Sherri B. Tomkowiak, M.D.
Resident in Adult Psychiatry at Southern Illinois University, Springfield, IL
Robert J. Pary, M.D.
Associate Professor of Psychiatry, Southern Illinois University, Springfield, IL
The Habilitative Mental Healthcare Newsletter
January/February 1995, Vol. 14, No. 1.
© 1995 Pysch-Media, Inc.
Reprinted with permission of Psych-Media, Inc., publishers of Psychiatric Aspects of Mental Retardation Reviews, Habilitative Mental Healthcare Newsletter, and the journal Mental Health Aspects of Developmental Disabilities.
Editor-in-Chief: Anne D. Hurley, Ph.D
P.O. Box 57
Bear Creek, NC 27207-0057
Fax: (336) 581-3766
To better understand why a connection between Down syndrome and AD has been proposed, it is necessary to review the neuropathological changes that occur with both disorders. Although AD is frequently diagnosed clinically, it can only be diagnosed with reasonable certainty after death by autopsy based upon the presence of a minimum number plaques, neurofibrillary tangles, and neuronal loss in a microscopic inspection of brain tissue. Unfortunately, even after death, the diagnosis is not always reliable because other brain pathology can fulfill histologic criteria for AD, and, some patients, who meet the neuropathological criteria for AD, may have had no clinical symptoms of dementia at the time of death.
Plaque formation in the brain is currently being studied in order to elicit the progression of AD pathology from the earliest insult to the later onset of clinically significant disease. The full story remains unclear, but there is a general agreement that amyloid production is an important factor in plaque formation and the progression of the disease.
Amyloid is composed of amyloid beta protein (90%), thought to be of neuronal origin by some, and a variety of other proteins. The synthesis of amyloid beta protein involves amyloid beta protein precursor (aBPP), a protein that may have trophic or toxic effects on neurons.11 Its gene is encoded on chromosome 21 and the extra 21st chromosome associated with Down syndrome may result in too much aBPP being produced. Some investigators speculate that an imbalance between the amount of amyloid BPP produced and the brain's ability to degrade it may cause the earlier onset of development of plaques.
Plaques found in the brains of persons with AD and those with Down syndrome consist of two different types - classical (neuritic) and diffuse. Classical plaques consist of several microglial cells surrounding a center core of amyloid that is fibrillized. This kind of plaque is associated with the presence of degenerating and dystrophic neurites (axons and dendrites). Diffuse plaques, on the other hand, contain amyloid deposits with few, if any, amyloid fibrils or abnormal neurons.
The process of formation and disintegration of neurological plaques remains controversial. It is believed that amyloid fibril deposition may initiate pathological changes such as degeneration of the neuron.2 These changes may be due to compression or trophic/toxic effects of either the amyloid, proteins associated with the amyloid, or both. Some investigators believe that diffuse plaques are an early form of classical plaques with amyloid precursor rather than true amyloid. Others think that they are an end stage with advanced removal of amyloid deposits and degenerating neurons.11 Current research gives more credence to the first hypothesis. The deposition of amyloid beta protein in nervous and vascular tissue is known to be an early event in AD, but the appearance of amyloid fibrils seems to be the initiating pathological change in the neurons. It is not known why some plaques fibrillize and others do not, but it is theorized that fibrillization may take place readily only in association with cells that produce not only amyloid but chaperone proteins that provide an environment conducive to fibrillization.11
A person with Down syndrome may have a long period of time when only diffuse plaques, containing amyloid deposits without fibrillization, are formed and therefore no neuronal degeneration occurs. Furthermore, diffuse plaques are not found exclusively in persons with Down syndrome. They are also present in AD (along with classical plaques) and in the brains of nondemented elderly. They also occur in persons who have sustained a head trauma, critical coronary disease, and other disease processes. The key concept is that both types of plaques may appear in the same individual at the same time, but only classical plaques appear to affect the structure and function of nervous tissues.
Neurofibrillary tangles are another feature of a diagnosis of AD. They were initially described by Alzheimer who described three stages - early, mature, and end. Although they are best known as a sign of AD, they are found in other conditions such as postencephalopathic Parkinson's disease, dementia pugilistica, Hallervorden-Spatz disease, and a few others.7 This suggests that tangle formation may be a common pathologic response to several different insults but not a common pathway for all types of brain injury.11 Bugiani and Giaccone1 found a connection between the presence of neurofibrillary tangles and a higher percentage of plaques with degenerating neurons. In the absence of neurofibrillary tangles, diffuse plaques are most commonly found.3
Several studies have discussed apparent age-dependent pattern of plaque formation in both persons with Down syndrome and without Down syndrome. A study of 44 persons with Down syndrome by Wisniewski, Wegiel, and Popovitch found that, in the younger population (ages 15- 40), there was a predominance of diffuse plaques and an absence or minimal presence of classical plaques. After age 40, classical plaques were found. The increase in numerical density of all plaques, but especially classical plaques, showed a strong correlation with age. Impairment of function in this study was related to appearance and increase in numbers of classical plaques.11 Another study by Popovitch and Wisniewski studied persons with mental retardation, but without Down syndrome. They found that the development of classical plaques is a slow process active over the course of several decades.7 They studied 385 patients and found some neurofibrillary tangles or plaques in 33% of those younger than 45, 56.8% in the 45-65 age group, and in 78% of those over 65.
The presence of diffuse plaques in younger subjects suggests that they may develop faster than classical plaques. One study showed that after trauma (6-18 days) diffuse plaques were found in 38% of patients with head injury.8 Persons with Down syndrome have a higher incidence of plaques than normal controls even at a young age (although these are almost all diffuse plaques) which results in the number of total plaques present in the elderly persons with Down syndrome being higher than in elderly controls.11
Classical plaques have been found to increase with age in many studies but neurofibrillary tangles seem to have a more complex relationship with age.9 Clinical implications of this are uncertain at this time.
A great deal of information is now available about neurofibrillary tangles and plaques, but the fundamental question to be addressed is the clinical meaning of these findings. Does the presence of plaques mean dementia? There have been conflicting reports. Younger persons with Down syndrome may have many diffuse plaques but not clinical dementia. Many elderly patients also have multiple diffuse plaques without exhibiting dementia. It is estimated that 15- 30% of persons with Down syndrome who are over 40 years develop dementia, but this number is difficult to substantiate given the special problems in diagnosing dementia in this population. Dementia is not easily detected in persons with Down syndrome. Nevertheless, one also does not want to conclude that a person has dementia without a vigorous search for potentially reversible causes such as major depression or hypothyroidism.
Several ongoing studies may give us more information and an earlier ability to detect plaques in the future. Many of these studies are looking at proteins and proteoglycans associated with amyloid. A study by Snow et al10 looked at heparin sulfate, which is a proteoglycan, present in amyloid deposits. It was present in abnormal locations and quantities in all Down syndrome patients studied, including several children, one as young as 1-day-old.10 This may be one of the earliest markers of accumulation of amyloid that could ultimately contribute to formation of not only diffuse plaques but possibly classical plaques. Yet, individuals such as Lucille Viola Klein are proof that some persons with Down syndrome live well over the age of 80 years without evidence of clinical dementia.