Cognitive Function Modulation During Aging: a Focus on L-Alpha-GPE

Home , Acetylcarnitine

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 pathways 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 feature 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 of Meynert, seems to be one of the most import- is ongoing to investigate whether the cellular ant neurochemical events involved in the devel- mechanisms of neuroplasticity mediate neuronal opment of the cognitive decline associated with health, hippocampal size and ultimately cognitive MCI. However, it is important to take into consid- function1. Studies23-27 on the plastic properties of eration that cholinergic neurons’ loss is preceded neurons, along with the data of “Brain Imaging” by a functional impairment of the same neurons on the structural and functional changes in dif- following the accumulation of toxic molecules, ferent brain areas elicited by positive and nega- such as b-amyloid, protein t and micro fibrillary tive environmental input have allowed a greater filaments which are associated with a reduced understanding of the most important brain areas connectivity between cholinergic neurons and involved in the modulation of cognitive functions those producing dopamine, glutamate, GABA and unveiled association between alterations in and norepinephrine. Moreover, astrocytes, mi- different receptors and the various chemical neu- croglia cells and the membrane lipid composition, rotransmitters, including g-aminobutyric acid such as phospholipids, stand as relevant factors (GABA), glutamate and dopamine in different involved in the modulation of neuronal plasticity neural circuits and cognitive deficits. To date, under both physiological and pathological condi- GABA transmission, within the prefrontal cor- tions. Accordingly, there is mounting evidence29 tex and the hippocampus, if inhibited, can have that interaction between neurons and microglia important implications on clinically relevant drives experience-dependent synapse remodeling cognitive functions24 while modulation of gluta- in the hippocampus promoting memory consoli- mate transmission via inhibition of the enzyme dation; thus, microglial cells contribute, via their glutamate carboxypeptidase II (GCPII) has been essential volume-related actions in the brain, to found to improve cognition26. Furthermore, the the maturation and plasticity of neural circuits importance of dopaminergic modulation of the that ultimately shape behavior30. prefrontal cortex for proper cognitive functions Finally, lipids, as key components of synaptic is also well supported by experimental evidence membranes, may also affect synaptic plasticity by from non-human primates and rodents. Alter- shaping the membrane and modulating the levels, ations of the dopaminergic system are frequently compartmentalization, interactions, trafficking reported in AD patients and are commonly linked and signaling properties of many proteins that are to cognitive and non-cognitive symptoms. Over- essential for synaptic function28. Thus, membrane all, dopamine is a well-recognized modulator of phospholipids (PL) and proteins may play a role in hippocampal synaptic plasticity and its binding to cognitive function and, as such, may be potential dopaminergic receptors in the dorsal hippocam- therapeutic targets in the management of MCI. pus is a major determinant of memory encoding25. However, the complex structural and molecular interconnectivity among prefrontal cortex and the Role of Membrane Phospholipids main nuclei (accumbens, amygdala, hippocam- and Proteins in Cognitive Function pus) of the limbic region indicates how it is diffi- cult to find molecules able to selectively interact Changes at the level of neuronal membrane and, with one or more specific receptors, transporters, in particular, its protein and lipid machinery that enzymes associated to the above-mentioned neu- controls neuronal plasticity (and ultimately cogni- ronal pathways. tive function) contribute to the clinical profile of the In line with the role in cognitive functions of ageing brain. Such alterations are correlated with basal forebrain cholinergic input to the hippocam- structural and functional changes in the neuronal pus, evidence28 suggests the involvement of ace- membrane composition (reduced PL synthesis and tylcholine (Ach) receptors in various aspects of modified PL/cholesterol ratio with an increase in neural plasticity, including long-term potentiation the latter component), lower availability of chemi- (LTP), regulation of brain-derived neurotrophic cal mediators (mainly Ach) and reduced number of factor (BDNF), and hippocampal neurogenesis – receptors and activation frontal and temporal cortex indicating novel ways of preventing age-related cells, thus impacting cognitive functioning12.

3017 G. Biggio, I. Di Fazio, C. Martini

PLs are the most abundant brain lipids and tion37. Honer et al37 suggests that greater amounts the fact that concentrations of phosphatidylcho- of specific presynaptic proteins and distinct pro- line (PC), phosphatidylserine (PS) and phospha- tein-protein interactions may be structural or func- tidylethanolamine (PE) varies between the white tional components of the cognitive reserve that (myelinated tracks) and grey matter (cell bodies) reduces risk of dementia with aging. Scholars38-40 underlies a correlation between lipid composition support the notion that de novo protein synthesis and brain function32. The characteristics of PL has an important function in synaptic transmission seem to be associated with neuronal features with and plasticity with mRNA translation in the hip- increased unsaturation and chain length providing pocampus being spatially controlled and dendritic higher membrane fluidity, connectivity and neu- protein synthesis being required for different forms rotransmitter release. The relationship between of long-term synaptic plasticity. Although progress different PLs and cognitive performance has been has been made in evaluating the connection be- evidenced in preclinical and clinical studies and tween memory consolidation processes and pro- relevant PLs in relation to cognitive performance teostasis, information on the lifetime of neuronal include PS and PC, as well as the related substanc- proteins or the dynamics of protein trafficking is es sphingomyelin, and the sialic-acid-containing still lacking39. gangliosides33. Furthermore, plasma PLs were Biochemical, cellular, molecular and patholog- associated with cognitive function during middle ical investigations improved our understanding adulthood, the risk of decline in verbal fluency, of how protein modification and misfolding may and a significant reduction in the risk of develop- directly harm synapses, alter neurotransmission ing all-cause dementia34,35. A ten-metabolite pro- and ultimately impair cognitive function. The file containing PCs (diacyl-PC and lyso-PC) and soluble small aggregates of Ab, AbOs, are cur- acylcarnitines – phospholipids that have essential rently regarded as the main species responsible structural and functional roles in the integrity and for the neuronal dysfunction seen in AD by virtue functionality of cell membranes – was found to of their ability to bind specifically to neurons, no- differentiate cognitively normal participants who tably to excitatory dendritic spines, and to induce will progress to amnestic MCI or AD within 2-3 synapse damage/loss and memory impairment by years, from those destined to remain cognitively multiple mechanisms41. Furthermore, a series of normal in the near future36. Overall, these results studies utilizing synthetic, natural, and human suggest that plasma PL levels may be useful in the AD-derived Aβ have indicated that soluble Aβ detection of MCI and dementia. oligomers are both necessary and sufficient to The concentration and composition PLs de- disrupt normal learning and memory function. At termine the activities of enzymes, receptors, and the two extremes of aggregation, monomers and other proteins involved in healthy cognitive func- fibrils appear to act in vivo both as sources and tion, thus providing an optimal membrane envi- sinks of certain metastable conformations that ronment for protein interactions, transmission and disrupt synaptic plasticity42. Tau protein has been function. Membrane presynaptic terminals are also proposed to contribute to cognitive impair- enriched with multiple proteins, each providing a ment based on the observation that MCI patients specialized contribution to neurotransmission and exhibiting the earliest detectable clinical symp- cognitive function. Dynamic changes in synaptic toms of dementia show accumulation of abnor- terminal number, membrane protein composition, mally phosphorylated t protein in CSF43. In line and function contribute to cognitive development with this point, researches in a mouse model of during brain growth and maturation and may me- inducible tauopathy have shown that the cognitive diate cognitive decline during aging37. Screening impairments appear to be a result of progressive analyses of the presynaptic protein relationships neuronal loss, as well as synaptic dysfunction, with global cognitive function in the elderly par- depending on the levels of phosphorylated t ex- ticipants of the MAP (Memory and Aging Project, pression44. a community-based study) study showed that ves- A better understanding of the mechanisms that icle-associated membrane protein (VAMP), com- lead to different protein expression patterns in the plexin-I, complexin-II and the SNAP-25/syntaxin neural circuits that change as a function of age are interaction were associated with cognitive func- urgently needed and may enable the development tioning. Greater cortical atrophy, a dementia bio- of more effective therapeutic treatments for mem- marker, was reported to be associated with lower ory loss. Technological advances have enabled complexin-II and lower SNAP-25/syntaxin interac- high-throughput and cost-effective measurement of

