European Review for Medical and Pharmacological Sciences 2021; 25: 3015-3027 Cognitive function modulation during aging: a focus on L-alpha-GPE G. BIGGIO1, I. DI FAZIO2, C. MARTINI3 1Department of Life and Environmental Sciences, Institute of Neuroscience, CNR, University of Cagliari, Cagliari, Italy 2Geriatric Evaluation and Rehabilitation Unit Richiedei Foundation, Palazzolo sull’Oglio, Brescia, Italy 3Department of Pharmacy, University of Pisa, Pisa, Italy All authors contributed equally to this work Abstract. – OBJECTIVE: The objectives of Introduction this review are to explore the neuronal path- ways and cellular and molecular mechanisms Cognitive impairment (CI) is a global health involved in both healthy and impaired cognitive issue and, as such, causes a substantial individ- function and to discuss the role of nootropics, ual, economic and societal burden. In addition, in particular, those with cholinergic activity, as promising interventions to preserve and/or im- CI can herald the onset of dementia, which is in- prove cognitive performance in patients in the creasingly associated with significant morbidity symptomatic pre-dementia stage, known as and mortality1,2. During the aging process, there mild cognitive impairment (MCI). is a decline in the ability to perform cognitive MATERIALS AND METHODS: Papers were re- tasks that require one to quickly process/trans- trieved by a PubMed search, using different com- form information to make a decision, includ- binations of keywords (e.g., cognitive function ing measures of speed of processing, working AND aging AND nootropics), without limitations in 1 terms of publication date or language. memory, and executive cognitive function . By RESULTS: Nootropics modulate the activities investigating the factors influencing the course of specific brain pathways involving neurotrans- of cognitive aging may be useful in both preven- mitters and neuromodulators that have distinct tion and treatment strategies aimed at preserv- roles in the cognitive processes. The nootropic ing cognition into advanced age. In the last de- a a L- -glyceryl-phosphoryl-ethanolamine (L- GPE), cade, the notion of successful aging and the idea by virtue of its action as a phospholipid (PL) precursor and acetylcholine (Ach) donor, targets of compression of morbidity – maximizing the neural stem cell aging, cholinergic depletion, oxi- span of effective functioning while minimizing dative stress and microglia activation, loss of en- the length of time in which individuals are func- torhinal cortex neurons, and reduced hippocam- tionally impaired – have been largely discussed pal volume. Cognitive reserve levels may be linked in the medical literature. In this scenario, inves- to the resilience and adaptability of the brain to tigating the neuronal circuits involved in cogni- a cope with age-related cognitive decline. L- GPE tive aging/decline is fundamental in prolonging may contribute to cognitive reserve preservation via its neuronal well-being promoting action. cognitive, physical, and psychological well-be- 3,4 CONCLUSIONS: The substantial burden of ing in older adults . age-related cognitive decline demands effec- Mild cognitive impairment (MCI) occurs tive long-term and well-tolerated interventions along a continuum from normal cognition to aimed at maximizing the span of effective func- dementia. Classified as a mild neurocognitive tioning. The use of inappropriate medication disorder by the World Health Organization may lower cognitive reserve, thus hastening the onset of symptomatic AD, while the use of (WHO), it is increasingly recognized as a rel- nootropics, such as L-a GPE may contribute to evant pathological condition with an estimated cognitive reserve preservation via its neuronal prevalence of 3-19% in the elderly population5,6. well-being promoting action. MCI is gaining recognition as a construct in a range of neurodegenerative diseases, includ- Key Words: Mild cognitive impairment, Aging, Memory, Neu- ing Alzheimer’s Disease (AD) and dementia, ronal plasticity, Nootropics. and its presence as a common feature in Par- kinson’s disease5, and multiple sclerosis7 is in- Corresponding Author: Giovanni Biggio, MD, Ph.D; e-mail: [email protected] 3015 G. Biggio, I. Di Fazio, C. Martini creasingly documented. MCI has been regarded Selection of Evidence as a concept in evolution as definitions of sub- Papers for consideration for the present review types, and diagnostic criteria have been intro- were retrieved by a PubMed search, using dif- duced and modified over time, thus reflecting ferent combinations of keywords (e.g., cognitive the evolving recognition of MCI as an early dis- function AND aging AND nootropics), without ease state in the AD continuum as well as the limitations in