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Background The ability to capture people’s movement throughout their home is a powerful approach to inform spatiotemporal patterns of routines associated with cognitive impairment. The study estimated indoor room activities over 24 hours and investigated relationships between diurnal activity patterns and mild cognitive impairment (MCI). Methods One hundred and sixty-one older adults (26 with MCI) living alone (age = 78.9 ± 9.2) were included from 2 study cohorts—the Oregon Center for Aging & Technology and the Minority Aging Research Study. Indoor room activities were measured by the number of trips made to rooms (bathroom, bedroom, kitchen, living room). Trips made to rooms (transitions) were detected using passive infrared motion sensors fixed on the walls for a month. Latent trajectory models were used to identify distinct diurnal patterns of room activities and characteristics associated with each trajectory. Results Latent trajectory models identified 2 diurnal patterns of bathroom usage (high and low usage). Participants with MCI were more likely to be in the high bathroom usage group that exhibited more trips to the bathroom than the low-usage group (odds ratio [OR] = 4.1, 95% CI [1.3–13.5], p = .02). For kitchen activity, 2 diurnal patterns were identified (high and low activity). Participants with MCI were more likely to be in the high kitchen activity group that exhibited more transitions to the kitchen throughout the day and night than the low kitchen activity group (OR = 3.2, 95% CI [1.1–9.1], p = .03). Conclusions The linkage between bathroom and kitchen activities with MCI may be the result of biological, health, and environmental factors in play. In-home, real-time unobtrusive-sensing offers a novel way of delineating cognitive health with chronologically-ordered movement across indoor locations.

Background: Withania somnifera (WS), also known as Ashwagandha, is commonly used in Ayurveda and other traditional medicine systems. WS has seen an increase in worldwide usage due to its reputation as an adaptogen. This popularity has elicited increased scientific study of its biological effects, including a potential application for neuropsychiatric and neurodegenerative disorders. Objective: This review aims to provide a comprehensive summary of preclinical and clinical studies examining the neuropsychiatric effects of WS, specifically its application in stress, anxiety, depression, and insomnia. Methods: Reports of human trials and animal studies of WS were collected primarily from the PubMed, Scopus, and Google Scholar databases. Results: WS root and leaf extracts exhibited noteworthy anti-stress and anti-anxiety activity in animal and human studies. WS also improved symptoms of depression and insomnia, though fewer studies investigated these applications. WS may alleviate these conditions predominantly through modulation of the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary axes, as well as through GABAergic and serotonergic pathways. While some studies link specific withanolide components to its neuropsychiatric benefits, there is evidence for the presence of additional, as yet unidentified, active compounds in WS. Conclusion: While benefits were seen in the reviewed studies, significant variability in the WS extracts examined prevents a consensus on the optimum WS preparation or dosage for treating neuropsychiatric conditions. WS generally appears safe for human use; however, it will be important to investigate potential herb-drug interactions involving WS if used alongside pharmaceutical interventions. Further elucidation of active compounds of WS is also needed.

Background: The medicinal herb Centella asiatica has been long been used for its neuroprotective and cognitive enhancing effects. We have previously shown that two weeks of treatment with a water extract of Centella asiatica (CAW) improves cognition and activates the endogenous antioxidant response pathway without altering amyloid-β (Aβ) plaque burden. Objective: Here, we assess the effect of long-term treatment of CAW in the 5xFAD mouse model of Aβ accumulation. Methods: Four-month-old 5xFAD mice were treated with CAW in their drinking water (2 g/L) for three months at which point they underwent cognitive testing as well as analysis of Aβ plaque levels and antioxidant and synaptic gene expression. In order to confirm the involvement of the antioxidant regulatory transcription factor NRF2 on the effects of CAW on synaptic plasticity, neurons isolated from 5xFAD mice were also treated with CAW and the targeted inhibitor ML385. Results: Three months of treatment with CAW improved spatial and contextual memory as well as executive function in 5xFAD mice. This improvement was accompanied by increased antioxidant gene expression and a decrease in Aβ plaque burden relative to untreated 5xFAD animals. In isolated neurons, treatment with ML385 blocked the effects of CAW on dendritic arborization and synaptic gene expression. Conclusion: These results suggest that prolonged CAW exposure could be beneficial in Alzheimer’s disease and that these effects likely involve NRF2 activation. Moreover, these findings suggest that targeting NRF2 itself may be a relevant therapeutic strategy for improving synaptic plasticity and cognitive function in Alzheimer’s disease.

