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PARKINSON’S DISEASE AND RELATED DISORDERS

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease, exceeded only by Alzheimer’s disease (AD). Its cardinal clinical features were first described by the English physician James Parkinson in 1817. James Parkinson was a general physician who captured the essence of this condition based on a visual inspection of a mere handful of patients, several of whom he only observed walking on the street and did not formally examine. It is estimated that the number of people with PD in the most populous nations worldwide is ~5 million persons, and this number is expected to double within 20 years based on the aging of the population. The mean age of onset of PD is about 60 years, and the lifetime risk is ~3% for men and 2% for women. The frequency of PD increases with age, but cases can be seen in individuals in their twenties and even younger, particularly when associated with a gene mutation.

Clinically, PD is characterized by rest tremor, rigidity (stiffness), bradykinesia (slowing), and gait dysfunction with postural instability. These are known as the classical or “cardinal” features of the disease. Additional clinical features can include freezing of gait, speech difficulty, swallowing impairment, and a series of nonmotor features that include autonomic disturbances, sensory alterations, mood disorders, sleep dysfunction, cognitive impairment, and dementia (see Table 435-1 and discussion below).

TABLE 435-1Clinical Features of Parkinson’s Disease

Pathologically, the hallmark features of PD are degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), reduced striatal dopamine, and intraneuronal proteinaceous inclusions in cell bodies and axons that stain for α-synuclein (known as Lewy bodies and Lewy neurites, collectively as Lewy pathology) (Fig. 435-1). While interest has focused on the dopamine system, neuronal degeneration with Lewy pathology can also affect cholinergic neurons of the nucleus basalis of Meynert (NBM), norepinephrine neurons of the locus coeruleus (LC), serotonin neurons in the raphe nuclei of the brainstem, and neurons of the olfactory system, cerebral hemispheres, spinal cord, and peripheral autonomic nervous system. This “nondopaminergic” pathology is likely responsible for the nonmotor clinical features listed above and in Table 435-1. It has been postulated that Lewy pathology can begin in the peripheral autonomic nervous system, olfactory system, and dorsal motor nucleus of the vagus nerve in the lower brainstem, and then spread in a predictable and sequential manner to affect the SNc and cerebral hemispheres ...

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