Neurodegenerative Diseases: Parkinson Disease
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Parkinson disease (PD) is clinically characterized by tremor, bradykinesia, rigidity, postural instability, and gait disturbance. Non-motor features of PD include pain and sensory phenomena, anxiety and depression, autonomic dysfunction, cognitive impairment, dementia, and psychosis and hallucinations.
In neuroradiology, a decreased volume or disappearance of pars compacta of substantia nigra is noted; hypointensities of putamen, substantia nigra, and caudate nucleus are possible (as caused by iron accumulation). A presynaptic dopamine transporter deficit with SPECT tracers like FP-CIT or β-CIT is evident upon nuclear medicine examination.
At the light-microscopic level, loss of neurons in the substantia nigra and locus coeruleus, deposition of melanin pigment in the neuropil or macrophages, and surviving neurons with intracytoplasmatic Lewy bodies are the hallmark of the disease.
Lewy bodies are eosinophilic structures with a dense core and a concentric lamellar structure which stain positive for α-synuclein; thus, PD is an α-synucleinopathy. Six stages in the evolution of PD-related pathology are defined.
Pathogenetic mechanisms at work include oxidative stress, reactive species production, mitochondrial dysfunction, excitotoxicity, increased intracellular free calcium, protein aggregation, ubiquitination of proteins, and inflammation. Confirmed causative genes in PD (autosomal dominant, and autosomal recessive) are named PARK1 until PARK19 which contain missense mutations that alter the protein sequence, duplications, and triplications. The most replicated PD risk loci are SNCA, LRRK2, MAPT, and GBA. Epigenetic mechanisms are involved which alter DNA methylation, histone modification, and non-coding RNAs.
Treatment includes medical therapies (with Levodopa, anticholinergics, amantadine, dopamine receptor agonists, catechol-O-methyltransferase (COMT) inhibition, and monoaminooxidase type B (MAO-B) inhibitors) as well as surgical therapies (deep brain stimulation, lesional surgery). Clinical outcome displays a slow progression of symptoms over several years, an average disease duration of 9–15 years. Side effects from medication include motor fluctuations and dyskinesias.
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