Withania somnifera (WS), also known as Ashwagandha, is commonly used in Ayurveda and other traditional medicine systems. WS has seen an increase in worldwide usage due to its reputation as an adaptogen. This popularity has elicited increased scientific study of its biological effects, including a potential application for neuropsychiatric and neurodegenerative disorders.This review aims to provide a comprehensive summary of preclinical and clinical studies examining the neuropsychiatric effects of WS, specifically its application in stress, anxiety, depression, and insomnia.Reports of human trials and animal studies of WS were collected primarily from the PubMed, Scopus, and Google Scholar databases.WS root and leaf extracts exhibited noteworthy anti-stress and anti-anxiety activity in animal and human studies. WS also improved symptoms of depression and insomnia, though fewer studies investigated these applications. WS may alleviate these conditions predominantly through modulation of the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary axes, as well as through GABAergic and serotonergic pathways. While some studies link specific withanolide components to its neuropsychiatric benefits, there is evidence for the presence of additional, as yet unidentified, active compounds in WS.While benefits were seen in the reviewed studies, significant variability in the WS extracts examined prevents a consensus on the optimum WS preparation or dosage for treating neuropsychiatric conditions. WS generally appears safe for human use; however, it will be important to investigate potential herb-drug interactions involving WS if used alongside pharmaceutical interventions. Further elucidation of active compounds of WS is also needed.

Centella asiatica (CA) is an edible plant and a popular botanical dietary supplement. It is reputed, in Ayurveda, to mitigate age-related cognitive decline. There is a considerable body of preclinical literature supporting CA’s ability to improve learning and memory. This study evaluated the contribution of CA’s triterpenes (TT), widely considered its active compounds, and caffeoylquinic acids (CQA) to the cognitive effects of CA water extract (CAW) in 5XFAD mice, a model of Alzheimer’s disease. 5XFAD mice were fed a control diet alone, or one containing 1% CAW or compound groups (TT, CQA, or TT + CQA) equivalent to their content in 1% CAW. Wild-type (WT) littermates received the control diet. Conditioned fear response (CFR) was evaluated after 4.5 weeks. Female 5XFAD controls showed no deficit in CFR compared to WT females, nor any effects from treatment. In males, CFR of 5XFAD controls was attenuated compared to WT littermates (p = 0.005). 5XFAD males receiving CQA or TT + CQA had significantly improved CFR (p < 0.05) compared to 5XFAD male controls. CFR did not differ between 5XFAD males receiving treatment diets and WT males. These data confirm a role for CQA in CAW’s cognitive effects.

Centella asiatica (CA) shows considerable promise for development as a botanical drug for cognitive decline. Its primary bioactive components include triterpene glycosides asiaticoside and madecassoside and their corresponding aglycones asiatic acid and madecassic acid. Exploration of the bioactivity of CA’s caffeoylquinic acids is ongoing. In this study, an aqueous extract of CA (CAW-R61J) was evaluated for drug interaction potential through inhibition or induction of P450 enzymes, as required by the US Food and Drug Administration. CAW-R61J was assessed for induction potential of CYP1A2, CYP2B6, and CYP3A4 using transporter-certified cryopreserved human hepatocytes in sandwich culture. Gene expression of these target P450s was quantified, and enzyme activities were determined to confirm gene expression results. No induction was observed up to 16.7 µg/ml CAW-R61J (equivalent to 1.1 µM asiaticoside, 0.8 µM madecassoside, 0.09 µM asiatic acid, and 0.12 µM madecassic acid). Reversible and time-dependent inhibitory effects of CAW-R61J on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 were evaluated using human liver microsomes. CAW-R61J showed weak reversible inhibition of most of the P450 forms tested, with the strongest being CYP2C9 (IC(50) of 330 µg/ml). CAW-R61J (≤1000 µg/ml) was not a time-dependent inhibitor of any of these P450 enzymes. In summary, CAW-R61J had no, or only a weak impact, on P450 induction and inhibition in vitro. The clinical relevance of these results will depend on the in vivo concentration of CAW-R61J components achieved in humans. Plasma triterpene concentrations measured in our recent clinical studies suggest minimal risk of P450-mediated drug interactions by these components. SIGNIFICANCE STATEMENT: A preparation of Centella asiatica is currently under clinical development for the prevention or treatment of cognitive decline. The US Food and Drug Administration required an evaluation of its potential for drug interactions mediated through drug-metabolizing enzymes. This in vitro study revealed minimal induction or inhibition of a range of P450 enzymes, including CYP3A4, by the C. asiatica extract, suggesting a low potential for drug interactions modulated by P450 metabolism.

