

The time course similarities do not hold for the final, seventh stage of AD, however. During this stage, functions that are acquired in infancy over only about a year-and-a-half are lost over many years in the course of progressive AD. Despite these differences, the overall temporal similarities between development and Alzheimer’s degeneration are remarkable. The total developmental time from birth to young adulthood is approximately twenty years, approximately the same as the total degenerative course of AD, from the earliest clinically manifest symptoms of AD at the beginning of stage 3, to the final 7f stage, when patients can no longer hold up their head independently.

In Alzheimer’s disease, not only do functional losses follow a retrogenic pattern of loss of capacity, losses of language abilities and general thinking abilities also follow a retrogenic pattern of loss. For example, studies have shown approximately the same relationship between a general mental-status measure of Alzheimer’s degeneration and the retrogenic progression of functional losses in Alzheimer’s disease as is seen between the mental age of children and scores on the same mental-status examination.

Because of the strong retrogenic relationships, in terms of both thinking ability and functioning, it is useful to translate the stages of Alzheimer’s into corresponding developmental ages. The developmental age of the Alzheimer’s patient provides very useful information about the patient. For example, certain involuntary motor responses that are present in infants, the so-called infantile neurologic reflexes, emerge in the Alzheimer’s patient at the developmental age-appropriate point. These infantile reflexes include the so-called sucking reflex and grasping reflex. Furthermore, the developmental age of the Alzheimer’ patient provides an accurate and useful index of the overall care and management needs of an Alzheimer’s patient. For example, an Alzheimer’s patient in stage 5, which corresponds to a developmental age of five to seven years, requires about the same amount of care as a five to seven year old. Similarly, an Alzheimer’s patient in stage 7, corresponding to an infantile developmental age, requires about the same amount of care as an infant.

Despite the general care and management implications of the developmental age model of the stages of Alzheimer’s, important differences between Alzheimer’s patients at each stage and their developmental age ‘‘peers’’ must be noted. For example, Alzheimer’s patients do not undergo a physical regression. Consequently, a stage 7 Alzheimer’s patient is much larger and stronger than an infant. Therefore, the stage 7 Alzheimer’s patient’s grasp reflex is stronger than an infant’s, and an Alzheimer’s patient can be much more difficult to care for and keep clean and hygienic than an infant. Also, Alzheimer’s patients have a history of learned skills and behaviors that infants lack. Consequently, Alzheimer’s patients late in stage 7 may on occasions utter seemingly forgotten words. It is also important to note that, like children, dignity is important for the Alzheimer’s patient, and neither the child nor the Alzheimer’s patient wishes to be humiliated or ‘‘infantilized.’’ A ten-year-old child would be infuriated and humiliated if treated like a four year old, and a stage 4 Alzheimer’s patient would be similarly infuriated and/or humiliated if treated like a stage 6 Alzheimer’s patient. Because of appropriate concerns regarding dignity, Alzheimer’s patients should be treated at all stages as adults with the mental and functional capacity of their corresponding developmental age. This melding in terms of treatment is termed the science of Alzheimer’s management.

The developmental age of the Alzheimer’s patient can be useful in assisting in understanding other aspects of the disease. For example, the developmental age also indicates the nature of some of the emotional changes seen in the Alzheimer’s patient. Wrong beliefs (so-called delusions) frequently occur in stage 5 and 6 Alzheimer’s patient’s. These wrong beliefs are similar to the fantasies seen in children at a corresponding developmental age (two to seven years).

Interestingly, the remarkable retrogenic relationships noted in Alzheimer’s patients are sometimes observed, to a greater or a lesser extent, in non-Alzheimer’s forms of dementia. For example, the order of loss of function in some patients with non-Alzheimer’s dementias is sometimes the same as in Alzheimer’s disease. In these cases, the reflex changes and emotional changes noted may be the same as those at the corresponding stage of Alzheimer’s disease, and, consequently, mirror the changes at the corresponding developmental age. However, the time-course retrogenic similarities generally do not apply in non-Alzheimer’s dementias.

Why do these retrogenic relationships occur in dementing disorders? One possible explanation is that the white matter covering the axonal processes extending out from the nerve cells is injured in retrogenic dementias such as Alzheimer’s. This white matter, known as myelin, is continuously produced throughout life and appears to protect the axon. A functional pathway is dependent upon this myelination process. The functional pathway may become stronger as myelin is produced over the years. The newer functional/axonal myelin pathways are the thinnest, and are probably also the most vulnerable to degenerative processes such as Alzheimer’s. Myelin vulnerability—based upon the thickness (age) of this protective sheath—may also be a factor in traumatic processes that produce other retrogenic dementias, such as lack of oxygen from a stroke.

Barry Reisberg Guarav Gandotra Sunnie Kennedy Emile Franssen

See also Alzheimer’s Disease; Brain; Language Disorders.

BIBLIOGRAPHY

Reisberg, B. ‘‘Dementia: A Systematic Approach to Identifying Reversible Causes.’’ Geriatrics 41, no. 4 (1986): 30–46.

Reisberg, B. ‘‘Functional Assessment Staging (FAST).’’ Psychopharmacology Bulletin 24 (1988): 653–659.

Reisberg, B.; Kenowsky, S.; Franssen, E. H.; Auer, S. R.; and Souren, L. E. M. ‘‘President’s Report: Towards a Science of Alzheimer’s Disease Management: A Model Based upon Current Knowledge of Retrogenesis.’’ International Psychogeriatrics 11 (1999): 7–23.

Reisberg, B.; Franssen, E. H.; Hasan, S. M.; Monteiro, I. Boksay, I.; Souren, L. E. M.; Kenowsky, S. Auer, S. R.; Elahi, S.; and Kluger, A. ‘‘Retrogenesis: Clinical, Physiologic and Pathologic Mechanisms in Brain Aging, Alzheimer’s, and Other Dementing Processes.’’ European Archives of Psychiatry and Clinical Neuroscience 249, supp. 3 (1999): 28–36.