3018 Cognitive impairment and nootropics plasma proteins. A proteome-wide study45 of cog- (p-Tau) Tau measures]. Of note, prodromal AD nitive trajectory showed that proteins involving mi- relates to only the amnestic portion of the MCI tochondrial activity or synaptic function increased clinical criteria, and it is augmented by evidence among individuals with cognitive stability irrespec- of Aβ either from PET scanning or CSF or the tive of β-amyloid plaques or neurofibrillary tangles. presence of an abnormal tau/Aβ ratio in the CSF8. Last but not least, lipoxidation during aging can In patients with MCI, an initial period of in- affect not only lipids but also lipids associated with creased brain activation in response to cognitive protein structures thus leading to loss of function demand is followed by decreased activation as of key proteins involved in cell metabolism46; such disease progression continues, eventually ex- detrimental effect underlines the contribution of hausting the compensatory response. In order for lipid, mostly PL, to provide an optimal membrane interventions targeting plasticity to be effective, environment to protein functions. While additional the brain must still be capable of compensation for studies are needed, this finding adds further evi- deficits that maintains functional ability or - per dence to the clinical relevance of capturing molec- formance. Although a degree of plasticity seems ular changes across all stages of cognitive decline to be maintained throughout the early stages of as they may be used for early intervention and AD, the critical period for treatment maybe prior prevention. Furthermore, integrating information to AD diagnosis supporting the clinical benefit of about these proteins with information on estab- an earlier intervention in MCI patients49. lished biomarkers for dementia, such as amyloid The pathophysiological signature of MCI in- β-42 and neurofilament light, may help in identi- cludes molecular, neurochemical and structural fying the biological pathways to exploit therapeu- alterations, synaptic degeneration, cell loss, re- tically for age-related cognitive decline, preferably duction in neurotrophic function and neuronal se- at the prodromal stage, when neuronal machinery lective vulnerability. Neuronal loss occurs in the may still be responsive47. To this end, it is impera- limbic medial temporal lobe and particularly in tive to characterize and unravel the structural and the entorhinal cortex, while the hippocampus dis- cellular pathobiological substrate of MCI and the plays a significant decline in plasticity48. Thus, the cerebral features that underlie disease course and limbic area appears particularly affected in MCI. symptom presentation. Structural MRI studies and functional studies using FDG-PET and brain perfusion single-photon emission computed tomography (SPECT) have Unravelling the Cerebral shown gray matter loss in the entorhinal and hip- Features In MCI pocampal areas and hypometabolism or hypoper- fusion in the posterior cingulate cortex and precu- Despite advances in defining the clinical pro- neus at MCI stage50,51. Interestingly, such profile file of MCI and the availability of consensus di- seems to predict rapid conversion to AD. Yue et agnostic criteria for MCI, its gross morphologic al52 have also shown that MCI patients displayed features are not easily identified with only a wid- significant decreased right hippocampal and ening of sulci, such as the ventral ramus of the amygdala volume than controls. For asymmetry lateral fissure, as well as a blunting of the anterior pattern, a ladder-shaped difference of left-larg- tip of the temporal pole found in patients with am- er-than-right asymmetry was found in amygdala nestic MCI compared to those with no cognitive with MCI > controls, and an opposite asymme- impairment48. try of left-less-than-right pattern was found with MCI is characterized by subtle clinical-neuro- controls > MCI in hippocampus. Furthermore, psychological changes which are related to syn- Wachinger et al53 investigating the symmetries aptic dysfunction and long-lasting pathological of neuroanatomical structures across subcorti- deposition of toxic proteins in the brain; how- cal and cortical brain regions have shown that ever, the clinical-neuropsychological assessment the hippocampus shows a significant increase in has limited accuracy for the prediction of poten- asymmetry longitudinally and both hippocam- tial MCI conversion to AD. Clinicians may take pus and amygdala display a significantly higher advantage from diagnostic biomarkers, such as asymmetry cross-sectionally concurrent with dis- neuroimaging [i.e., MRI, F-18 fluorodeoxyglu- ease severity above and beyond an ageing effect. cose-positron emission tomography (FDG-PET) Importantly, shape asymmetry in hippocampus, and amyloid-PET] and cerebrospinal fluid-CSF amygdala, caudate and cortex appears predictive [i.e., Aβ42, total (t-Tau) and phosphorylated of disease onset.

