The role of medial prefrontal cortex in cognition, aging and Parkinson disease

: The prefrontal cortex (PFC) is a vital center for executive control, influencing cognition, emotion, memory, and sociability. Specifically, the medial prefrontal cortex (mPFC), a part of the PFC, monitors actions toward goals, aids decision-making, and regulates cognitive control. It assesses outcomes relative to expected rewards, selects appropriate behavior based on continuous performance analysis, and facilitates strategic adaptation in response to adverse results. Unfortunately, these cognitive functions decline with age due to changes in neuroplasticity, especially in neurodegenerative disorders like Parkinson's Disease (PD) and Alzheimer's Disease (AD). Neu-rodegenerative diseases disrupt normal brain activity, leading to tissue atrophy and cognitive impairment caused by degeneration and neuronal death. PD is the second most common neuro-degenerative disease globally, characterized by a decline in neurotransmitters and dopaminergic neuron death in the substantia nigra, along with the presence of Lewy bodies. Recognizing these factors as risk factors for PD development is crucial. This article examines how aging affects cognitive activities regulated by the mPFC, a pivotal region for critical cognitive functions. Through a narrative review of literature published between 2010 and 2022 in the Medline (Pubmed) database, the study explores the topics of "cognition and Parkinson's disease," "prefrontal cortex," and "cognition and aging." By applying predetermined criteria, the review selects the most relevant articles to provide a comprehensive understanding of cognitive deficits mediated by the mPFC in both healthy and pathological aging.


Introduction
The prefrontal cortex (PFC) is a neocortical area that, along the evolutionary process, was more developed in human beings and in primates [1]. The PFC is responsible for transmitting and receiving information originated from various encephalic regions and

Methodology
A gathering of scientific literature was done, in the PubMed database, in the years from 2010 to 2022, about Parkinson, aging and cognitive decline of the medial prefrontal cortex. In the PubMed database, 321 articles were found using the association of the descriptors "cognition [mesh terms] and parkinson disease [mesh terms]", besides "prefrontal cortex and cognition and aging" in the years from 2010 to 2022, using the filters "Review e Systematic Review", of which 64 articles were selected after their title was read ( Figure 1). The second exclusion criterion was the reading of the abstracts, of which 33 were selected according with the theme that will be addressed. The exclusion criteria were titles that were not associated with aging, Parkinson's disease and prefrontal cortex, articles published in another language that wasn´t English and studies that were published outside of the period from 2010 to 2022.
Studies with experiments related to animal models, even if pertinent to the subject, were excluded. Besides, although the main theme of the present study is not associated with Alzheimer's disease, some studies related to the association between aging and Alzheimer´s were included for addressing cognitive decline in aging. Furthermore, 14 articles were selected through PubMed following a relevance for the synthesis of the present study. Besides these, 15 articles were manually added from the reference list of the eligible articles, totalizing 29 added articles. Finally, 62 original articles in English (including reviews and systematic reviews) remained ( Figure 2).

