A striking feature of these disease processes is their specificity for particular types of neurons. In PD there is extensive destruction of the dopaminergic neurons of the substantia nigra; neurons in the cortex and many other areas of the brain are unaffected. In contrast, neural injury in AD is most severe in the hippocampus and neocortex, and even varies dramatically in different functional cortical regions. In HD, the mutant gene responsible for the disorder is expressed throughout the brain and in many other organs, yet the pathological changes are most prominent in the neostriatum. In ALS, there is loss of spinal motor neurons and the cortical neurons that provide their descending input. Currently, the processes of neural injury are viewed as the interaction of genetic and environmental influences with the intrinsic physiological characteristics of the affected populations of neurons.
Genetic predisposition plays a role in the etiology of neurodegenerative disorders. HD is transmitted by autosomal dominant inheritance, and the molecular nature of the genetic defect has been defined (see below). Most cases of PD, AD, or ALS are sporadic, but familial links occur and studies of familial disease are yielding clues to the pathogenesis of the disorders. Mutations in four different proteins can lead to genetically determined forms of PD: a-synuclein, an abundant synaptic protein; parkin, a ubiquitin hydrolase; UCHL1, which also participates in ubiquitin-mediated degradation of proteins in the brain; and DJ-1, a protein thought to be involved in the neuronal response to stress. Mutations in the genes encoding the amyloid precursor protein (APP) and proteins known as the presenilins, which may be involved in APP processing, lead to inherited forms of AD. Mutations in the gene encoding copper-zinc superoxide dismutase (SOD1) account for -2% of cases of adult-onset ALS.
Apolipoprotein E (apoE) is a genetic risk factor for AD. There are four distinct isoforms of apoE, which is involved in transport of cholesterol and lipids in blood. Although all the isoforms function equally well, individuals who are homozygous for the apoE 4 allele ("4/4") have a much higher lifetime risk of AD than do those homozygous for the apoE 2 allele ("2/2"). The mechanism by which the apoE 4 protein increases the risk of AD is not known.
The decline in metabolic activity with age, oxidative stress, and the local production of oxygen radicals from the metabolism of dopamine via the Fenton reaction (Figure 20-1) may play roles in the etiology of some of these diseases.
CLINICAL OVERVIEW AND PATHOPHYSIOLOGY Parkinsonism has four cardinal features: bradykinesia (slowness and poverty of movement), muscular rigidity, resting tremor (which usually abates during voluntary movement), and an impairment of postural balance leading to disturbances of gait and falling. The pathological hallmark of PD is a loss of the pigmented, dopaminergic neurons of the substantia nigra pars compacta (SNpc) that provide dopaminergic innervation to the striatum (caudate and putamen). Progressive loss of dopaminergic neurons is a feature of normal aging; however, symptoms of PD coincide with excessive loss (70-80%) of these neurons. Without treatment, PD progresses over 5-10 years to a rigid, akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism. The availability of effective pharmacological treatment has altered radically the prognosis of PD; in most cases, good functional mobility can be maintained for many years, and the life expectancy increased substantially. Several disorders other than PD also may produce parkinsonism, including some relatively rare neurode-generative disorders, stroke, and intoxication with dopamine-receptor antagonists. Drugs in common clinical use that may cause parkinsonism include antipsychotics such as haloperidol and thorazine (see Chapter 18) and antiemetics such as prochloperazine and metoclopramide (see Chapter 37). Parkinsonism arising from other causes usually is refractory to all forms of treatment.
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