3019 G. Biggio, I. Di Fazio, C. Martini

Hippocampal shrinkage and synapse loss els as faces the physician in clinical practice of occur early in the pre-symptomatic and MCI having to distinguish between MCI and the ini- phases of AD, thus promoting earlier therapeutic tial stages of AD. Although these animal models interventions to remove disease triggers and stop have been used to test drugs for the treatment of neurodegeneration before overt memory loss54. the memory deficits, a validation of the models Alterations in plasticity and connectivity have through comparable therapeutic results in ani- also been reported in MCI as disruption and loss mals and humans is lacking. Much research is of synaptic connectivity result in progressive being carried out to identify alternative models cognitive decline due to white-matter abnor- of CI with sleep deprivation recently endorsed as malities and anatomical/functional deficits2. A a cognitive challenge model of CI arising in AD primary mechanism by which synaptic connec- by virtue of both partially overlapping spectrum tivity is altered may involve expression and re- of induced cognitive deficits and their response to sponsiveness to neurotrophins. Within the adult pharmacological treatment59. hippocampus, trophic factors in BDNF, play a central role in synaptic remodeling associated with memory. Siuda et al55 showed that low- Therapeutic Targets in MCI: er BDNF serum levels were directly correlated Exploiting Cortex and Hippocampus with the severity of CI with significantly lower Cell Types and Functions levels in AD patients compared to those with MCI and control subjects. Changes in neuronal To date, research in cognitive impairment circuits involved in cognition have been docu- and AD has been neuron-oriented but Nirzhor mented in MCI with cholinergic basal forebrain et al60 suggest that glial cells are linked to AD neurons containing early and late tau confor- pathogenesis and may offer potential therapeutic mational markers of neurofibrillary tangles and targets against AD by virtue of their role in pre- increased activity of choline acetyltransferase serving the structural integrity of neurons and in both hippocampus and superior frontal cor- maintaining homeostasis (i.e., concentration of tex48. From a cellular standpoint, alternations in ions, neurotransmitters, etc.) within the CNS. In- essential metabolic processes for energy supply creases in microglial activation in the prodromal and PL membrane function have been implicat- stage of AD have been reported, including in in- ed in the pathological process. FDG-PET stud- ferior and medial temporal regions where early ies56 have shown glucose hypometabolism in the neurodegenerative changes occur. Furthermore, retrosplenial cortex (RSC) and medial temporal in MCI patients a relationship between microgli- lobe in people with MCI while postmortem stud- al activation and fibrillary amyloid deposition in ies found reduced levels of the major membrane cortical regions that typically have high plaque components, such as PC, PE and phosphatidy- load in AD was observed providing additional linositol. The human brain is highly vulnerable evidence for the microglia as potential cellular to changes in energy metabolism, due to its rel- targets in MCI61. atively large energy consumption. It is subject Neuronal ‘well-being’ also relies on the neu- to free radical-induced lipid peroxidation (it ral stem cells (NSCs) – a subpopulation of cells uses one-third of the inspired oxygen), is rich in in the dentate gyrus of the hippocampus and in polyunsaturated fatty acid (targets for free radi- the subventricular zone of the lateral ventricles cal attack), is high in redox transition metal ions capable of self-renewal and differentiation (adult and low in antioxidant capacity57. As a result, in- neurogenesis). Adult neurogenesis is related to creasing evidence indicates oxidation of lipids, the amelioration of impaired neurons and CI. Al- numerous proteins, DNA, and RNA in multiple though neurogenesis continues throughout life, brain regions in subjects with MCI. it decreases with age due to an intrinsic decline To better understand the pathogenic mecha- in NSC responsiveness10. Furthermore, in aged nisms of MCI, appropriate models of CI are nec- NSCs, changes in the amount and composition essary. Middle-aged rats and mice, rats with brain of membrane proteins/lipids have been reported ischemia, transgenic mice overexpressing amy- leading to a reduction in membrane fluidity and loid precursor protein and presenilin 1 (tested at cholinergic activities. As a result, molecules that an early stage), or aging monkeys are promising are effective at normalizing membrane compo- candidates58. However, a major concern is how to sition and cholinergic signaling may counteract distinguish MCI models from AD animal mod- stem cell aging10.

3020 Cognitive impairment and nootropics

The secretome of human NSCs plays a pivotal or preventing further progressive deficits. Given role in promoting neuroprotection and regenera- the well-documented pathophysiological relation- tion. Factors produced by NSCs provide an envi- ship between MCI and AD, therapeutic interven- ronment that allows injured cells to resist further tions for MCI are based on treatment strategies degeneration, promote repair, drive regeneration for AD including acetylcholinesterase inhibitors of injured tissue, and decrease inflammation62. (AChEIs), antioxidants, nootropics, and anti-in- BDNF secreted from NSCs is essential in res- flammatory drugs. Nootropics have been avail- cuing cognitive function in AD. The beneficial able for over three decades and are the agents effects of NSCs on cognition are not mediated most frequently indicated for the initial treatment by alteration of Aβ or tau pathology, instead, of dementia-related symptoms and age related NSC-derived cells increase hippocampal BDNF cognitive impairment66. Also known as ‘smart leading to improved synaptic density and resto- drugs’, nootropics are thought to enhance cogni- ration of hippocampal-dependent cognition63. tive parameters, such as memory, creativity, mo- Cell function can also be used as a target in MCI tivation, attention and more in general the exec- management. Mitochondria regulate the func- utive processes2. Multiple mechanisms of action tions of healthy neurons that are highly depen- have been proposed for the beneficial effects of dent on oxidative phosphorylation to meet energy nootropics on memory and learning, including demands and are particularly susceptible to en- blockage of calcium channels, inhibition of AChE ergy hypometabolism. Neurons are non-dividing activities, increase in the level of antioxidants and cells and are not replaced during life, with the in synaptic and mitochondrial response genes. exception of the hippocampus that continuously Kell et al67 suggested that therapeutically rele- generates new neurons during adulthood. This vant in vitro and in vivo concentrations of pirac- means that neurons accumulate oxidative stress etam, the prototype of the so-called ‘nootropic’ and defective mitochondria during aging64 and at drugs, are able to improve mitochondrial dysfunc- the early stages of AD65 have been documented. tion associated with oxidative stress and/or aging. The mitochondrial cascade hypothesis identifies Mitochondrial stabilization and protection might mitochondrial dysfunction as a central pathologic be an important mechanism to explain many of mechanism in age-related degenerative disorders piracetam’s beneficial effects in elderly patients. and indicates mitochondria as promising targets Gray et al68 have shown in vivo that Centella Asiati- for therapeutic strategies. Pharmacological stud- ca, a nootropic of natural origin, modulates antiox- ies on improving mitochondrial function, such idant and mitochondrial pathways. Daniele et al10 as ATP production and respiration or in reducing in human stem cells have shown that L-a-glycer- mitochondrial harmful by-products, such as rad- yl-phosphoryl-ethanolamine (L-aGPE) cell treat- ical oxygen species, (ROS) are indicated5. MCI ment significantly protected the redox state and is neuropathologically complex and cannot be functional integrity of mitochondria, and counter- defined within a single framework. Determining acted senescence and NF-κB activation. which factors primarily drive neurodegeneration Nootropics may also have neuroprotective and dementia and which are secondary features effects reducing Aβ accumulation, synaptic dys- of disease progression requires further research. functions, inflammation, apoptosis, and oxidative Nevertheless, available evidence indicates poten- stress69. Nootropics have been demonstrated to tial therapeutic avenues that are worth pursuing, protect against experimentally induced disrup- such as the nootropics that modulate the activities tion of acquisition, retention or retrieval in animal of specific brain pathways involving neurotrans- models in either passive avoidance or similar pro- mitters and neuromodulators that have distinct cedures70. Advantages of the nootropics include roles in the cognitive processes2. absence of adverse effects usually associated with neuropsychotropic drugs, good long-term toler- ability and adherence to therapy. They improve MCI Clinical Management: cognitive functions70 and have documented long- Role of Nootropics term efficacy in a variety of conditions involving decreased mental acuity from mild to moderate. The goals of MCI management are to improve The cholinergic system plays an important memory loss and prevent further cognitive de- role in the regulation of synaptic communica- cline. Early interventions and treatments should tion and plasticity in the hippocampus and the improve cognitive performance while delaying firing of cholinergic inputs into the hippocampus