The role of the medial prefrontal cortex in cognition activity
The right stimulation can evoke different familiar reactions in a fast and automatic way through simple and stereotyped behaviors, known as bottom-up processing. On the other hand, the diversification of behavioral possibilities demands more flexible patterns of interaction between stimulus and answer16. However, this repose flexibilization en-hances the disorder risks, needing a coordination of attention and decision making [4,16].
The simultaneous and coordinated operation from the numerous cortical and subcortical structures focused on one aim is known as cognitive control and acts through a top-bottom processing [17] (Figure 3). Cognitive control consists, generally, of maintaining active the representation of relevant stimuli and of the goal, evaluating if the obtained results are adequate to the objective and doing possible necessary adjustments. Thus, in case the given answer is not in agreement with the objective, through cognitive control it is possible to suppress actions or thoughts regulating the behavior [18]. The executive control of behavior, emotions, thoughts, planning and intentionally flexible decision making receives the name of executive functions, acting through the control of the cognitive domain [19]. Generally, cognitive flexibility, inhibiting control, attention, working memory and decision making compose the executive functions [4]. Many structures participate in this processing, but the prefrontal cortex (PFC) is consistently pointed out as the command center of executive control, receiving, and transmitting information from almost every sensorial and motor systems [16]. On the other hand, this group of processes intrinsic to cognitive control are possible due to working memory, which consists in the temporary storage of information and its manipulation through previous knowledge focused on one goal, being essential for learning and problem solution and having PFC as a neural correlate [20].
Besides, some aspects of cognitive control, such as attention and decision making, can be influenced by emotions. In contrast, cognition is also responsible for the regulation of emotional answers [21]. Inserted in this mechanism, PFC acts in the regulation of biogenic amines liberation, such as dopamine, noradrenaline, and serotonin, that generate humor alterations4. Other studies also linked cognitive control and PFC as intrinsically related to social cognition that involves the elaboration of answers adequate to the norms, values, and moral judgements [22]. Therefore, prefrontal lesions or neurodegenerative processes that damage PFC can cause personality changes, as well as in the other functions previously mentioned [23].
A portion of the PFC named medial prefrontal cortex (mPFC) plays a key part in this process of monitoring action focused on one goal. In particular, the anterior cingulate cortex (ACC), a region that integrates the mPFC and regulates the detection of errors and conflict monitoring [24]. The mPFC acts in the strategic adaptation of behavior adjusting to adverse outcomes. Thus, mPFC is central for decision making and cognitive control, monitoring the result in relation to the expected reward and selecting the adequate behavior to the situation through a continuous performance analysis. This flexible monitoring also demands an analysis and temporal adjustment of the action aiming the answer precision and efficiency, modulation consistently associated with the activity of the mPFC [25]. mPFC can be divided in subdivision named dorsomedial prefrontal cortex (dmPFC) which communicates predominantly with neocortical regions; and ventromedial PFC (vmPFC) whose communication predominantly occurs with limbic structures and basal ganglia [21].
Outside this perspective, mPFC is responsible for rescuing long term memories aiming to identify, in past experiences, the most adequate answer to each situation, directing the behavior [26]. Therefore, this task involves selecting a convenient memory and rejecting memories that are irrelevant to the task, which is only possible due to the communication between the mPFC and hippocampus, mainly the ventral hippocampus [27]. The motivation plays a fundamental role in orienting the behavior, in relation to the search for rewards and when possible, errors or conflicts with the goal are identified [24,26]. Other evidence points out the hippocampus´ s role in providing emotional aspects and spatial contexts that project to the mPFC and subsidize the selection of an adequate behavior to the context. On the other hand, the activity of mPFC also acts in the memory consolidation, establishing information that was just obtained and facilitating the learning process. Studies suggest that during periods of greater inactivation, such as during sleep, the hippocampus is activated again and recreates an acquired memory, which also generates its repetition in cortical structures. This process creates the consolidation of acquired memory [26]. The synchrony between the mediodorsal thalamus and the mPFC is associated to working memory, in which the inhibition of the mediodorsal thalamus makes the action directed to the task more difficult and decreases the efficiency in the selection of adequate behavior, as well as maintaining the representations of the stimulus in the working memory [28] (Figure 3).
Additionally, the association between mPFC and nucleus accumbens is essential to the modulation of the goal-directed behavior, mainly those directed to rewards. The reward anticipation regulated by these structures originates from the comparison of information coming from emotional evaluations in the amygdala and spatial contextualization in the hippocampus and leads to the planning and execution of adequate goal-directed behaviors [29]. Besides, the activation of mPFC acts in the intermediation of the attention allocation, which works through the neglect of irrelevant stimuli and focus on the selected stimuli. Thus, the mPFC is fundamental for the efficiency of the executive functions and its compromise can cause numerous damages in the control of these functions [21].

The relationship between medial prefrontal cortex and the aging process
The aging process is constantly accompanied by numerous neuroanatomical and neurophysiological modifications [30]. Therefore, many of the cognitive deficiencies that accompany the healthy aging process are explained by alterations in the medial prefrontal cortex, which plays a critical part in the cognitive decline in aging, including cognitive flexibility and attention [4]. Studies show that even in healthy aging there is a decrease in the connections of the mPFC with other cortical and subcortical areas leading to decline [31]. Corroborating with these findings, a study performed in rodents demonstrates the deterioration of the cognitive function during normal aging, in which occurs a reduction in the velocity information processing when compared to younger rats [32].
In this context, evidence demonstrates notorious deficits related to age in a series of cognitive functions mediated by the medial prefrontal cortex. This data is reinforced by findings in neurophysiological experiments in elder non-human primates, which presented damage in the working memory with reduced processing velocity [30].
Another important relation that should be highlighted is the decrease in volume and thickness of gray matter in the mPFC, besides alterations in the pathways of the white matter in healthy elders, in a way that the elderly with less volume of gray matter presented increased cognitive repercussion, impacting in the distraction and in the neural suppression of irrelevant information, affecting memory. Similar results were found in elders with decrease of the white matter's integrity [33]. Thus, studies evidenced that any structural or functional alterations in mPFC can lead to loss of the normal function [2].

