Displaying all 11 publications

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  1. Paudel YN, Angelopoulou E, Jones NC, O'Brien TJ, Kwan P, Piperi C, et al.
    ACS Chem Neurosci, 2019 10 16;10(10):4199-4212.
    PMID: 31532186 DOI: 10.1021/acschemneuro.9b00460
    Emerging findings point toward an important interconnection between epilepsy and Alzheimer's disease (AD) pathogenesis. Patients with epilepsy (PWE) commonly exhibit cognitive impairment similar to AD patients, who in turn are at a higher risk of developing epilepsy compared to age-matched controls. To date, no disease-modifying treatment strategy is available for either epilepsy or AD, reflecting an immediate need for exploring common molecular targets, which can delineate a possible mechanistic link between epilepsy and AD. This review attempts to disentangle the interconnectivity between epilepsy and AD pathogenesis via the crucial contribution of Tau protein. Tau protein is a microtubule-associated protein (MAP) that has been implicated in the pathophysiology of both epilepsy and AD. Hyperphosphorylation of Tau contributes to the different forms of human epilepsy and inhibition of the same exerted seizure inhibitions and altered disease progression in a range of animal models. Moreover, Tau-protein-mediated therapy has demonstrated promising outcomes in experimental models of AD. In this review, we discuss how Tau-related mechanisms might present a link between the cause of seizures in epilepsy and cognitive disruption in AD. Untangling this interconnection might be instrumental in designing novel therapies that can minimize epileptic seizures and cognitive deficits in patients with epilepsy and AD.
    Matched MeSH terms: Mild Cognitive Impairment/metabolism*
  2. Bhattamisra SK, Shin LY, Saad HIBM, Rao V, Candasamy M, Pandey M, et al.
    CNS Neurol Disord Drug Targets, 2020;19(3):174-183.
    PMID: 32418534 DOI: 10.2174/1871527319666200518102130
    The interlink between diabetes mellitus and neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD) has been identified by several researchers. Patients with Type-2 Diabetes Mellitus (T2DM) are found to be affected with cognitive impairments leading to learning and memory deficit, while patients with Type-1 Diabetes Mellitus (T1DM) showed less severe levels of these impairments in the brain. This review aimed to discuss the connection between insulin with the pathophysiology of neurodegenerative diseases (AD and PD) and the current therapeutic approached mediated through insulin for management of neurodegenerative diseases. An extensive literature search was conducted using keywords "insulin"; "insulin resistance"; "Alzheimer's disease"; "Parkinson's disease" in public domains of Google scholar, PubMed, and ScienceDirect. Selected articles were used to construct this review. Studies have shown that impaired insulin signaling contributes to the accumulation of amyloid-β, neurofibrillary tangles, tau proteins and α-synuclein in the brain. Whereas, improvement in insulin signaling slows down the progression of cognitive decline. Various therapeutic approaches for altering the insulin function in the brain have been researched. Besides intranasal insulin, other therapeutics like PPAR-γ agonists, neurotrophins, stem cell therapy and insulin-like growth factor-1 are under investigation. Research has shown that insulin insensitivity in T2DM leads to neurodegeneration through mechanisms involving a variety of extracellular, membrane receptor, and intracellular signaling pathway disruptions. Some therapeutics, such as intranasal administration of insulin and neuroactive substances have shown promise but face problems related to genetic background, accessibility to the brain, and invasiveness of the procedures.
    Matched MeSH terms: Mild Cognitive Impairment/metabolism
  3. Abdo Qaid EY, Zulkipli NN, Zakaria R, Ahmad AH, Othman Z, Muthuraju S, et al.
    Int J Neurosci, 2021 May;131(5):482-488.
    PMID: 32202188 DOI: 10.1080/00207454.2020.1746308
    Hypoxia has been associated with cognitive impairment. Many studies have investigated the role of mTOR signalling pathway in cognitive functions but its role in hypoxia-induced cognitive impairment remains controversial. This review aimed to elucidate the role of mTOR in the mechanisms of cognitive impairment that may pave the way towards the mechanistic understanding and therapeutic intervention of hypoxia-induced cognitive impairment. mTORC1 is normally regulated during mild or acute hypoxic exposure giving rise to neuroprotection, whereas it is overactivated during severe or chronic hypoxia giving rise to neuronal cells death. Thus, it is worth exploring the possibility of maintaining normal mTORC1 activity and thereby preventing cognitive impairment during severe or chronic hypoxia.
    Matched MeSH terms: Mild Cognitive Impairment/metabolism*