3021 G. Biggio, I. Di Fazio, C. Martini from the medial septum seems to be important in L-a GPE: Preclinical and Clinical learning and memory71. Given the role played by Evidence In MCI Ach in learning and memory, the effectiveness of nootropics with a cholinergic activity is well doc- L-a GPE improves the neuronal structures umented72. Compounds that induce a sustained involved in learning and memory by two mecha- activation of postsynaptic Ach receptors, such as nisms: as a precursor of PC and as a direct source lecithin, citicoline, acetylcarnitine and choline al- of the major components of the phospholipid bilay- foscerate are mainly used in the treatment of cog- er, PE and PC11. Accordingly, the latter has been nitive deficits with a vascular and degenerative shown to contribute to recover astrocytes from the origin. However, increasing Ach availability with general redox derangement induced by different only precursor administration may not always amyloid fragments and possibly to protect from be correlated with improved cognitive function- inflammation, gliosis and neurodegeneration11. Re- ing. This is in contrast to what observed in PD storing the membrane stores of PL is promising in in which improving dopamine availability via its counteracting NSC aging as evidence suggests that precursor L-Dopa causes an immediate function- replenishing the NSC membrane composition by al improvement. In MCI restoring Ach bioavail- PC supplementation improves hippocampal neu- ability seems not to be sufficient. One reason may rogenesis while reducing soluble tumor necrosis be that Ach exerts cellular, genomic and function- factor-alpha (TNF-α) levels and ultimately coun- al activities thereby promoting a virtuous circuit teracting systemic inflammation. Furthermore, improving neuronal well-being. It has therefore the glycerophospholipid PS has been shown to been suggested that rather than just providing a improve NSC function and cholinergic transmis- substrate, it is necessary to also ensure that the sion, leading ultimately to improvement of mem- neuronal environment is ‘plastic’ and responsive ory and learning10. These observations provided to allow Ach to contribute to neuronal well-being. the rationale to investigate if administration of To this end, it can be hypothesized that, along L-a GPE counteracts NSCs senescence. Daniele with Ach availability, the normalization of PL et al10 demonstrated that L-a GPE improved pro- content at the neuronal membrane level is critical liferative potential of cells and mitochondrial me- as it may contribute to neuronal plasticity and in tabolism, decreased ROS production, and blocked general to an efficient neuronal ecosystem where the inflammatory pathway by reducing NF-kB preservation of PL pool is crucial not only for activation – properties that may be in part associ- membrane fluidity but also for PL biosignalling ated with its ability to act as a PC precursor and function. Modulation of membrane PL content an Ach donor10. In human hippocampal neurons, influences organelles and protein function; fur- L-a GPE increased phospholipids (PC and PE) and thermore, the lipid composition of membranes Ach, leading to improved membrane function by may also influence the processing pathways of the reducing lipid peroxidation and enhancing mem- transmembrane protein APP or the formation of brane fluidity, as well as inducing autophagy and toxic oligomeric Aβ73-75. Among nootropic com- exerting cytoprotective effects in aged cells. Over- pounds, citicoline potentiates neuroplasticity and all, these results show the beneficial effects of L-a is a natural precursor of phospholipid synthesis, GPE supplementation and support its use as a po- chiefly phosphatidylcholine, and was hypothe- tential therapeutic agent to preserve hippocampal sized to protect cell membranes by accelerating neurons and memory performance9. resynthesis of phospholipids, thus resulting in L-a GPE demonstrated a significant improve- rapid repair of injured cell surface and mitochon- ment in behavioral performance in in vivo models drial membranes76. Whether the supplemented of cognitive impairment, such as the active avoid- choline restored deficits of particular lipid me- ance-conditioning test77. Furthermore, sub-chron- tabolites in the cellular lipid pool, or if it boosted ic administration enhanced receptor-mediated the levels of key metabolites that may have great- neuronal signal transduction (cAMP and IP pro- er bioactivity is less clear74. Among nootropics, duction), possibly by increasing coupling between L-a-glyceryl-phosphorylethanolamine (L-a neurotransmitter receptors and their intracellular GPE), known to improve cognitive impairment effectors through improved neuronal membrane in neurodegenerative diseases, is unique and is fluidity. It has been suggested that these neuro- involved in the biosynthesis of the cellular mem- chemical modifications may explain at least in brane PL as a direct substrate for the synthesis of part, the molecular mechanisms of L-a GPE at PE and then PC11. the brain level. These preclinical observations