Aging neurodegenerative-associated disorders involving the medial prefrontal cortex
Neurodegenerative diseases (ND) are diseases of common cause and crescent morbidity worldwide, mainly in elderly people, and are responsible for and atrophy of the brain tissue leading to a decreased cognition capacity, diminishing the normal brain function that tends to worsen with the chronicity of the condition [10,12]. In addition to that, phenotypes of neuroimage associated with aging, integrity of the white matter tract, quantitative decrease of neurons in the prefrontal cortex (PFC) [34] are correlated with aging, which is inherently connected to a deterioration of the cognitive function associated with a greater hypermetabolic activity [4]. Thus, considering that one of the main functions of the medial prefrontal cortex (mPFC) is orienting the actions in time, having decision-making as its central utility, since deciding which will be the moment of choice is as important as selecting the appropriate actions in the context; in truth, the right action at the wrong time usually will lead to terrible outcomes. Therefore, when these alterations associated with neurodegeneration, vascular accidents or traumas occur in mPFC can be observed mainly by deterioration of the executive function (defining goals, memorizing, planning, and executing activities), besides also affecting the decision-making process, which was evidenced by functional changes in working memory and cognitive flexibility6. It is valid to highlight that the cited deficits are more accentuated and rapidly progressive in the presence of ND, but aging itself is already responsible for some of these alterations [30]. Amongst them is the deficiency of cognitive control, causing depletion of sustained and selective attention, inhibitory control, working memory and multitasking skills. Additionally, the arithmetic, the comprehension, the perception of emotions and the emotional control, despite being associated with the PFC, do not present decline associated with age. Therefore, cognitive decline is not present in all elderly people [35]. Thus, studies provide evidence that neurodegenerative disorders alter the mPFC's function in a pathologic way, them being Alzheimer's disease, Huntignton's disease and Parkinson's disease4.
Alzheimer's disease (AD) represents from 60% to 80% of all the dementia cases in the world, being the most common manifestation of neurodegeneration and, corresponding to about 24 million people globally. This prevalence is directly proportional to aging, leading to an increase superior to 15 times when our observed sample is between the age gap of 65 to 85 years old. In addition to this statistic, a north American study in which the prevalence reaches 50% in people with more than 85 years old. In the face of this data, it is easy to understand why AD is considered a disease of elderly people [12]. In a physiologic approach, there is deposition of extracellular plaques of beta-amyloid peptide and formation of intracellular neurofibrillary tangles in the brain cortex, these alterations will be clinically perceived as severe cognitive deficits, emotional depression, and progressive motor dysfunction, besides loss of working memory, spatial memory and anterograde memory [2].
Since the mPFC is responsible for working memory, its association with AD is clear. Finally, it is worth mentioning that the hippocampus, a subcortical region of the brain with close relation to the PFC, is responsible for learning, memory consolidation, affective behaviors, and mood regulation. It is believed that neurobiological alterations ob-served in the aged hippocampus, including increase in oxidative stress and neuroinflammation, altered intracellular signalization and gene expression, as well as reduced neurogenesis and synaptic plasticity, are associated with the cognitive decline related to the age. This region being one of the first sites of action of AD, probably the most documented and known characteristic of the disease is its visualized hippocampal atrophy, mainly in magnetic resonances. Since the typical AD, in which there is memory compromise, represents about 60% of all cases and its main characteristic is the medial temporal lobe atrophy (MTA) along with the atrophy of other temporal regions and atrophy of the posterior cingulate/ precuneus. It is also important to highlight that this alteration can be used to differentiate prodrome phases of AD in healthy individuals, as well as excluding other diagnoses [36] (table 01). Thus, when taking into consideration its communication with the PFC it is demonstrated that AD is a neurodegenerative disorder related to aging [10].
Parkinson's disease (PD) is one of the most common neurodegenerative diseases, standing only behind AD [12,14]. Its prevalence is of 0,3% in the general population, ~1% in elderly people above 60 years-old and ~3% in elders 80 years-old or above (8 to 18 people from 100.000 per year), being most common in men (1,5 to 2 times greater than women) with medium age of 60 years and life expectancy of 15 years after the diagnosis [12]. This age association comes from the lack of dopamine and motor and non-motor deficits of the disease, besides environmental and genetic factors, such as mitochondrial dysfunction, oxidative stress, protein aggregation, damaged autophagy and neuroinflammation, which influence the risk of PD [13].
Its pathology acts through the presence of aggregates of alpha-synuclein in the brain, containing Lewy Bodies in the brain's substantia nigra, causing synucleinopathy and the loss of dopaminergic neurons in the par's compacta [13][14]37], leading to a motor control disorder and some complications, such as the deterioration of cognitive functions in 40% of cases, being a risk factor for dementia. Some of these cognitive alterations are executive function, visuospatial abilities, and attention deficits [11]. This deterioration could be, in part, by the alpha-synuclein spreading from substantia nigra pars compacta to cortical structures, affecting, among other areas, the mPFC, progressing according to a Braak stages (Figure 4).