  4. Hou Z, He P, Imam MU, Qi J, Tang S, Song C, et al.
    Oxid Med Cell Longev, 2017;2017:7205082.
    PMID: 29104731 DOI: 10.1155/2017/7205082
    Menopause causes cognitive and memory dysfunction due to impaired neuronal plasticity in the hippocampus. Sirtuin-1 (SIRT1) downregulation in the hippocampus is implicated in the underlying molecular mechanism. Edible bird's nest (EBN) is traditionally used to improve general wellbeing, and in this study, we evaluated its effects on SIRT1 expression in the hippocampus and implications on ovariectomy-induced memory and cognitive decline in rats. Ovariectomized female Sprague-Dawley rats were fed with normal pellet alone or normal pellet + EBN (6, 3, or 1.5%), compared with estrogen therapy (0.2 mg/kg/day). After 12 weeks of intervention, Morris water maze (four-day trial and one probe trial) was conducted, and serum estrogen levels, toxicity markers (alanine transaminase, alkaline phosphatase, urea, and creatinine), and hippocampal SIRT1 immunohistochemistry were estimated after sacrifice. The results indicated that EBN and estrogen enhanced spatial learning and memory and increased serum estrogen and hippocampal SIRT1 expression. In addition, the EBN groups did not show as much toxicity to the liver as the estrogen group. The data suggested that EBN treatment for 12 weeks could improve cognition and memory in ovariectomized female rats and may be an effective alternative to estrogen therapy for menopause-induced aging-related memory loss.
    Matched MeSH terms: Mild Cognitive Impairment/metabolism
  5. Ooi TC, Meramat A, Rajab NF, Shahar S, Ismail IS, Azam AA, et al.
    Nutrients, 2020 Aug 30;12(9).
    PMID: 32872655 DOI: 10.3390/nu12092644
    Intermittent fasting (IF) refers to various dietary regimens that cycle between a period of non-fasting and a period of total fasting. This study aimed to determine the effects of IF on cognitive function among elderly individuals who practice IF who have mild cognitive impairment (MCI). A total of 99 elderly subjects with MCI of Malay ethnicity without any terminal illness were recruited from a larger cohort study, LRGS TUA. The subjects were divided into three groups, comprising those who were regularly practicing IF (r-IF), irregularly practicing IF (i-IF), and non-fasters (n-IF). Upon 36 months of follow-up, more MCI subjects in the r-IF group reverted to successful aging with no cognitive impairment and diseases (24.3%) compared to those in i-IF (14.2%) and n-IF groups (3.7%). The r-IF group's subjects exhibited significant increment in superoxide dismutase (SOD) activity and reduction in body weight, levels of insulin, fasting blood glucose, malondialdehyde (MDA), C-reactive protein (CRP), and DNA damage. Moreover, metabolomics analysis showed that IF may modulate cognitive function via various metabolite pathways, including the synthesis and degradation of ketone bodies, butanoate metabolism, pyruvate metabolism, and glycolysis and gluconeogenesis pathways. Overall, the MCI-afflicted older adults who practiced IF regularly had better cognitive scores and reverted to better cognitive function at 36 months follow-up.
    Matched MeSH terms: Mild Cognitive Impairment/metabolism*
  6. Lee LK, Shahar S, Rajab N, Yusoff NA, Jamal RA, Then SM
    J Nutr Biochem, 2013 May;24(5):803-8.
    PMID: 22898566 DOI: 10.1016/j.jnutbio.2012.04.014
    The present work explores the effect of dietary omega-3 polyunsaturated fatty acids (PUFAs) intake on lipid peroxidation among mild cognitive impairment (MCI) patients. The plasma lipid hydroperoxide (LPO) levels in 67 MCI patients were compared to those of 134 healthy elderly controls. Omega-3 PUFA intake was assessed using an interviewer-administered food frequency questionnaire. Apolipoprotein E genotyping was performed using polymerase chain reaction and restriction enzyme digestion. The association between various confounders and lipid peroxidation was evaluated using regression analysis. The influence of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) intake on LPO level was investigated. The results revealed that LPO levels were significantly higher in the MCI group than in the control group. Inverse correlations were found between DHA and EPA intake and LPO level among the MCI group. LPO levels decreased significantly with increasing DHA and EPA intake. In summary, the findings revealed that DHA and EPA can play a role in alleviating oxidative stress and reducing the risk of neurodegenerative diseases.
    Matched MeSH terms: Mild Cognitive Impairment/metabolism*
  7. Hammad MA, Syed Sulaiman SA, Aziz NA, Mohamed Noor DA
    Diabetes Metab Syndr, 2019 04 12;13(3):1797-1803.
    PMID: 31235097 DOI: 10.1016/j.dsx.2019.04.006
    AIMS: The study was intended to evaluate the association of cognitive impairment with statins therapy among diabetic outpatients.

