The adjective degenerative has no great appeal to the modern physician. The term originated with the discredited concept from past centuries of the heritability of “degenerate” personal characteristics. It currently implies a large group of disorders that are characterized by n inexplicable decline from a previous level of normalcy to a lower level of function. It would be tempting to attribute all progressive diseases of the nervous system that are of unknown cause to degeneration. This is certainly not the case as at least some of the molecular and cell-biologic mechanisms of degenerative diseases are now known, and a proportion is caused by germ line genetic changes. All are currently called degenerative, but this is a transitional method of holding a place while awaiting more refined understanding.
The principle behind what is currently called degenerative disease of the nervous system is a pattern of progressive neuronal loss in functionally related cells such as those of the basal ganglia, cerebellum, cerebral cortex, and so on. Therefore, one identifying feature of degenerative disease is their tendency to affect restricted and often related areas of the nervous system; that is, most are “system disorders.” These diseases can be identified clinically by a more or less smoothly progressive loss of neurologic function referable to the affected system, for example, parkinsonian features, ataxia, or dementia. Many of these diseases are characterized by the accumulation of abnormal deposition of proteins. What is lacking at the moment is a precise subcellular mechanism for cellular loss; knowledge that a protein aggregates within or between cells, a characteristic of many degenerative disorders, is not equivalent to understanding the cause of an illness. Degeneration is also used as a pathologic term that refers to a process of neuronal, myelin, or tissue breakdown, the degradative products of which evoke a reaction of phagocytosis and cellular astrogliosis but usually with minimal or no inflammation.
Gowers, in 1902 suggested the term abiotrophy to encompass degenerative diseases, by which he meant a lack of “vital endurance” of the affected neurons, resulting in their premature death. This concept embodies an unproven hypothesis—that aging and degenerative changes of cells are based on the same process. Understandably, contemporary investigators are reluctant to attribute to simple aging the diverse processes of cellular diseases that are constantly being revealed by ultrastructural and molecular genetic techniques. It is increasingly evident that many of the diseases included in this category depend on genetic factors. Even more diseases, not differing in any fundamental way from the degenerative ones, occur sporadically, but still, genetic factors such as single nucleotide polymorphisms and copy number variations are often involved in pathogenesis, even if only as predispositions to the disease.
As mentioned above, the central concept that has been introduced in degenerative neurological disease is that certain types of protein deposition in the brain are toxic to neurons. Amyloid, tau, and synuclein are most often cited as implicated ...