3022 Cognitive impairment and nootropics provided further evidence for the use of L-a GPE memory function, we are still missing many piec- in humans to maintain brain function during the es of the puzzle and we only partially appreciate aging process, and the scientific rationale for in- the complexity behind the transition from normal vestigation in patients with mild age-related cog- ageing to CI. There are many hurdles to overcome nitive disturbances77. In an early clinical study before we can effectively manage MCI and suc- in patients with senile psycho-organic syndrome cessfully implement interventions targeting mor- treatment with L-a GPE resulted in a significant bidity compression and preservation of cognitive symptoms’ reduction and improved learning and reserve. memory functions compared to placebo, as well Diagnosis of MCI is problematic since patients as significant reductions in depressed mood, in- who report having cognitive problems may have somnia and cenesthopathy12. A subsequent pilot normal scores on global cognitive scales or in brief double-blind, randomized, parallel group multi- neuropsychological instruments. In addition, the center study was carried out in patients with mild variability in clinical practices across centers de- to moderate AD to compare efficacy and safety of mands better biomarker counseling and training to L-a GPE with donepezil. Although no significant improve communication skills. Future initiatives differences were reported in clinical parameters should address the importance of communicat- such as the Gottries-Brain-Steen Scale (GBS), ing preventive strategies and advance planning. It Questionnaire for Memory Disorders (QDM) and is critical to assess instrumental activities of dai- Clinical Global Impression (CGI), greater clinical ly living (iADL) that reflect complex activities in improvement in Alzheimer’s Disease Assessment the evaluation of individuals with MCI as their Scale-cognitive subscale (ADAS-Cog) score was impairment, combined with changes in cognitive observed in L-a GPE treated patients13. While markers, indicates a higher risk of progression to these observations are promising, further clinical dementia78. As advocated by Kasper et al6, it is vi- studies are urgently awaited to determine the ther- tal to update existing guidelines based on available apeutic role of L-a GPE in a range of cognitive evidence and to disseminate consensus diagnostic impairment-associated neurological conditions. criteria for MCI when available, as well as working The rationale for use of L-a GPE is based on towards an early recognition and accurate classifi- its neuroprotective properties as a result of its cation of MCI subtypes. Such approach may help us ability to provide both precursors of the main to improve management of MCI and recognize the membrane PL, thus preserving membrane fluidi- importance of this disease stage within the AD con- ty, and of Ach by restoring neuronal transmission, tinuum which is important as mixed pathologies are as well as its action on the neural stem cells pool common in MCI and a multi-targeted treatment ap- and microglia, which both contribute to improve proach should be pursued. Finally, to define a profile neuronal plasticity and function. Furthermore, characterizing the state of MCI, we may take advan- given the potentiality of antidepressant drugs to tage from brain tissue banks that use standardized stimulate both NSCs proliferation and the ex- MCI criteria, neuropathological protocols including pression of BDNF in the hippocampus, L-a GPE staining and scoring techniques79. could be used in synergy with antidepressants to Identifying biological correlates of late life cog- potentiate cognitive processes. nitive function is important if we are to ascertain biomarkers and to develop treatments to help re- duce age-related CI. Future studies should focus Future Perspectives on which lipids change with age in different areas of the brain areas and how they relate both to the The world’s population is ageing with implica- function of the area and to the dysfunction leading tions for all sectors of our society. Interventions to neuropathology. The available evidence is on aimed at decreasing the social and financial costs qualitative alterations in lipid composition, howev- of declining cognitive function are increasingly er, quantitative lipidomic analyses may contribute being investigated. Characterization of the cellular to accurately define changes80. As the composition and molecular mechanisms involved in CI during of neuronal proteins ultimately dictates synaptic aging and its progression to frank neurodegenera- function, it might be effective for future studies to tive diseases is vital to understand the aging pro- focus on determining how biological correlates of cess. Despite major advances in neuroscience that aging affect the synthesis and activity of proteins have enabled us to gain an in-depth knowledge known to have roles in long-lasting forms of syn- of the role of synaptic plasticity in learning and aptic plasticity and memory.

3023 G. Biggio, I. Di Fazio, C. Martini

Available evidence indicates a series of potential ated interventions aimed at maximizing the span therapeutic avenues worth pursuing including the of effective functioning. The use of inappropriate nootropics, able to modulate the activities of specif- medication may lower cognitive reserve thus has- ic brain pathways involving neurotransmitters and tening the onset of symptomatic AD, while the neuromodulators that have distinct roles in the cog- use of nootropics such as L-a GPE may contrib- nitive processes. The nootropic L-a GPE, by virtue ute to cognitive reserve preservation via its neu- of its action as a PL precursor and Ach donor, holds ronal well-being promoting action. great promise as an effective option to target the hallmarks of MCI including neural stem cell aging, cholinergic depletion, oxidative stress and microg- Declaration of Funding lia activation, loss of entorhinal cortex neurons and This work was carried out thanks to an unrestricted educa- reduced hippocampal volume9-13. However, despite tional grant from Angelini Pharma (Rome, Italy). its widespread use in clinical practice, published evidence from clinical trials is limited12,13 and further studies to support its promising potential in MCI Declaration of Financial/Other Relationships management are required. Nevertheless, it appears Angelini did not play any role in design, planning, or execu- preferable to other commonly used nutritional ap- tion of the review. The terms of the financial support from proaches, including flavonoids, some vitamins and Angelini included freedom for the authors to reach their own conclusions, and an absolute right to publish the results other natural substances that are claimed to be bene- of this work, irrespective of any conclusions reached. ficial for the maintenance of a good cognitive perfor- mance81. Compared to nutraceuticals which display a late onset of action, L-a GPE is rapidly absorbed Authors’ Contributions at a gastrointestinal level and when administered in All authors contributed equally to this work. All authors take animal models a rapid uptake from systemic tissues responsibility for the integrity of the work as a whole and have including brain has been observed82. The course of given their approval for this version to be published. AD implies a preclinical stage whose duration in part depends on the rate of pathologic progression, which is offset by compensatory mechanisms, referred to Acknowledgments as cognitive reserve. Cognitive reserve levels may Writing and editing assistance, including preparation of a be linked to the resilience and adaptability of the draft manuscript under the direction and guidance of the brain to cope with age-related cognitive decline. The authors, incorporation of author feedback, and manuscript use of inappropriate medication may lower cogni- submission, was provided by EDRA, with the helpful support of Chiara Degirolamo, PhD, and supported by an tive reserve thus hastening the onset of symptomatic unconditioned grant from Angelini Pharma (Rome, Italy). AD83, while the use of nootropics, such as L-a GPE may contribute to cognitive reserve preservation via its neuronal well-being promoting action. Conflict of Interests The authors declare that they have no conflict of interest. Conclusions

By integrating three different perspectives References namely biology, pharmacology and clinical prac- 1) Murman DL. The impact of age on cognition. tice, our work explores how contributions stem- Semin Hear 2015; 36: 111-121. ming from neuronal pathways and cellular mech- 2) Onaolapo AY, Obelawo AY, Onaolapo OJ. Brain age- anisms may impact MCI onset, progression to ing, cognition and diet: a review of the emerging roles AD and its therapeutic management. Along with of food-based nootropics in mitigating age-related a review of the latest available evidence on the memory decline. Curr Aging Sci 2019; 12: 2-14. 3) Greenwood PM, Parasuraman R. Neuronal and cellular and molecular mechanisms underpinning cognitive plasticity: a neurocognitive framework both healthy and impaired cognitive function for ameliorating cognitive aging. Front Aging Neu- during aging, we focus our attention on how this rosci 2010; 2: 150. knowledge can be applied to better address dis- 4) Hertzog C, Kramer AF, Wilson RS, Lindenberger ease course and management objectives. Overall, U. Enrichment effects on adult cognitive development: can the functional capacity of older adults the substantial burden of age-related cognitive de- be preserved and enhanced? Psychol Sci Public cline demands effective long-term and well-toler- Interest 2008; 981: 1-65.