    METHODS: Mini-Addenbrooke's Cognitive Examination (M-ACE) was conducted for 280 cases in a cross-sectional study at Hospital Pulau Pinang. M-ACE score is 30, and the cut-off score for mild cognitive impairment is ≤ 21 and ≤ 16 for dementia.

    RESULTS: The cognitive impairment was distributed among 59 (55.1%) patients with mild cognitive impairment and 48 (44.9%) patients with dementia. From 177 patients using statins, about 80 (45.2%) cases had cognitive impairment. While from 103 statins non-users, only 27 (26.2%) had cognitive impairment. The relative risk of cognitive impairment associated with statins use in diabetic patients is (RR: 1.72, 95% CI: 1.2-2.48) and the excess relative risk is 72.4%. The absolute risk is 19%, and the number needed to harm is 6. Spearman's test indicated a positive association between statins usage and cognitive impairment incidence (r: 0.188, p-value: 0.002). However, Spearman's test showed a non-significant correlation amongst statins and dementia incidence (P-value: 0.587, RR: 1.16, 95% CI: 0.67-2.02).

    CONCLUSIONS: Statins therapy has a higher association with cognitive impairment risk than statins-free treatment; however, there is no association between statin use and dementia incidence among diabetic patients.
    Matched MeSH terms: Mild Cognitive Impairment/metabolism
  8. Jayasingh Chellammal HS, Veerachamy A, Ramachandran D, Gummadi SB, Manan MM, Yellu NR
    Biomed Pharmacother, 2019 Jan;109:1454-1461.
    PMID: 30551397 DOI: 10.1016/j.biopha.2018.10.189
    The progressive accumulation of amyloid beta (Aβ) peptide is neurotoxic and leads to Alzheimer's type dementia. Accumulation of Aβ has been associated with dysfunction of hypothalamic-pituitary-adrenal (HPA) axis and elevated pro-inflammatory cytokines. In this study, we investigated the effect of 1`δ-1`-acetoxyeugenol acetate (DAEA), isolated from Alpinia galanga (L.), on Aβ(25-35) induced neurodegeneration in mice. Mice were treated with three different doses of DAEA (12.5 mg/kg, 25 mg/kg and 50 mg/kg) for 28 days. Aβ(25-35) was injected by intracerebroventricular (i.c.v.) injection on the 15th day of 28 days. Open field, water maze and step-down inhibitory tests were performed on the 27th day to determine the habituation memory, spatial learning, and short- and long-term memory, respectively. Acetylcholinesterase (AChE), Corticosterone, biogenic amines (serotonin and dopamine), tumour necrosis factor-α (TNF-α), and antioxidant parameters such as superoxide dismutase, catalase, glutathione peroxidase and vitamin C were evaluated in brain homogenates after behavioural tests to ascertain the cognitive improvement through neuro-immune-endocrine modulation. The DAEA treatment with 25 mg/kg and 50 mg/kg resulted in significant (p < 0.001) improvement of habituation memory and step-down inhibitory avoidance task. In spatial learning, the cognitive improvement was significantly improved (p < 0.001) by reduction in escape latency. In the biochemical study, the significant (p < 0.001) reduction of AChE indicates the preeminent neuroprotection. Corticosterone and TNF-α were significantly (p < 0.01) reduced and biogenic amines were increased with antioxidant markers, which signify the potential influence of DAEA on neuroprotection. Our investigation revealed that the drug DAEA attenuates stress mediated through the HPA axis and regulates the neuroendocrine and neuroimmune function to improve the cognition. DAEA could be a potential lead candidate for the treatment of neurodegeneration.
    Matched MeSH terms: Mild Cognitive Impairment/metabolism
  9. Tan AH, Chong CW, Lim SY, Yap IKS, Teh CSJ, Loke MF, et al.
    Ann Neurol, 2021 03;89(3):546-559.
    PMID: 33274480 DOI: 10.1002/ana.25982
    OBJECTIVE: Gut microbiome alterations in Parkinson disease (PD) have been reported repeatedly, but their functional relevance remains unclear. Fecal metabolomics, which provide a functional readout of microbial activity, have scarcely been investigated. We investigated fecal microbiome and metabolome alterations in PD, and their clinical relevance.

    METHODS: Two hundred subjects (104 patients, 96 controls) underwent extensive clinical phenotyping. Stool samples were analyzed using 16S rRNA gene sequencing. Fecal metabolomics were performed using two platforms, nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry.