terms of publication date and lan- phenotyping-driven patient classification based guage. Papers were selected for inclusion accord- on impairments in multiple or single cognitive ing to their relevance for the topic, as judged by domains. Different diagnostic criteria and sub- the Authors. types of MCI have been proposed and revised over time with the further implementation of the presence of biomarkers indicative for AD patho- Neuronal Plasticity physiology. A very recent and detailed overview and Cognitive Function: of the evolution of MCI diagnostic criteria has the Brain As a Dynamic Organ been recently published6. One important key fea- ture is the observation that MCI causes cognitive Imaging techniques, such as positron emis- changes that do not affect the individuals’ ability sion tomography (PET) and magnetic resonance to carry out everyday activities and, importantly, imaging (MRI), and increasing research in the does not always lead to dementia. In addition, in field of cognitive neuroscience provide a unique some individuals, MCI may even revert, as ob- opportunity to explore brain function by relating served in population-based studies6. Thus, MCI functional imaging to brain cell biology, neuro- as a diagnostic entity has stood the test of time physiology, and metabolism14. Recent advanc- and currently stands as an important treatment es in neuroscience led to a greater awareness of target6,8. However, there is currently no effective the dynamic nature of our brain in which large- pharmacological intervention able to prevent or scale integration among local subnetworks un- slow the course of MCI. A major research effort derlies information processing and cognitive is currently directed towards interventions that tasks – overall, we are increasingly aware that slow the rate of cognitive decline while reducing our brain is restless even at rest15. Thus, it is not cognitive morbidity6. surprising that structural and functional dynamic Nootropics may serve as promising treatment changes take place in the brain across the entire options to strengthen and enhance cognitive per- lifespan (during adolescence or aging)16,17, and in formance across a wide range of brain pathologies both physiological (pregnancy and lactation18) by virtue of their effects on brain dopaminergic, and pathological conditions, including depres- glutamatergic/cholinergic and serotonergic sys- sion19 and Parkinson’s disease20. Evidence of the tems. While research has led to the synthesis of connection between physical changes that occur several drugs with nootropic effects, more re- at individual synapses and behavioral evidence cently, attention has shifted to the identification of learning and memory were provided by Eric of nootropics from natural sources for the pre- Kandel et al21, who coined the term “neuronal vention and management of age-related cognitive plasticity” as the ability of neurons to modify the decline2. Among nootropics of natural origin, strength and efficacy of synaptic transmission L-a-glyceryl-phosphoryl-ethanolamine (L-a- through a diverse number of activity-dependent GPE) is a promising option to target the hallmarks mechanisms. Being plastic, neurons can modify of MCI, including neural stem cell aging, cholin- their molecular, structural and functional out- ergic depletion, oxidative stress and microglia put, through changes in morphology, activation activation, loss of entorhinal cortex neurons, and of intracellular signaling cascades, regulation of reduced hippocampal volume9-13. synaptic density, and neurotransmitter release This work explores the neuronal pathways (or a combination of these events) in response to and the cellular and molecular mechanisms un- specific stimuli. Interestingly, the entire neuronal derpinning both healthy and impaired cognitive network is constantly evolving as being plastic function during aging and discusses the potential and encompassing not only single neurons but of nootropics, particularly those with cholinergic also the extracellular environment. activity, to promote neuronal well-being and pre- Neuronal plasticity is due to the physical and serve and/or improve cognitive performance in chemical changes that occur in our brain during patients with MCI. learning and memory processing. There is evi- 3016 Cognitive impairment and nootropics dence that learning and memory, synaptic plas- memory decline and perhaps slowing cognitive ticity, and neurogenesis are inter-related phenom- impairments associated with neurodegenerative ena. Specifically, the latter two are thought to disorders. Accordingly, a reduction of cholinergic provide a substrate for specific aspects of learning transmission, due to the atrophy of basal nucleus and memory function22. Furthermore, research