The neurobiological basis of cognitive impairment in Parkinson's disease

Abstract

The recent formalization of clinical criteria for PD with dementia (PD-D) codifies many studies on this topic, including those assessing biological correlates. These studies show that the emergence of PD-D occurs on the background of severe dopamine deficits with the main pathological drivers of cognitive decline being a synergistic effect between α -synuclein and Alzheimer's disease pathology. The presence of these pathologies correlates with a marked loss of limbic and cortically projecting dopamine, noradrenaline, serotonin and acetylcholine neurons, although the exact timing of these relationships remains to be determined. Genetic factors, such as triplications in the α-synuclein gene, lead to a clear increased risk of PD-D, while others, such as parkin mutations, are associated with a reduced risk of PD-D. The very recent formalization of clinical criteria for PD with mild cognitive impairment (PD-MCI) allows only speculation on its biological and genetic bases. Critical assessment of animal models shows that chronic low dose MPTP treatment in primates recapitulates PD-MCI over time, enhancing the current biological concept of PD-MCI as having enhanced dopamine deficiency in frontostriatal pathways as well as involvement of other neurotransmitter systems. Data from other animal models support multiple transmitter involvement in cognitive impairment in PD. While dopamine dysfunction has been highlighted because of its obvious role in PD, the role of the other neurotransmitter systems, neurodegenerative pathologies and genetic factors in PD-MCI remain to be fully elucidated.

Propagated but topologically distributed forebrain neurons expressing alpha-synuclein in aged macaques

“…Then, the appearance of α-syn-positive neurons finally reaches other areas of the prefrontal cortex, such as the ventrolateral and medial prefrontal cortices, and in area 4 of the motor cortex (i.e., the primary motor cortex). Although all these frontal cortical areas are likely to receive dopaminergic input from the VTA/medial SNc [53][54][55][56], it remains unclear whether the development in the α-syn pathology may be correlated with the richness of dopaminergic innervation. There is a consensus that the prefrontal cortical areas, including the anterior cingulate cortex and the orbitofrontal cortex, are greatly involved in diverse cognitive functions [38,52,57,58].…”

Neurochemicals, Behaviours and Psychiatric Perspectives of Neurological Diseases

“…Progression of PD is associated with increased degeneration of A9 nigrostriatal neurons that results in increased motor deficits. These deficits are ameliorated upon dopamine replacement [209,210]. Studies in animal models suggest that the loss of norepinephrinergic neurons might exacerbate dopaminergic neuronal damage in PD.…”

Neurokognitív zavarok diagnosztizálási és kezelési lehetőségei Parkinson-kórban

“…A kognitív teljesít-mény romlása, a motiváció csökkenése, a mozgásterve-zési, az összehangolási és a végrehajtási nehézségek a praefrontalis kéreg sérülésére utalhatnak, ám az ilyen tünetek jelenléte Parkinson-kórban kevésbé kérgi káro-sodással, mintsem a praefrontalis körök működészavará-val magyarázhatók [5]. A nigrostriatalis pályarendszer dopaminerg neuronjainak pusztulása mellett a kolinerg, a szerotoninerg és a noradrenerg rendszer károsodása is kimutatható, ami magyarázatot adhat arra, hogy az affektív és motivációs problémák mellett a kognitív mű-ködés zavara is megjelenhet [5,6]. A frontostriatalis pályarendszer sérülésének köszönhetően jelentkező praefrontalis károsodás egyik következménye a diszexekutív szindróma [7].…”