Figure 4:
Alpha-synuclein prion-like spreading. From substantia nigra pars compacta to cortical structures, this misfolded protein causes neurodegeneration that, in chronic cases, may lead to cognitive functions impairment.
Previously, it was believed that intellect maintained itself unaltered in PD, but recent studies already demonstrated the prevalence of deficit and all kinds of cognitive dysfunctions in the disease [37]. Thus, cognitive compromise in PD still has its physiology as an incognito in current medicine, but the most accepted theories are that alterations in the cholinergic, dopaminergic, and noradrenergic systems exist. Furthermore, the cognitive reduction affects 80% of patients with PD38, with a higher prevalence in patients with greater age and disease time [12]. Example of that is: 19-38% of patients present dementia with a PD diagnosis of 10 years, which increases to 75% with additional 10 years of PD and, posteriorly, to 83% when patients have had PD for 20 years [12]. Thus, the clinical evolution to dementia can be observed in manifestations such as working memory and executive function deficiencies [38].
Finally, it is valid to highlight that there is a strong correlation between the neuropathology of neurodegeneration and the gray matter's atrophy, being considered a cardinal sign. Accordingly, we emphasize that this article addressed the main neurodegenerative diseases: AD and PD. The first presents prominent medial temporal lobe atrophy (MTA) as a typical manifestation from the early stages of the disease, which has been considered a useful biomarker in the pre-dementia states of AD that can diagnose and be used as support. On the other hand, PD has a more heterogeneous pathophysiology, resulting in numerous clinical manifestations. Therefore, the atrophy pattern was still not established in a conclusive way for this disease, but recent studies identified specific atrophy patterns in the initial phase that can predict the malignant prognosis of PD, including cognitive decline. Thus, new methodologic approaches showed that the appearance of cognitive deficits in the pathology can be associated with atrophy of areas of cortical projection in the prefrontal and posterior cortical regions due to the loss of cholinergic nuclei in the prosencephalon [36].