    RESULTS: Fecal microbiome and metabolome composition in PD was significantly different from controls, with the largest effect size seen in NMR-based metabolome. Microbiome and NMR-based metabolome compositional differences remained significant after comprehensive confounder analyses. Differentially abundant fecal metabolite features and predicted functional changes in PD versus controls included bioactive molecules with putative neuroprotective effects (eg, short chain fatty acids [SCFAs], ubiquinones, and salicylate) and other compounds increasingly implicated in neurodegeneration (eg, ceramides, sphingosine, and trimethylamine N-oxide). In the PD group, cognitive impairment, low body mass index (BMI), frailty, constipation, and low physical activity were associated with fecal metabolome compositional differences. Notably, low SCFAs in PD were significantly associated with poorer cognition and low BMI. Lower butyrate levels correlated with worse postural instability-gait disorder scores.

    INTERPRETATION: Gut microbial function is altered in PD, characterized by differentially abundant metabolic features that provide important biological insights into gut-brain pathophysiology. Their clinical relevance further supports a role for microbial metabolites as potential targets for the development of new biomarkers and therapies in PD. ANN NEUROL 2021;89:546-559.

    Matched MeSH terms: Mild Cognitive Impairment/metabolism
  10. Damodaran T, Cheah PS, Murugaiyah V, Hassan Z
    Neurochem Int, 2020 10;139:104785.
    PMID: 32650028 DOI: 10.1016/j.neuint.2020.104785
    BACKGROUND: Clitoria ternatea (CT) is an herbal plant that has been used as a memory booster in folk medicine. CT root extract has been proven to restore chronic cerebral hypoperfusion (CCH)-induced memory deficits in a rat model, but the underlying mechanisms and the toxicity profile following repeated exposure have yet to be explored.

    THE AIM OF THE STUDY: To investigate the effects of the chronic (28 days) oral administration of CT root extract on CCH-induced cognitive impairment, neuronal damage and cholinergic deficit, and its toxicity profile in the CCH rat model.

    MATERIALS AND METHODS: The permanent bilateral occlusion of common carotid arteries (PBOCCA) surgery method was employed to develop a CCH model in male Sprague Dawley (SD) rats. Then, these rats were given oral administration of CT root extract at doses of 100, 200, and 300 mg/kg, respectively for 28 days and subjected to behavioural tests. At the end of the experiment, the brain was harvested for histological analysis and cholinesterase activities. Then, blood samples were collected and organs such as liver, kidney, lung, heart, and spleen were procured for toxicity assessment.

    RESULTS: Chronic treatment of CT root extract at doses of 200 and 300 mg/kg, restored memory impairments induced by CCH. CT root extract was also found to diminish CCH-induced neuronal damage in the CA1 region of the hippocampus. High dose (300 mg/kg) of the CT root extract was significantly inhibited the increased acetylcholinesterase (AChE) activity in the frontal cortex and hippocampus of the PBOCCA rats. In toxicity study, repeated doses of CT root extract were found to be safe in PBOCCA rats after 28 days of treatment.

    CONCLUSIONS: Our findings provided scientific evidence supporting the therapeutic potential of CT root extract in the treatment of vascular dementia (VaD)-related cholinergic abnormalities and subsequent cognitive decline.

    Matched MeSH terms: Mild Cognitive Impairment/metabolism
  11. Tiang N, Ahad MA, Murugaiyah V, Hassan Z
    J Pharm Pharmacol, 2020 Nov;72(11):1629-1644.
    PMID: 32743849 DOI: 10.1111/jphp.13345
    OBJECTIVES: Xanthones isolated from the pericarp of Garcinia mangostana has been reported to exhibit neuroprotective effect.

    METHODS: In this study, the effect of xanthone-enriched fraction of Garcinia mangostana (XEFGM) and α-mangostin (α-MG) were investigated on cognitive functions of the chronic cerebral hypoperfusion (CCH) rats.

    KEY FINDINGS: HPLC analysis revealed that XEFGM contained 55.84% of α-MG. Acute oral administration of XEFGM (25, 50 and 100 mg/kg) and α-MG (25 and 50 mg/kg) before locomotor activity and Morris water maze (MWM) tests showed no significant difference between the groups for locomotor activity.

    CONCLUSIONS: However, α-MG (50 mg/kg) and XEFGM (100 mg/kg) reversed the cognitive impairment induced by CCH in MWM test. α-MG (50 mg/kg) was further tested upon sub-acute 14-day treatment in CCH rats. Cognitive improvement was shown in MWM test but not in long-term potentiation (LTP). BDNF but not CaMKII was found to be down-regulated in CCH rats; however, both parameters were not affected by α-MG. In conclusion, α-MG ameliorated learning and memory deficits in both acute and sub-acute treatments in CCH rats by improving the spatial learning but not hippocampal LTP. Hence, α-MG may be a promising lead compound for CCH-associated neurodegenerative diseases, including vascular dementia and Alzheimer's disease.

    Matched MeSH terms: Mild Cognitive Impairment/metabolism
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