Studies demonstrated impairment in the control of saccadic eye movements in Alzheimer's disease (AD) and people with mild cognitive impairment (MCI) when conducting the pro-saccade and antisaccade tasks. Research showed that changes in the pro and antisaccade latencies may be particularly sensitive to dementia and general executive functioning. These tasks show potential for diagnostic use, as they provide a rich set of potential eye tracking markers. One such marker, the coefficient of variation (CV), is so far overlooked. For biological markers to be reliable, they must be able to detect abnormalities in preclinical stages. MCI is often viewed as a predecessor to AD, with certain classifications of MCI more likely than others to progress to AD. The current study examined the potential of CV scores on pro and antisaccade tasks to distinguish participants with AD, amnestic MCI (aMCI), non-amnesiac MCI (naMCI), and older controls. The analyses revealed no significant differences in CV scores across the groups using the pro or antisaccade task. Antisaccade mean latencies were able to distinguish participants with AD and the MCI subgroups. Future research is needed on CV measures and attentional fluctuations in AD and MCI individuals to fully assess this measure's potential to robustly distinguish clinical groups with high sensitivity and specificity.

Disorders of arousal (DOA) is an umbrella term initially covering classical sleepwalking, sleep terrors, and confusional arousals, and now including a wider spectrum of specialised forms of non rapid eye movement (non REM) parasomnias such as sexsomnia, sleep-related eating disorder, and sleep-related choking syndrome. Growing evidence has shown that DOA are not restricted to children but are also prevalent in adults (2%-4% of the adult population). While DOA run in family, genetics studies remain scarce and inconclusive. In addition to the risk of injury on themselves and others (including sexual assaults in sexsomnia), adults with DOA frequently suffer from excessive daytime sleepiness, pain, and altered quality of life. The widespread view of DOA as automatic and amnesiac behaviours has now been challenged by subjective (dream reports) and objective (dream-enacting behaviours documented on video-polysomnography) observations, suggesting that sleepwalkers are 'dream walking' during their episodes. Behavioural, experiential, cognitive, and brain (scalp electroencephalography [EEG], stereo-EEG, high density-EEG, functional brain imaging) data converge in showing a dissociated pattern during the episodes. This dissociated pattern resembles the new concept of local arousal with a wake-like activation in motor and limbic regions and a preserved (or even increased) sleep intensity over a frontoparietal network. EEG and behavioural criteria supporting the DOA diagnosis with high sensitivity and specificity are now available. However, treatment is still based on controlling priming and precipitating factors, as well as on clinicians' personal experience with sedative drugs. Placebo-controlled trials are needed to improve patients' treatment. DOA deserve more attention from sleep researchers and clinicians.

Acetylcholinesterase (AChE) inhibitors increase the retention of acetylcholine (ACh) in synapses. Although they alleviate cognitive deficits in Alzheimer's disease, their limited benefits warrant investigations of plant extracts with similar properties. We studied the anti-AChE activity of Convolvulus pluricaulis (CP) in a zebrafish model of cognitive impairment induced by scopolamine (SCOP). CP is a perennial herb with anti-amnesiac and anxiolytic properties. It contains alkaloid, anthocyanin, coumarin, flavonoid, phytosterol and triterpenoid components. Isoxazole (ISOX) was used as a positive control for AChE inhibition. CP-treated 168 hpf larvae showed a similar pattern of AChE inhibition (in the myelencephalon and somites) as that of ISOX-treated larvae. CP was superior to ISOX as evidenced by the retention of avoidance response behavior in adult zebrafish. Molecular docking studies indicated that ISOX binds Ser203 of the catalytic triad on the human AChE. The active components of CP-scopoletin and kaempferol-were bound by His447 of the catalytic triad, the anionic subsite of the catalytic center, and the peripheral anionic site. This suggested the ability of CP to mediate both competitive and non-competitive modes of inhibition. Surprisingly, SCOP showed AChE inhibition in larvae, possibly mediated via the choline-binding sites. CP + SCOP induced a concentration-dependent increase in AChE inhibition and ACh depletion. Abnormal motor responses were observed with ISOX, CP, ISOX + SCOP, and CP + SCOP, indicative of undesirable effects on the peripheral cholinergic system. Our study proposes the examination of CP, SCOP, and CP + SCOP as potential AChE inhibitors for their ability to modulate cognitive deficits.