3024 Cognitive impairment and nootropics

5) Weil RS, Costantini AA, Schrag AE. Mild cogni- 20) Summerfield C, Junqué C, Tolosa E, Salgado-Pi- tive impairment in Parkinson’s disease-what is it? neda P, Gomez-Anson B, Marti MJ, Pastor P, Curr Neurol Neurosci Rep 2018; 18: 17. Ramirez-Ruiz B, Mercader J. Structural brain 6) Kasper S, Bancher C, Eckert A, Förstl H, Frölich L, changes in Parkinson disease with dementia. Hort J, Korczyn AD, Kressig RW, Levin O, Palomo A voxel-based morphometry study. Arch Neurol MSM. Management of mild cognitive impairment 2005; 62: 281-285. (MCI): the need for national and international guide- 21) Kandel ER. Search of Memory: The Emergence lines. World J Biol Psychiatry 2020; 21: 579-594. of a New Science of Mind. New York: WW Norton; 7) Islas MA, Ciampi E. Assessment and impact of 2006. cognitive impairment in multiple sclerosis: an 22) Stuchlik A. Dynamic learning and memory, syn- overview. Biomedicines 2019; 7: 22. aptic plasticity and neurogenesis: an update. 8) Pedersen RC, Caracciolo B, Brayen C, Gauthier S, Front Behav Neurosci 2014; 8: 106. Jelic V, Fratiglioni L. Mild cognitive impairment: a 23) Bast T, Pezze M, McGarrity S. Cognitive deficits concept in evolution. J Intern Med 2014; 275: 214-228. caused by prefrontal cortical and hippocampal neural 9) Daniele S, Mangano G, Durando L, Ragni L, Martini disinhibition. Br J Pharmacol 2017; 174: 3211-3225. C. The nootropic drug A-glyceryl-phosphoryl-etha- 24) McQuail JA, Frazier CJ, Bizon JL. Molecular aspects nolamine exerts neuroprotective effects in human of age-related cognitive decline: the role of GABA hippocampal cells. Int J Mol Sci 2020; 21: 941. signaling. Trends Mol Med 2015; 21: 450-460. 10) Daniele S, Da Pozzo E, Iofrida C, Martini C. 25) Nobili A, Latagliata EC, Viscomi MT, Cavallucci Human neural stem cell aging is counteracted by V, Cutuli D, Giacovazzo G, Krashia P, Rizzo FR, α-Glycerylphosphorylethanolamine. ACS Chem Marino R, Federici M, De Bartolo P, Aversa D, Neurosci 2016; 7: 952-963. Dell’Acqua MC, Cordella A, Sancandi M, Keller 11) Bisaglia M, Venezia V, Biglieri M, Russo C, Manci- F, Petrosini L, Puglisi-Allegra S, Mercuri NB, ni F, Milanese C, Schettini G. Alpha-glyceryl- Coccurello R, Berretta N, D’Amelio M. Dopamine phosphorylethanolamine rescues astrocytes from neuronal loss contributes to memory and reward mitochondrial impairment and oxidative stress dysfunction in a model of Alzheimer’s disease. induced by amyloid beta-peptides. Neurochem Nat Commun 2017; 8: 14727. Int 2004; 44: 161-170. 26) Rahn KA, Slusher BS, Kaplin AI. Glutamate in 12) Bernocchi P, Bracchi R, Ferri F, Fedeli S. La CNS neurodegeneration and cognition and its sindrome psicorganica. Esperienza clinica con regulation by GCPII inhibition. Curr Med Chem alpha-GPE per via iniettiva. Drugs 1995; 11. 2012; 19: 1335-1345. 13) Fioravanti M, Rosignoli MT, Olivieri L, Dionisio P. 27) Yin C, Li S, Zhao W, Feng J. Brain imaging of mild L-alpha-glicerofosforiletanolamina nel trattamen- cognitive impairment and Alzheimer’s disease. to di pazienti con malattia di Alzheimer. Studio in Neural Regen Res 2013; 8: 435-444. doppio cieco controllato verso donezepil. Geri- 28) Maurer SV and Williams CL. The cholinergic sys- atria 2001; 13: 199-206. tem modulates memory and hippocampal plas- 14) Raichle ME. Functional brain imaging and human ticity via its interactions with non-neuronal cells. brain function. J Neuroscience 2003; 23: 3959-3962. Front Immunol 2017; 8: 1489. 15) Lombardo D, Cassé-Perrot C, Ranjeva JP, Le 29) Nguyen PT, Dorman LC, Pan S, Vainchtein I, Han Troter A, Guye M, Wirsich J, Payoux P, Bar- R, Nakao-Inoue H, Taloma S, Barron J, Molofsky trés-Faz D, Richardson J, Felician O, Jirsa V, A, Kheirbek M, Molofsky A. Microglia remodel- Blin O Didic M, Battaglia D. Modular slowing of ing of the extracellular matrix promotes synapse resting-state dynamic. Functional connectivity plasticity. Cell 2020; 182: 388-403. as a marker of cognitive dysfunction induced 30) Dos Santos SE, Medeiros M, Porfirio J, Tavares by sleep deprivation. NeuroImage 2020; 222: W, Pessoa L, Grinberg L, Leite R, Ferretti-Rebus- 117155. tini R, Suemoto C. Similar microglial cell densities 16) Whitaker KJ, Vértes PE, Romero-Garcia R, Vasa across brain structures and mammalian species: F, Moutoussis M, Prabhu G,Weiskopf N, Cal- implications for brain tissue function. J Neurosci laghan MF, Wagstyl K. Adolescence is associ- 2020; 40: 4622-4643. ated with genomically patterned consolidation of 31) Dotti CG, Esteban J A and Ledesma MD. Lipid dynam- the hubs of the human brain connectome. PNAS ics at dendritic spines. Front Neuroanat 2014; 8: 76. 2016; 113: 9105-9110. 32) Joensuu M, Wallis TP, Saber SH, Meunier FA. 17) Fjell AM and Walhovd KB. Structural brain chang- Phospholipases in neuronal function: A role in es in aging: courses, causes and cognitive con- learning and memory? J Neurochem 2020; 153: sequences. Rev Neurosci 2010; 21: 187-221. 300-333. 18) Hoekzema E, Barba-Muller E, Pozzobon C, Pica- 33) Scholey AB, Camfield DA, Hughes ME, Woods do M, Lucco F, Garcia-Garcia D, Soliva JC, Tobe- W, Stough C, White DJ, Gondalia S, Frederiksen na A, Desco M, Crone E, Ballesteros A, Carmona P. A randomized controlled trial investigating the S, Vilarroya O. Pregnancy leads to long-lasting neurocognitive effects of Lacprodan® PL-20, a changes in human brain structure. Nat Neurosci phospholipid-rich milk protein concentrate, in el- 2017; 20: 287-296. derly participants with age-associated memory 19) Zhang F, Peng W, Sweeney JA, Jia Z, Gong Q. impairment: The Phospholipid Intervention for Brain structure alterations in depression: psy- Cognitive Ageing Reversal (PLICAR): study pro- choradiological evidence. CNS Neurosci Ther tocol for a randomized controlled trial. Trials 2013; 2018; 24: 994-1003. 14: 404.