Background The current clinical trial assessment methodology relies on a combination of self-report measures, cognitive and physical function tests, and biomarkers. This methodology is limited by recall bias and recency effects in self-reporting and by assessments that are brief, episodic, and clinic based. Continuous monitoring of ecologically valid measures of cognition and daily functioning in the community may provide a more sensitive method to detect subtle, progressive changes in patients with cognitive impairment and dementia. Objective This study aimed to present an alternative trial approach using a home-based sensing and computing system to detect changes related to common treatments employed in Alzheimer disease (AD). This paper introduces an ongoing study that aims to determine the feasibility of capturing sensor-based data at home and to compare the sensor-based outcomes with conventional outcomes. We describe the methodology used in the assessment protocol and present preliminary results of feasibility measures and examples of data related to medication-taking behavior, activity levels, and sleep. Methods The EVALUATE-AD (Ecologically Valid, Ambient, Longitudinal and Unbiased Assessment of Treatment Efficacy in Alzheimer’s Disease) trial is a longitudinal naturalistic observational cohort study recruiting 30 patients and 30 spouse coresident care partners. Participants are monitored continuously using a home-based sensing and computing system for up to 24 months. Outcome measures of the automated system are compared with conventional clinical outcome measures in AD. Acceptance of the home system and protocol are assessed by rates of dropout and protocol adherence. After completion of the study monitoring period, a composite model using multiple functional outcome measures will be created that represents a behavioral-activity signature of initiating or discontinuing AD-related medications, such as cholinesterase inhibitors, memantine, or antidepressants. Results The home-based sensing and computing system has been well accepted by individuals with cognitive impairment and their care partners. Participants showed good adherence to the completion of a weekly web-based health survey. Daily activity, medication adherence, and total time in bed could be derived from algorithms using data from the sensing and computing system. The mean monitoring time for current participants was 14.6 months. Medication adherence, as measured with an electronic pillbox, was 77% for participants taking AD-related medications. Conclusions Continuous, home-based assessment provides a novel approach to test the impact of new or existing dementia treatments generating objective, clinically meaningful measures related to cognition and everyday functioning. Combining this approach with the current clinical trial methodology may ultimately reduce trial durations, sample size needs, and reliance on a clinic-based assessment. International Registered Report Identifier (IRRID) DERR1-10.2196/17603

The water extract of Centella asiatica (CAW) improves cognitive and mitochondrial function and activates the nuclear factor erythroid 2-related factor 2 (NRF2) regulated antioxidant response pathway in aged mice. Here we investigate whether NRF2 activation is required for the cognitive and mitochondrial effects of prolonged CAW exposure during aging. Five-month-old NRF2 knockout (NRF2KO) and wild-type mice were treated with CAW for 1, 7, or 13 months. Each cohort underwent cognitive testing and hippocampal mitochondrial analyses. Age-related cognitive decline was accelerated in NRF2KO mice and while CAW treatment improved cognitive performance in wild-type mice, it had no effect on NRF2KO animals. Hippocampal mitochondrial function also declined further with age in NRF2KO mice and greater hippocampal mitochondrial dysfunction was associated with poorer cognitive performance in both genotypes. Long-term CAW treatment did not affect mitochondrial endpoints in animals of either genotype. These data indicate that loss of NRF2 results in accelerated age-related cognitive decline and worsened mitochondrial deficits. NRF2 also appears to be required for the cognitive enhancing effects of CAW during aging.

Centella asiatica (CA) herb is a traditional medicine, long reputed to provide cognitive benefits. We have reported that CA water extract (CAW) treatment improves cognitive function of aged Alzheimer&rsquo, s disease (AD) model Tg2576 and wild-type (WT) mice, and induces an NRF2-regulated antioxidant response in aged WT mice. Here, CAW was administered to AD model 5XFAD female and male mice and WT littermates (age: 7.6 +/ &minus, 0.6 months), and object recall and contextual fear memory were tested after three weeks treatment. CAW&rsquo, s impact on amyloid-&beta, plaque burden, and markers of neuronal oxidative stress and synaptic density, was assessed after five weeks treatment. CAW antioxidant activity was evaluated via nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2) and NRF2-regulated antioxidant response element gene expression. Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden, and marginally increased synaptic density markers in the hippocampus and prefrontal cortex. CAW treatment increased Nrf2 in hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit). Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice. We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.

