Abstract
Parkinson disease (PD) is the second most common neurodegenerative disorder in elderly people. It is characterized by the aggregation of misfolded alpha-synuclein throughout the nervous system. Aside from cardinal motor symptoms, cognitive impairment is one of the most disabling non-motor symptoms that occurs during the progression of the disease. The accumulation and spreading of alpha-synuclein pathology from the brainstem to limbic and neocortical structures is correlated with emerging cognitive decline in PD. This review summarizes the genetic and pathophysiologic relationship between alpha-synuclein and cognitive impairment in PD, together with potential areas of biomarker advancement.
Highlights
Parkinson disease (PD) is the second most common neurodegenerative disease
We focus on why PD patients eventually develop cognitive decline and the presumed role of αS, including the contribution of genetics, αS protein–protein interaction, and αS cell-to-cell propagation
Synucleinopathy underlies a wide spectrum of clinical syndromes, including PD, PDD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF)
Summary
Parkinson disease (PD) is the second most common neurodegenerative disease. Pathologically, it is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), and the proteinaceous aggregates composed predominantly of alphasynuclein (αS), known as Lewy bodies, within neuronal cell bodies [1]. Synucleinopathy underlies a wide spectrum of clinical syndromes, including PD, PDD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF). In order to provide diagnostic accuracy and define patients likely to respond to disease modifying therapy, a hierarchical classification has been proposed based on the underlying pathological protein deposition (αS), cellular inclusions (Lewy bodies or glial cytoplasmic inclusion, GCI), and clinical phenotypes (parkinsonism, dementia, or autonomic failure) [20]. There is emerging agreement in clinical trials and research settings that PDD and DLB should be distinguished as two syndromes Another emerging concept connecting pathophysiology and cognitive function in neurodegenerative diseases is oscillopathies, which refer to conditions characterized by the abnormal synchronization of synaptic activity [35]. Distinct patterns of brain oscillations may correlate with clinical symptoms and network impairment secondary to physiopathological changes [36]
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