3025 G. Biggio, I. Di Fazio, C. Martini

34) Li D, Misialek JR, Boerwinkle E, Gottesman RF, 47) Harris SE, Cox SR, Bell S, Marioni R, Prins B, Sharrett AR, Mosley TH, Coresh J, Wruck LM, Pattie A, Corley J, Maniega SM, Hernandez MV, Knopman DS, Alonso A. Plasma phospholipids Morris Z, John S, Bronson PG, Tucker-Drob EM, and prevalence of mild cognitive impairment and/ Starr JM, Bastin ME, Wardlaw JM, Butterworth or dementia in the ARIC Neurocognitive Study AS, Deary IJ. Neurology-related protein biomark- (ARIC-NCS). Alzheimer Dement (Amst) 2016; 3: ers are associated with cognitive ability and brain 73-82. volume in older age. Nat Commun 2020; 11: 800. 35) Kosicek M, Hecimovic S. Phospholipids and Alz- 48) Mufson EJ, Binder L, Counts SE, DeKosky S, de heimer’s Disease: alterations, mechanisms and Tolledo-Morrell L, Ginsberg S, Ikonomovic MD, potential biomarkers. Int J Mol Sci 2013; 14: 1310- Perez SE, Scheff SW. Mild cognitive impairment: 1322. pathology and mechanisms. Acta Neuropathol 36) Mapstone M, Cheema AK, Fiandaca MS, Zhong 2012; 123: 13-30. X, Mhyre T, MacArthur L, Hall W, Fisher S, Pe- 49) Hill NL, Kolanowski AM and Gill DJ. Plasticity in terson D, Haley JM, Nazar MD, Rich SA, Berlau early Alzheimer’s disease: an opportunity for in- DJ, Peltz CB, Tan MT, Kawas CH, Federoff HJ. tervention. Top Geriatr Rehabil 2011; 27: 257-267. Plasma phospholipids identify antecedent mem- 50) Zanchi D, Giannakopoulos P, Borgwardt S, ory impairment in older adults. Nat Med 2014; 20: Rodriguez C, Haller S. Hippocampal and amyg- 415-418. dala gray matter loss in elderly controls with 37) Honer WG, Barr AM, Sawada K, Thornton A, subtle cognitive decline. Front Aging Neurosci Morris M, Leurgans S, Schneider J, Bennett D. 2017; 9: 50. Cognitive reserve, presynaptic proteins and de- 51) Matsuda H. the role of neuroimaging in mild mentia in the elderly. Transl Psychiatry 2012; 2: cognitive impairment. Neuropathology 2007; 27: e114. 570-577. 38) Schimanski LA, Barnes CA. Neural protein syn- 52) Yue L, Wing T, Wang J, Li G, Wang J, Li X, Li W, thesis during aging: effects on plasticity and Hu M, Xiao S. Asymmetry of hippocampus and memory. Front Aging Neurosci 2010; 2: 26. amygdala defect in subjective cognitive decline 39) Rosenberg T, Ben-Ari SG, Dieterich DC, Kreutz among the community dwelling Chinese. Front M, Ziv N, Gundelfinger E, Rosenblum K. The Psych 2018; 9: 226. roles of protein expression in synaptic plasticity 53) Wachinger C, Salat DH, Weiner M, Reuter M. and memory consolidation. Front Mol Neurosci Whole-brain analysis reveals increased neuro- 2014; 7: 86. anatomical asymmetries in dementia for hippo- 40) Cajigas IJ, Will T, Schuman EM. Protein homeo- campus and amygdala. Brain 2016; 139: 3253- stasis and synaptic plasticity. EMBO J 2010; 29: 3266. 2746-2752. 54) Sri S, Pegasiou C, Cave CA, Hough K, Wood 41) Forloni G, Balducci C. Alzheimer’s disease, oligo- N, Gomez-Nicola D, Deinhardt K, Bannerman mers, and inflammation. J Alzheimers Dis 2018; D, Perry VH, Vargas-Caballero M. Emergence 62: 1261-1276. of synaptic and cognitive impairment in a ma- 42) Rajmohan R, Reddy PH. Amyloid Beta and phos- ture-onset APP mouse model of Alzheimer’s dis- phorylated Tau accumulations cause abnormali- ease. Acta Neuropathol Commun 2019; 7: 25. ties at synapses of Alzheimer’s disease neurons. 55) Siuda J, Patalong-Ogiewa M, Żmuda W, Tar- J Alzheimers Dis 2017; 57: 975-999. gosz-Gajniak M, Niewiadomska E, Matuszek I, 43) Arari H, Ishiguro K, Ohno H, Moriyama M, Itoh N, Jedrzejowska-Szypulka H, Rudzinska-Bar M. Okamura N, Matsui T, Morikawa Y, Horikawa E, Cognitive impairment and BDNF serum levels. Kohno H, Sasaki H, Imahori K. CSF phosphory- Neurol Neurochir Pol 2017; 51: 537. lated tau protein and mild cognitive impairment: 56) Rijpma A, van der Graaf M, Meulenbroek O, Olde a prospective study. Exp Neurol 2000; 166: 201- Rikkert M, Heerschap A. Altered brain high-en- 203. ergy phosphate metabolism in mild Alzheimer’s 44) Di J, Cohen LS, Corbo CP, Philips GR, Idrissi disease: a 3-dimensional 31P MR spectroscopic AE, Alonso AD. Abnormal tau induces cognitive imaging study. NeuroImage Clinical 2018; 18: impairment through two different mechanisms: 254-261. synaptic dysfunction and neuronal loss. Sci Rep 57) Markesbery WR, Lovell MA. Damage to lipids, 2016; 6: 20833. proteins, DNA and RNA in mild cognitive impair- 45) Wingo AP, Dammer EB, Breen MS, Logsdon ment. Arch Neurol 2007; 64: 954-956. BA, Duong DM, Troncosco JC, Thambisetty M, 58) Pepeu G. Mild cognitive impairment: animal mod- Beach TG, Serrano GE, Reiman EM, Caselli els. Dialogues Clin Neurosci 2004; 6: 369-377. RJ, Lah JJ, Seyfried NT, Levey AI, Wingo TS. 59) Fortier-Brochuer E, Morin CM. Cognitive impair- Large-scale proteomic analysis of human brain ment in individuals with insomnia: clinical signifi- identifies proteins associated with cognitive tra- cance and correlates. Sleep 2014; 37: 1787-1798. jectory in advanced age. Nat Commun 2019; 10: 60) Nirzhor SSR, Khan RI, Neelotpol S. The biology 1619. of glial cells and their complex roles in Alzhei- 46) Jové M, Pradas I, Dominguez-Gonalez M, Fer- mer’s disease: new opportunities in therapy. Bio- rer I, Pamplona R. Lipids and lipoxidation in molecules 2018; 8: 93. human brain aging. Mitochondrial ATP-synthase 61) Kreisl WC. Discerning the relationship between as a key lipoxidation target. Redox Biol 2019; 23: microglial activation and Alzheimer’s disease. 101082. Brain 2017; 140: 1825-1828.