Introduction The phytochemical composition of plant material governs the bioactivity and potential health benefits as well as the outcomes and reproducibility of laboratory studies and clinical trials. Objective The objective of this work was to develop an efficient method for the in‐depth characterisation of plant extracts and quantification of marker compounds that can be potentially used for subsequent product integrity studies. Centella asiatica (L.) Urb., an Ayurvedic herb with potential applications in enhancing mental health and cognitive function, was used as a case study. Methods A quadrupole time‐of‐flight analyser in conjunction with an optimised high‐performance liquid chromatography (HPLC) separation was used for in‐depth untargeted fingerprinting and post‐acquisition precursor ion quantification to determine levels of distinct phytochemicals in various C. asiatica extracts. Results We demonstrate the utility of this workflow for the characterisation of extracts of C. asiatica. This integrated workflow allowed the identification or tentative identification of 117 compounds, chemically interconnected based on Tanimoto chemical similarity, and the accurate quantification of 24 phytochemicals commonly found in C. asiatica extracts. Conclusion We report a phytochemical analysis method combining liquid chromatography, high resolution mass spectral data acquisition, and post‐acquisition interrogation that allows chemical fingerprints of botanicals to be obtained in conjunction with accurate quantification of distinct phytochemicals. The variability in the composition of specialised metabolites across different C. asiatica accessions was substantial, demonstrating that detailed characterisation of plant extracts is a prerequisite for reproducible use in laboratory studies, clinical trials and safe consumption. The methodological approach is generally applicable to other botanical products., Botanical products are popular for promoting resilience, maintaining health and preventing or treating disease. Challenges in defining effects of botanical products reside in achieving batch‐to‐batch reproducibility regarding their composition and product stability, i.e. providing consistent products for clinical trials and consumers. In this work, using Centella asiatica (L.) Urb. as a case study, we demonstrate the efficacy of integrating untargeted high‐resolution mass spectrometry with post acquisition precursor ion extraction for determining chemical profiles and quantifying selected marker compounds.

Oxidative stress (OS), when oxidative forces outweigh endogenous and nutritional antioxidant defenses, contributes to the pathophysiology of multiple sclerosis (MS). Evidence of OS is found during acute relapses, in active inflammatory lesions, and in chronic, longstanding plaques. OS results in both ongoing inflammation and neurodegeneration. Antioxidant therapies are a rational strategy for people with MS with all phenotypes and disease durations. PURPOSE OF REVIEW: To understand the function of OS in health and disease, to examine the contributions of OS to MS pathophysiology, and to review current evidence for the effects of selected antioxidant therapies in people with MS (PwMS) with a focus on lipoic acid (LA). RECENT FINDINGS: Studies of antioxidant interventions in both animal and in vivo models result in reductions in serum markers of OS and increases in levels and activity of antioxidant enzymes. Antioxidant trials in PwMS, while generally underpowered, detect short-term improvements in markers of OS and antioxidant defenses, and to a lesser extent, in clinical symptoms (fatigue, depression). The best evidence to date is a 2-year trial of LA in secondary progressive MS which demonstrated a significant reduction of whole-brain atrophy and trend toward improvement in walking speed. Antioxidant therapy is a promising approach to treat MS across the spectrum and duration of disease. Rigorous and well-powered trials are needed to determine their therapeutic benefits.

BACKGROUND: Diabetic neuropathy (DN), a common complication of diabetes mellitus, results from hyperglycemia, poor microcirculation and attendant nerve damage. Currently available treatments relieve symptoms, but do not modify the neurodegeneration underlying DN. Centella asiatica (CA) triterpenes improved microcirculation in earlier clinical studies, and showed neurotropic effects in preclinical models suggesting a potential disease modifying effect in DN. This 52-week, randomized, double-blind, placebo-controlled trial examined the effects of CAST, a standardized CA extract containing triterpenes, on neuropathy symptoms in Type II diabetic subjects. PATIENTS AND METHODS: The study enrolled patients with a history of Type II diabetes, with evidence of symptomatic symmetrical DN with total symptom score (TSS) ≥4, and stable HbA1c level