Genetic Physiology of Parkinson's Disease
The advance in research demonstrated that the genetic scope was essential to better the comprehension of Parkinson's disease. From numerous investigated genes, the most well studied include LRRK2, SNCA, VPS35, Parkin and PINK1. Thus, the mechanisms of each cited gene interfere in the development of Parkinson's disease [39]. However, it is known that 5 to 10% of PD cases are related to genetic mutations, being LRRK-2 the most frequently altered gene [40] and the most frequent cause in idiopathic PD cases, even covering specific ethnic groups, given that in a sample of 248 affected patients from families with autosomal dominant parkinsonism, 7 were identified for transporting a LRRK-2 (G2019S) heterozygotic alteration, where such patients are from the United States, Norway, Ireland and Poland [41][42][43]. Furthermore, in models of patients with sporadic Parkinson's disease from the same populations, additional six patients with LRRK2 G2019S were identified, and no alteration was found in individual control41. Besides, in another great study, it was discovered that the frequency of mutations was of 1% amongst the sporadic patients and 4% amongst the familial PD patients, but with the greatest frequency of mutation amongst the Arabic and Ashkenazi-North African populations: 39% and 38% amongst the arabic people from the north of Africa, and 10% and 28% between the Ashkenazi jews with sporadic and familial PD, respectively [44,45].
In this context, LRRK-2 contains numerous functional domains, including the I2020T kinase domain, which has shown to have divergent effects, some increasing activity 46, whilst others ended up demonstrating its decrease47, since the LRRK-2 superexpression promotes neuronal toxicity, causing cell death, shortening of dendrites and, consequently, neurodegeneration [48][49][50]. However, it is worth mentioning that such degenerative consequences were softened with chemical inhibitors of LRRK-2 or with inactive kinase mutations that were inserted47. Furthermore, the substrates of LRRK-2 phosphorylation (except autophosphorylation) were also unknown until recently, however, Rab GTPases (Rab5 and Rab7) substrates were identified not long ago, which affect signaling cascades, degradation and endosomal traffic [51]. Sequentially, abnormal morphologies and mitochondrial functions were observed amongst the LRRK-2 alterations, as well as an abnormal accumulation in autophagic vacuoles, which are believed to be bind through the 5'AMP-activated protein kinase (AMPK) [51]. Additionally, the intensified activities of LRRK-2 increase the PD risk since the amplification of the kinase ac-tivity has been associated with nigrostriatal degeneration and with the formation of Lewy bodies.
Secondly, when referring to the alpha-synuclein gene (SNCA), the pathogenicity mechanism is still not totally clear, since the PD associated with SNCA demonstrates an effect of gene dosage suspected of function gain. Thus, it was recently showed that an increase in the number of SNCA copies leads to elevated levels of mRNA and wild-type SNCA protein [52] and that such ampliation in the quantity of copies has been associated with an earlier beginning of the disease, a more severe phenotype with some atypical characteristics, including myoclonus, and a faster progression than in the duplication [53]. Besides, a case of gene triplication reported by Singleton et al. had a notorious clinical course because of its early beginning and a postmortem examination notable for a prominently cortical and subcortical pathology [54]. Duplications were also reported in numerous ADPD families [55] as well as in sporadic PD [56,57] in which the reported phenotypes include prominent psychiatric symptoms, including visual hallucinations [55]. Thus, although the alteration in the SNCA gene is rare, the abnormal conglomerates of alpha-synuclein protein are present in all the PD patients, in which such gene is the main component of the Lewy bodies, the pathologic mark of Parkinson's disease [58].
Finally, it is valid to highlight the PARKIN gene, whose pathogenicity mechanism is also not totally clear. Parkin is an E3 ubiquitin ligase protein, which catalyzes the ubiquitin transference to its specific target protein. Therefore, numerous target proteins with highly variable functions were suggested as possible Parkin substrates, where a role in the protein goal for proteasomal degradation was proposed [59]. Besides, PARKIN also triggers a job with the PINK1 gene in the control of organelle quality through the activation of mitophagy in the context of mitochondrial damage60. The pre-exposed PINK1 gene is a serine/ threonine kinase, which also contains critical regulatory locations, where its mutations are the second most common cause of ARPD after Parkin, with some superposition with the Parkin phenotype. Its locus was identified for the first time in a Sicilian family (Marsala kindred) with four members affected by early beginning PD, with course notorious for slow progression and a sustained response to Levodopa. Sequentially, as suggested for the first time by Valente et al. through cell culture studies, PINK1 is localized in mitochondria imported to the segmentation pathway61 and its alterations lead to a complete loss of kinase activity and are associated with an early beginning PD [62].Thus, PINK1 works in a more prominent way along with Parkin in the mitophagy activation, accumulating in the external mitochondrial membrane in the context of mitochondrial damage [62].

Conclusion
Through the advances in medicine, there was an increase in life expectancy and in the elderly population. In parallel, the prevalence of diseases related to age that led to cognitive decline increased, amongst them Parkinson's disease. In this review, we discussed how aging affects cognitive functions mediated by the medial prefrontal cortex, which has a key role in a series of critical cognitive functions. Thus, this study will contribute to a better characterization of cognitive deficits mediated by the mPFC in the healthy and pathologic aging process.

Funding: None.
Research Ethics Committee Approval: The study was approved by the Directorate of Clínica Luanda Medical Center under the direction of the Center for Advanced Studies in Medical Education and Training at Agostinho Neto University. The preservation and confidentiality of patient information were guaranteed, following all standards for research on human beings following the Declaration of Helsinki on ethical principles for research on human beings.