Resveratrol has been reported to exhibit neuroprotective activities in vitro and in vivo. However, little is known about resveratrol tetramers of hopeaphenol, vitisin A, and vitisin B with the same molecular mass in the improvement of degenerative disorders. In this study, two 95% ethanol extracts (95EE) from stem parts of Sieb. & Zucc. (VT-95EE) and from the root (R) parts of var. (VTT-R-95EE) showed comparable acetylcholinesterase (AChE) inhibitory activities. It was found that VT-95EE and VTT-R-95EE showed different distribution patterns of identified resveratrol and resveratrol tetramers of hopeaphenol, vitisin A, and vitisin B based on the analyses of HPLC chromatographic profiles. The hopeaphenol, vitisin A, and vitisin B, showed AChE and monoamine oxidase-B inhibitions in a dose-dependent manner, among which vitisin B and vitisin A exhibited much better activities than those of resveratrol, and had neuroprotective activities against methylglyoxal-induced SH-SY5Y cell deaths. The scopolamine-induced amnesiac ICR mice treated with VT-95EE and its ethyl acetate-partitioned fraction (VT-95EE-EA) at doses of 200 and 400 mg/kg, or vitisin A at a dose of 40 mg/kg, but not vitisin B (40 mg/kg), were shown significantly to improve the impaired learning behaviors by passive avoidance tests compared to those in the control without drug treatments ( < 0.05). Compared to mice in the control group, the brain extracts in the vitisin A-treated mice or donepezil-treated mice showed significant reductions in AChE activities and malondialdehyde levels ( < 0.05), and elevated the reduced protein expressions of brain-derived neurotrophic factor (BDNF) and BDNF receptor, tropomyosin receptor kinase B (TrkB). These results revealed that vitisin A was the active constituent in the VT-95EE and VTT-95EE, and the VT medicinal plant and that the endemic variety of VTT has potential in developing functional foods for an unmet medical need for neurodegenerative disorders.

The bioactive peptide PAYCS (Pro-Ala-Tyr-Cys-Ser) identified from anchovy hydrolysates has been reported to be positive in memory alleviation. The gut microbiota-brain axis plays a vital role in brain functions, which could be affected by nutritional supplementation. Herein, we found that PAYCS at different concentrations (PAYCS-L and PAYCS-H) showed various improving effects in behavioral tests and alleviation effects on oxidative as well as inflammatory stress in the scopolamine-induced AD mouse model. The 16S rRNA results illustrated that PAYCS-L altered the ratio of Bacteroidetes/Firmicutes and PAYCS treatment elevated the relative abundance of Cacteroidaceae and Prevotellaceae. Notably, administration of PAYCS significantly upregulated memory-related metabolites and neurotransmitters. Overall, PAYCS-L reversed memory deficits of amnesiac mice partially via the modulation of gut microbiota-metabolites-brain neurotransmitter axis. For PAYCS-H, functions might be involved in the reversal of oxidative and inflammatory impairments in the liver and serum, which was also associated with the changed intestinal microbiota and fecal metabolites.

Agricultural waste from the hulls of water caltrop ( Nakai, TT-hull) was extracted by either steeping them in cold 95% ethanol (C95E), refluxing 95E, refluxing 50E, or refluxing hot water (HW) to obtain C95EE, 95EE, 50EE, and HWE, respectively. These four extracts showed acetylcholinesterase (AChE) inhibitory activities and free radical scavenging activities, as well as anti-non-enzymatic protein glycation in vitro. Eight compounds were isolated from TT-hull-50EE and were used to plot the chromatographic fingerprints of the TT-hull extracts, among which tellimagrandin-I, tellimagrandin-II, and 1,2,3,6-tetra-galloylglucose showed the strongest AChE inhibitory activities, and they also exhibited anti-amyloid β peptide aggregations. The scopolamine-induced amnesiac ICR mice that were fed with TT-hull-50EE or TT-hull-HWE (100 and 200 mg/kg) or tellimagrandin-II (100 and 200 mg/kg) showed improved learning behavior when evaluated using passive avoidance or water maze evaluation, and they showed significant differences ( < 0.05) compared to those in the control group. The enriched hydrolysable tannins of the recycled TT-hull may be developed as functional foods for the treatment of degenerative disorders.