This review describes in detail the phytochemistry and neurological effects of the medicinal herb Centella asiatica (L.) Urban. C. asiatica is a small perennial plant that grows in moist, tropical and sub-tropical regions throughout the world. Phytochemicals identified from C. asiatica to date include isoprenoids (sesquiterpenes, plant sterols, pentacyclic triterpenoids and saponins) and phenylpropanoid derivatives (eugenol derivatives, caffeoylquinic acids, and flavonoids). Contemporary methods for fingerprinting and characterization of compounds in C. asiatica extracts include liquid chromatography and/or ion mobility spectrometry in conjunction with high-resolution mass spectrometry. Multiple studies in rodent models, and a limited number of human studies, support C. asiatica’s traditional reputation as a cognitive enhancer, as well as its anxiolytic and anticonvulsant effects. Neuroprotective effects of C. asiatica are seen in several in vitro models, for example against beta amyloid toxicity, and appear to be associated with increased mitochondrial activity, improved antioxidant status, and/or inhibition of the pro-inflammatory enzyme, phospholipase A2. Neurotropic effects of C. asiatica include increased dendritic arborization and synaptogenesis, and may be due to modulations of signal transduction pathways such as ERK1/2 and Akt. Many of these neurotropic and neuroprotective properties of C. asiatica have been associated with the triterpene compounds asiatic acid, asiaticoside and madecassoside. More recently, caffeoylquinic acids are emerging as a second important group of active compounds in C. asiatica, with the potential of enhancing the Nrf2-antioxidant response pathway. The absorption, distribution, metabolism and excretion of the triterpenes, caffeoylquinic acids and flavonoids found in C. asiatica have been studied in humans and animal models, and the compounds or their metabolites found in the brain. This review highlights the remarkable potential for C. asiatica extracts and derivatives to be used in the treatment of neurological conditions, and considers the further research needed to actualize this possibility.

Flower reversion is the result of genetic or environmental effects that reverse developmental steps in the transition from the vegetative to the reproductive phase in plants. Here, we describe peculiar floral abnormalities, homeotic conversions, and flower reversion in several wild-type accessions of the natural allopolyploid Arabidopsis suecica. Microscopy was used to illustrate the phenotype in detail and we experimented with varying photoperiod lengths to establish whether or not the phenotype was responsive to the environment. We also profiled the transcriptional activity of several floral regulator genes during flower reversion using real-time PCR. We showed that the frequency of floral reversion was affected by day length and the position of the flower along the inflorescence axis. In reverting flowers we found unusual gene expression patterns of floral promoters and inflorescence maintenance genes, including lower mRNA levels of AGAMOUS-LIKE-24 (AGL-24), APETALA1 (AP1), and SHORT VEGETATIVE PHASE (SVP), and higher mRNA levels of SUPRESSOR OF CONSTANS1 (SOC1) compared with normal flowers. We conclude that the floral reversion frequency in A. suecica is susceptible to photoperiod changes, and that the floral abnormalities coincide with the competing expression of floral promoters and floral repressors in reverting floral tissue.

Allopolyploids contain complete sets of chromosomes from two or more different progenitor species. Because allopolyploid hybridization can lead to speciation, allopolyploidy is an important mechanism in evolution. Meiotic instability in early-generation allopolyploids contributes to high lethality, but less is known about mitotic fi delity in allopolyploids. We compared mitotic stability in resynthesized Arabidopsis suecica- like neoallopolyploids with that in 13 natural lines of A. suecica (2 n = 4 x = 26). We used fl uorescent in situ hybridization to distinguish the chromosomal contribution of each progenitor, A. thaliana (2 n = 2 x =10) and A. arenosa (2 n = 4 x = 32). Surprisingly, cells of the paternal parent A. arenosa had substantial aneuploidy, while cells of the maternal parent A. thaliana were more stable. Both natural and resynthesized allopolyploids had low to intermediate levels of aneuploidy. Our data suggest that polyploidy in Arabidopsis is correlated with aneuploidy, but varies in frequency by species. The chromosomal composition in aneuploid cells within individuals was variable, suggesting somatic mosaicisms of cell lineages, rather than the formation of distinct, stable cytotypes. Our results suggest that somatic aneuploidy can be tolerated in Arabidopsis polyploids, but there is no evidence that this type of aneuploidy leads to stable novel cytotypes.