Table 23.3 Features of the Major Neurodegenerative Diseases which serve as histologic hallmarks of specific disorders
Table 23.3 ). Aggregates may arise because of mutations that alter the protein’s conformation or that disrupt pathways involved in processing or clearance of the proteins. In other situations, there may be a subtle imbalance between protein synthesis and clearance (due to genetic, environmental, or stochastic factors) that allows gradual accumulation of proteins. The aggregates often are resistant to degradation by normal cellular proteases, accumulate within cells, elicit an inflammatory response, and may be directly toxic to neurons. As is evident from
Table 23.3 , the same proteins may be present as aggregates in multiple diseases. The clinical phenotype of the neurodegenerative disease is determined more by the distribution of the aggregates than by the nature of the aggregating protein.
Two other features are common to many neurodegenerative diseases:
There is experimental evidence that many of the protein aggregates that accumulate in neurons affected in these diseases appear to be capable of spreading to healthy neurons. Thus, aggregates can seed the development of more aggregates, and the disease process can spread, like prions. However, there is no evidence for transmission from affected to healthy individuals.
Activation of the innate immune system is a common feature of neurodegenerative diseases. The importance of this interaction between the brain and the immune system has been further strengthened by the identification of genes that confer risk for diseases (e.g., TREM2 for Alzheimer disease) that encode components of immune regulatory pathways.
Alzheimer disease (AD) is the most common cause of dementia in older adults, with an increasing incidence as http://ebooksmedicine.net a function of age. The incidence is about 3% in individuals 65 to 74 years of age, 19% in those 75 to 84 years of age, and 47% in those older than 84 years of age. Most cases of AD are sporadic, but at least 5% to 10% are familial. Sporadic cases rarely present before 50 years of age, but early onset is seen with some heritable forms.
The disease usually manifests with the insidious onset of impaired higher intellectual function, memory impairment, and altered mood and behavior. Over time, disorientation and aphasia, findings indicative of severe cortical dysfunction, often develop; those in the final phases of AD are profoundly disabled, often mute and immobile. Death usually occurs from intercurrent pneumonia or other infections.
The fundamental abnormality in AD is the accumulation of two proteins (Aβ and tau) in specific brain regions, in the forms of plaques and tangles, respectively; these changes result in secondary effects including neuronal dysfunction, neuronal death, and inflammatory reactions. Plaques are deposits of aggregated Aβ peptides in the neuropil, while tangles are aggregates of the micro-tubule binding protein tau, which develop intracellularly and then persist extracellularly after neuronal death. Both plaques and tangles appear to contribute to neural dysfunction. The details of the interplay between the processes that lead to the accumulation of these abnormal aggregates are a critical aspect of AD pathogenesis that has yet to be unraveled.
Clinical and experimental evidence strongly suggests that Aβ generation is the critical initiating event for the development of AD. Notably, mutations or alterations in copy number of the gene encoding the precursor protein for Aβ are associated with an elevated risk of AD, whereas mutations in the gene for tau do not give rise to AD but rather cause frontotemporal lobar degenerations. Overexpression of Aβ can replicate the disease in animal models.
The pathogenesis of AD involves Aβ and Tau deposits, as well as other risk factors and inflammatory reactions.
• Role of Aβ. Aβ is created when the transmembrane protein amyloid precursor protein (APP) is sequentially cleaved by the enzymes β-amyloid–converting enzyme (BACE) and γ-secretase (