Experimental Models of Cognitive Impairment for Use in Parkinson’s Disease Research: The Distance Between Reality and Ideal

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Cognitive impairment is one of the key non-motor symptoms of PD, affecting both mortality and quality of life. However, there are few experimental studies on the pathology and treatments of PD with mild cognitive impairment (PD-MCI) and PD dementia (PDD) due to the lack of representative models. To identify new strategies for developing representative models, we systematically summarized previous studies on PD-MCI and PDD and compared differences between existing models and diseases. Our initial search identified 5432 articles, of which 738 were duplicates. A total of 227 articles met our inclusion criteria and were included in the analysis. Models fell into three categories based on model design: neurotoxin-induced, transgenic, and combined. Although the neurotoxin-induced experimental model was the most common type that was used during every time period, transgenic and combined experimental models have gained significant recent attention. Unfortunately, there remains a big gap between ideal and actual experimental models. While each model has its own disadvantages, there have been tremendous advances in the development of PD models of cognitive impairment, and almost every model can verify a hypothesis about PD-MCI or PDD. Finally, our proposed strategies for developing novel models are as follows: a set of plans that integrate symptoms, biochemistry, neuroimaging, and other objective indicators to judge and identify that the novel model plays a key role in new strategies for developing representative models; novel models should simulate different clinical features of PD-MCI or PDD; inducible α-Syn overexpression and SH-SY5Y-A53T cellular models are good candidate models of PD-MCI or PDD.

Spontaneous Object Exploration in a Recessive Gene Knockout Model of Parkinson’s Disease: Development and Progression of Object Recognition Memory Deficits in Male Pink1–/– Rats

“…Currently, there are few available therapeutic options that are effective in preventing or slowing the progression of cognitive and memory decline in PD ( Goldman and Weintraub, 2015 ; Mack and Marsh, 2017 ; Goldman et al, 2018 ; Fang et al, 2020 ). Thus, in addition to clinical trials, animal and especially rodent models are being used to support controlled investigations into the risk factors and pathophysiological mechanisms that contribute to cognitive disturbance in PD and to test new ways of mitigating them ( Fan et al, 2021 ). There are several reasons to predict that Pink1 –/– rats may be well-suited for these purposes.…”

Chronic Cerebral Hypoperfusion Aggravates Parkinson’s Disease Dementia-Like Symptoms and Pathology in 6-OHDA-Lesioned Rat through Interfering with Sphingolipid Metabolism

“…It would seriously affect the patient's quality of life. The etiology of PDD involves genetics, neurophysiology, neuropathology, neuroimaging, environment, vascular factors, and other aspects of research [ 3 ]. On the one hand, a growing number of studies showed that synergistic effects of alpha-synuclein ( α -Syn) and beta-amyloid (A β ) are closely associated with PDD severity [ 4 , 5 ].…”

“…Bilateral common carotid artery occlusion (BCCAO) is a common method to induce CCH in rat [ 11 , 12 ]. Therefore, we selected BCCAO to simulate chronic cerebral hypoperfusion in the rat model of PD induced by typical neurotoxin 6-hydroxy dopamine (6-OHDA) [ 3 , 13 , 14 ]. Then, we explored the autonomic motor and cognitive functions of those rats through open field test (OFT) and Morris water maze test (MWM).…”

Spontaneous object exploration in a recessive gene knockout model of Parkinson’s disease: Development and progression of object recognition memory deficits in male Pink1-/- rats

“…Currently, there are few available therapeutic options that are effective in preventing or slowing the progression of cognitive and memory decline in PD (Goldman and Weintraub 2015, Mack and Marsh 2017, Goldman, Vernaleo et al 2018, Fang, Lv et al 2020). Thus, in addition to clinical trials, animal and especially rodent models are being used to support controlled investigations into the risk factors and pathophysiological mechanisms that contribute to cognitive disturbance in PD and to test new ways of mitigating them (Fan, Han et al 2021). There are several reasons to predict that Pink1 -/- rats may be well-suited for these purposes.…”

“…Thus, there is a powerful interpretive framework at hand for gaining insights into the neural circuits that may be most affected by pathophysiology and where targeted therapeutics may be most beneficial. Given these benefits, it is not surprising that NOR, NOL and to a lesser extent OiP tasks continue to be widely used to assess cognitive deficits in a range of rodent models of PD (Grayson, Leger et al 2015, Johnson and Bobrovskaya 2015, Haghparast, Esmaeili-Mahani et al 2018, Ikram and Haleem 2019, Kyser, Dourson et al 2019, Bharatiya, Bratzu et al 2020, Boi, Pisanu et al 2020, Fan, Han et al 2021, Kakoty, K et al 2021, Pinizotto 2022). This study extends this utilization for the first time to Pink1 -/- rats in longitudinal comparative evaluations of object recognition memories in single cohorts of knockout and wildtype (WT) male Long Evans rats.…”