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KEY CONCEPTS

KEY CONCEPTS

  • Neurodegenerative diseases, of which Alzheimer and Parkinson diseases are among the most common, are a diverse group of disorders characterized by progressive brain atrophy associated with the death of neurons.

  • These diseases are variably associated with deficits in cognition and motor function, psychiatric disturbances, and other impairments that arise from the region–specific vulnerability of different neuronal populations to a range of pathogenic mechanisms.

  • The major processes by which neurons die are necrosis and apoptosis (programmed cell death); once thought distinct, these two processes have significant overlap and involve cascades of proteins including proteolytic enzymes of the caspase family.

  • Processes initiating cell death include mitochondrial dysfunction, excitotoxicity, oxidative stress, and disruption in protein metabolism.

  • The neuropathologic hallmarks of Alzheimer disease, the most common cause of severe memory impairment in the elderly, are amyloid plaques and neurofibrillary tangles.

  • Alzheimer disease may arise in part from improper biochemical processing of amyloid precursor protein (APP) and the subsequent accumulation of amyloid β peptide (Aß).

  • Inherited forms of Alzheimer disease have been linked to mutations in APP or in proteins called presenilins, which regulate the processing of APP and other proteins.

  • Accumulation of the microtubule–associated protein tau, which forms neurofibrillary tangles, also plays a critical role in the pathogenesis of Alzheimer disease and several other neurodegenerative diseases.

  • While symptomatic therapies with modest effectiveness exist (eg, acetylcholinesterase inhibitors), there are currently no disease modifying treatments for Alzheimer disease. Several pharmacologic strategies for preventing the buildup of Aß or tau or enhancing their clearance have not yet shown promise in large scale clinical trials.

  • Frontotemporal dementias comprise several other neurodegenerative disorders, most of which involve abnormal aggregation of tau or transactive response (TAR) DNA binding protein of 43 kDa (TDP-43).

  • Parkinson disease, characterized as a movement disorder despite its frequent involvement of cognitive and emotional impairments, results primarily from loss of dopamine input to the basal ganglia; restoration of dopamine function, for example, with the dopamine precursor L-dopa, remains the mainstay of therapy for the disease.

  • Relatively infrequent familial forms of Parkinson disease are caused by mutation in several genes related to protein metabolism or mitochondrial function, examples of which are glucocerebrosidase (GBA), leucine rich repeat kinase 2 (LRRK2), α-synuclein (SNCA), and parkin 2 (PARK2 or PRKN).

  • Huntington disease is caused by a CAG trinucleotide repeat expansion in the gene for huntingtin; the mutation increases the number of glutamine residues expressed in the protein, which is pathogenic.

  • Amyotrophic lateral sclerosis (ALS) is caused by the selective death of upper motor neurons in the cerebral cortex and lower motor neurons in the spinal cord.

  • While the majority of ALS cases are sporadic, an increasing number of genes have been shown to contribute to disease pathogenesis, including chromosome 9 open reading frame 72 (C9orf72), superoxide dismutase 1 (SOD1), and TDP-43. The overlap in genetic contributions to ALS and several other neurodegenerative disorders underscores ...

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