This study aimed to explore the synergistic action of pentapeptides Gln-Met-Asp-Asp-Gln (QMDDQ) and Ala-Gly-Leu-Pro-Met (AGLPM) on memory improvement against scopolamine-induced impairment in mice compared to those of either peptide alone. In behavioral tests, the codelivery of QMDDQ and AGLPM was superior to the individual supplements of either peptide alone not only in enhancing the memory ability at training trials but also in recovering the memory impairment in scopolamine-induced amnesiac mice in test trials. Furthermore, combination treatment with QMDDQ and AGLPM could significantly reduce the acetylcholinesterase (AChE) level and increase the acetylcholine (ACh) level in the hippocampus, and noticeably improve the pathological morphology of the neuron cells in hippocampal regions CA1 and CA2 and dentate gyrus (DG). The findings indicated that the combination treatment with QMDDQ and AGLPM could improve the memory function by regulating the cholinergic system.

In , the mushroom bodies (MB) constitute the central brain structure for olfactory associative memory. As in mammals, the cAMP/PKA pathway plays a key role in memory formation. In the MB, Rutabaga (Rut) adenylate cyclase acts as a coincidence detector during associative conditioning to integrate calcium influx resulting from acetylcholine stimulation and G-protein activation resulting from dopaminergic stimulation. encodes a secreted neuropeptide required in the MB for two phases of aversive olfactory memory. Previous sequence analysis has revealed strong homology with the mammalian pituitary adenylate cyclase-activating peptide (PACAP). Here, we examined whether is involved in cAMP/PKA dynamics in response to dopamine and acetylcholine co-stimulation in living flies. Experiments were conducted with both sexes, or with either sex. Our data show that is necessary for the PKA activation process that results from coincidence detection in the MB. Since PACAP peptide is cleaved by the human membrane neprilysin hNEP, we searched for an interaction between Amnesiac and Neprilysin 1 (Nep1), a fly neprilysin involved in memory. We show that when Nep1 expression is acutely knocked down in adult MB, memory deficits displayed by hypomorphic mutants are rescued. Consistently, Nep1 inhibition also restores normal PKA activation in mutant flies. Taken together, the results suggest that Nep1 targets Amnesiac degradation to terminate its signaling function. Our work thus highlights a key role for Amnesiac in establishing within the MB the PKA dynamics that sustain middle-term memory (MTM) formation, a function modulated by Nep1. The gene encodes a secreted neuropeptide whose expression is required for specific memory phases in the mushroom bodies (MB), the olfactory memory center. Here, we show that Amnesiac is required for PKA activation resulting from coincidence detection, a mechanism by which the MB integrate two spatially distinct stimuli to encode associative memory. Furthermore, our results uncover a functional relationship between Amnesiac and Neprilysin 1 (Nep1), a membrane peptidase involved in memory and expressed in the MB. These results suggest that Nep1 modulates Amnesiac levels. We propose that on conditioning, Amnesiac release from the MB allows, via an autocrine process, the sustaining of PKA activation-mediating memory, which subsequently is inactivated by Nep1 degradation.

Dementia is a chronic brain disorder classified by four distinct diseases that impact cognition and mental degeneration. Each subgroup exhibits similar brain deficiencies and mutations. This review will focus on four dementia subgroups: Alzheimer's disease, vascular dementia, frontotemporal dementia and dementia Lewy body.

Domoic acid (DA) is an excitatory neurotoxin produced by marine algae and responsible for Amnesiac Shellfish Poisoning in humans. Current regulatory limits (˜0.075-0.1 mg/kg/day) protect against acute toxicity, but recent studies suggest that the chronic consumption of DA below the regulatory limit may produce subtle neurotoxicity in adults, including decrements in memory. As DA-algal blooms are increasing in both severity and frequency, we sought to better understand the effects of chronic DA exposure on reproductive and neurobehavioral endpoints in a preclinical nonhuman primate model. To this end, we initiated a long-term study using adult, female Macaca fascicularis monkeys exposed to daily, oral doses of 0.075 or 0.15 mg/kg of DA for a range of 321-381, and 346-554 days, respectively. This time period included a pre-pregnancy, pregnancy, and postpartum period. Throughout these times, trained data collectors observed intentional tremors in some exposed animals during biweekly clinical examinations. The present study explores the basis of this neurobehavioral finding with in vivo imaging techniques, including diffusion tensor magnetic resonance imaging and spectroscopy. Diffusion tensor analyses revealed that, while DA exposed macaques did not significantly differ from controls, increases in DA-related tremors were negatively correlated with fractional anisotropy, a measure of structural integrity, in the internal capsule, fornix, pons, and corpus callosum. Brain concentrations of lactate, a neurochemical closely linked with astrocytes, were also weakly, but positively associated with tremors. These findings are the first documented results suggesting that chronic oral exposure to DA at concentrations near the current human regulatory limit are related to structural and chemical changes in the adult primate brain.