PD is primarily a movement disorder resulting from the loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). It is diagnosed by the presence of resting tremor, bradykinesia (slowness of voluntary movement), rigidity (stiff muscles, expressionless face), and postural instability (poor recovery of balance). The gait of individuals with PD is also distinctive, with a tendency to lean unnaturally forwards or backwards, a diminished arm swing, and a shuffling step. Although loss of DA-containing neurons is a hallmark pathological feature of the disease, other neuronal populations are also affected.62 Structures that are initially affected in stages 1-2 of PD include the vagal nerve, the dorsal motor nucleus and the olfactory bulb, and the anterior olfactory nucleus. At stage 3, involvement of basal portions of the midbrain and forebrain and a number of cholinergic nuclei and the tuberomamillary nucleus is apparent. At stage 4, portions of the cerebral cortex are affected. Stages 3-4 are where individuals begin the transition from presymptomatic to symptomatic phases of PD and progressively deteriorate through stages 5-6, with complete loss of midbrain neurons. PD symptoms are not manifest until 50-80% of dopaminergic neurons are lost, making maintenance of the survival of the remaining 20-50% of these neurons critical.
It is estimated that 1.5 million individuals in the US are affected by PD. The disease usually presents after the age of 60 with a disease course that can last 10-20 years. The most commonly used scales for PD diagnosis and clinical trial evaluation are the Hoehn and Yahr staging of PD, the unified PD rating scale (UPDRS), and the Swab and England activities of daily living scales.63 However, like AD, PD is a diagnosis based on exclusion, and definitive diagnosis is made at autopsy.
There are currently no biomarkers approved for PD diagnosis to determine disease status or clinical outcomes. Radiotracer imaging with probes such as [18F]fluorodopa, [123I]b-CIT, and [11C]dihydrotetrabenazine, to measure neuronal viability based on the presence of the DA transporter (DAT), the vesicular monoamine transporter (VMAT), or dopaminergic or monoaminergic nerve terminals, is being used in clinical trials, although its utility as a surrogate marker is unclear since the loss of marker can reflect either overt neuron loss or a downregulation of the radiotracer target, DAT.64 For instance, kinase inhibitors can downregulate DAT,65 making data interpretation complex and questioning the degree of validation of this biomarker.
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