3026 Cognitive impairment and nootropics

62) Willis CM, Nicaise AM, Peruzzotti-Jametti L, 73) Penke B, Paragi G, Gera J, Berkecz R, Kovacs Z, Pluchino S. The neural stem cell secretome and Crul T, Vigh L. The role of lipids and membranes its role in brain repair. Brain Res 2020; 1729: in the pathogenesis of Alzheimer’s disease: a 146615. comprehensive view. Curr Alz Res 2018; 15: 1-22. 63) Blurton-Jones M, Kitazawa M, Martinez-Coria 74) Chin EWN, Goh ELK. Modulating neuronal plas- H, Castello NA, Muller F, Loring J, Yamasaki T, ticity with choline. Neural Regen Res 2019; 14: Poon W, Green K, LaFerla F. Neural stem cells 1697-1698. improve cognition via BDNF in a transgenic 75) Tayebati SK. Phospholipid and lipid derivatives model of Alzheimer disease. PNAS 2009; 106: as potential neuroprotective compounds. Mole- 13594-13599. cules 2018; 23: 2257. 64) Lejri I, Agapouda A, Grimm A, Eckert A. Mi- 76) Gareri P, Castagna A, Cotroneo AM, Putignano tochondria- and oxidative stress-targeting sub- S, De Sarro G, Bruni AC. The role of citicoline in stances in cognitive decline-related disorders: cognitive impairment: pharmacological character- from molecular mechanisms to clinical evidence. istics, possible advantages, and doubts for an old Oxid Med Cell Longev 2019; 2019: 9695412. drug with new perspectives. Clin Intervent Aging 65) Liu B, Teschemacher AG, Kasparov S. Astroglia 2015; 10: 1421-1429. as a cellular target for neuroprotection and treat- 77) Florio T, Bajetto A, Thellung S, Arena S, Corsaro A, ment of neuro-psychiatric disorders. Glia 2017; Bonavia R, Merlino M, Schettini G. Prolonged treat- 65: 1205-1226. ment with α-glycerylphosphorylethanolamine facili- 66) Jelic V, Kivipelto M, Winblad B. Clinical trials in tates the acquisition of an active avoidance behavior mild cognitive impairment: lessons for the future. and selectively increases neuronal signal transduction J Neurol Neurosurg Psychiatry 2006; 77: 429- in rats. Aging Clin Exp Res 1999; 11: 335-342. 443. 78) Cloutier S, Chertkow H, Kergoat M, Gélinas I, 67) Keil U, IScherping I, Hauptmann S, Schuessel K, Gauthier S, Belleville S. Trajectories of decline on Eckert A, Müller WE. Piracetam improves mito- instrumental activities of daily living prior to de- chondrial dysfunction following oxidative stress. mentia in persons with mild cognitive impairment. Br J Pharmacol 2006; 147: 199-120. Int J Geriatr Psychiatry 2021; 36: 314-323. 68) Gray NE, Harris CJ, Quinn JF, Soumyanath 79) Stephan BCM, Hunter S, Harris D, Llewellyn D, A. Centella asiatica modulates antioxidant and Siervo M, Matthews F, Brayne C. The neuro- mitochondrial pathways and improves cognitive pathological profile of mild cognitive impairment function in mice. J Ethnopharmacol 2016; 180: (MCI): a systematic review. Mol Psychiatry 2012; 78-86. 17: 1056-1076. 69) Chiroma SM, Taib CN, Moklas MAM, Baharuldin 80) Ledesma MD, Martin MG, Dotti CG. Lipid changes M, Amom Z, Jagadeesan S. The use of noot- in the aged brain: effect on synaptic function and ropics in Alzheimer’s disease: is there light at neuronal survival. Prog Lipid Res 2012; 51: 23-35. the end of the tunnel? Biomed Res Ther 2019; 6: 81) Mecocci P, Tinarelli C, Schulz RJ, Polidori MC. 2937-2944. Nutraceuticals in cognitive impairment and Alz- 70) Malik R, Sangwan A, Saihgal R, Jindal D, Piplani heimer’s disease. Front Pharmacol 2014; 5: 147. P. Towards better brain management: nootropics. 82) Esto (L-alpha A-Glyceryl-Phosphoryl-Ethanol- Curr Med Chem 2007; 14: 123-131. amine), Summary of Product Characteristics. 71) Drever BD, Riedel G, Platt B. The cholinergic Last updated Version. system and hippocampal plasticity. Behav Brain 83) Moga DC, Beech BF, Abner EL, Schmitt F, Khouli Res 2011; 211: 505-514. R, Martinez A, Eckmann L, Huffmyer M, George 72) Colucci L, Bosco M, Ziello AR, Rea R, Amenta R, Jicha G. INtervention for Cognitive Reserve F, Fasanaro AM. Effectiveness of nootropic drugs Enhancement in delaying the onset of Alzhei- with cholinergic activity in treatment of cognitive mer’s Symptomatic Expression (INCREASE), a deficit: a review. J Experimental Pharmacol 2012; randomized controlled trial: rationale, study de- 4: 163 -117. sign, and protocol. Trials 2019; 20: 806.

3027