Porth's Essentials of Pathophysiology, 4e

949

Disorders of Brain Function

C h a p t e r 3 7

Pathology Alzheimer disease most often presents with a subtle onset of memory loss followed by slowly progressive demen- tia that has a course of several years. Evidence from familial forms of AD indicates that the accumulation of a peptide (amyloid beta or A β ) in the brain initiates a chain of events that result in the morphologic changes of AD and dementia. This peptide is derived from a larger membrane-spanning protein known as amyloid precur- sor protein (APP), which can be processed in either of two ways. It can be cleaved by the enzymes, α -secretase and γ -secretase, in a proteolytic pathway that prevents the formation of A β , or it can be cleaved by β -secretase and γ -secretase in a pathway that generates A β . 1 Diagnostic imaging of the brain reveals diffuse atro- phy of the cerebral cortex with enlargement of the ven- tricles (Fig. 37-18). The major microscopic features of Alzheimer disease include neuritic (senile) plaques , patches or flat areas composed of clusters of degenerat- ing nerve terminals arranged around a central amyloid core. In the cytoplasm of abnormal neurons are neuro- fibrillary tangles, which consist of fibrous proteins that are wound around each other in a helical fashion. These tangles are resistant to chemical or enzymatic break- down, and they persist in brain tissue long after the neuron in which they arose has died and disappeared. Smaller cerebral vessels also exhibit amyloid angiopa- thy, in which there is deposition of A β in vessel walls. Some plaques and tangles can be found in the brains of older persons who do not show cognitive impairment. The number and distribution of the plaques and tangles appear to contribute to the intellectual deterioration that occurs with Alzheimer disease. In persons with the disease, the plaques and tangles are found throughout the neocortex and in the hippocampus and amygdala,

with relative sparing of the primary sensory cortex. 1 Hippocampal function in particular may be compro- mised by the pathologic changes. The hippocampus is crucial to information processing, acquisition of new memories, and retrieval of old memories. Neurochemically, AD has been associated with a decrease in the level of choline acetyltransferase activity in the cortex and hippocampus. This enzyme is required for the synthesis of acetylcholine, a neurotransmitter that is associated with memory. The reduction in choline acetyltransferase is quantitatively related to the numbers of neuritic plaques and severity of dementia. It is likely that AD is caused by several factors that interact differently in different persons. Progress in the genetics of inherited early-onset AD shows that muta- tions in at least three genes—the APP gene on chromo- some 21; presenilin-1 ( PS1 ), a gene on chromosome 14; and presenilin-2 ( PS2 ), a gene on chromosome 1—can cause AD in certain families. 1,4 The APP gene is associ- ated with an autosomal dominant form of early-onset AD and can be tested clinically. Virtually all persons with Down syndrome (trisomy 21) exhibit the patho- logic features of AD as they age. Presenilin-1 and pre- senilin-2, both intracellular proteins, are components of γ -secretase and possibly part of a multiprotein complex containing the proteolytic site for breakdown of A β . A fourth gene, the apolipoprotein E (ApoE) gene, has been found to increase the risk of AD and lowers the age of onset of the disease. 4,68 The gene, which is found on chromosome 19, has three common alleles—E2, E3, or E4. Each person inherits one copy of the gene from each parent. An increased risk of late-onset and sporadic AD is associated with inheritance of the E4 gene, particu- larly if it is inherited from both parents. Conversely, the E2 gene may confer some protection. The age of onset in late-onset AD also correlates with the gene, with E4/E4

FIGURE 37-18. Functional imaging of the brain with positron emission tomography (PET). Perfusion and metabolism in a normal brain (A) and hypoperfusion and hypometabolism due to brain atrophy in a brain with Alzheimer disease (B) (From Alzheimer’s Disease: Unraveling the Mystery Images. National Institutes of Health, National Institute of Aging.) A B