CSF and Plasma Cholinergic Markers in Patients With Cognitive Impairment

IntroductionAlzheimer’s disease (AD) is the most prevalent form of dementia with symptoms of deteriorating cognitive functions and memory loss, partially as a result of a decrease in cholinergic neurotransmission. The disease is incurable and treatment with cholinesterase inhibitors (ChEIs) is symptomatic. Choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine (ACh), has been proven recently to be present in both cerebrospinal fluid (CSF) and plasma. As ChAT plays a role in regulating the extracellular ACh levels, it may have an impact on prognosis and cognitive performance in AD patients.ObjectivesTo measure ChAT activity and its protein concentration in CSF and plasma from patients with AD, mild cognitive impairment (MCI), or Subjective cognitive impairment (SCI).MethodsPlasma and CSF samples were obtained from 21 AD, 32 MCI, and 30 SCI patients. The activity and protein levels of ChAT and acetylcholinesterase (AChE), the enzyme catalyzing the hydrolysis of ACh, were analyzed using an integrated activity and protein concentration ELISA-like assay. A Cholinergic Index was calculated as the ratio of ChAT to AChE activities in CSF. The data were analyzed in relation to dementia biomarkers and cognitive performance of the patients.ResultsThe CSF ChAT activity was significantly higher (55–67%) in MCI patients compared to AD and SCI cases. The CSF Cholinergic Index was 41 and 22% lower in AD patients than in MCI and SCI subjects, respectively. This index correlated positively with the Aβ42/p-tau ratio in CSF in SCI but negatively with that in AD and MCI. The ChAT activity and protein levels in plasma exhibited significant differences with the pattern of AD>>MCI>SCI.ConclusionThis is the first study investigating soluble levels of the key cholinergic enzyme, ChAT, in both plasma and CSF of individuals at different clinical stages of dementia. Although further validation is needed, the overall pattern of the results suggests that in the continuum of AD, the cholinergic signaling exhibits an inverse U-shape dynamic of changes in the brain that greatly differs from the changes observed in the plasma compartment.

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Investigating Associations Between Inflammatory Biomarkers, Gray Matter, Neurofilament Light and Cognitive Performance in Healthy Older Adults

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.719553 ◽

2021 ◽

Vol 13 ◽

Author(s):

Hollis C. Karoly ◽

Carillon J. Skrzynski ◽

Erin Moe ◽

Angela D. Bryan ◽

Kent E. Hutchison

Keyword(s):

Older Adults ◽

Cognitive Impairment ◽

Cognitive Performance ◽

Gray Matter ◽

Regression Models ◽

Normal Aging ◽

Neurofilament Light ◽

Healthy Older Adults ◽

Analytic Models ◽

The Brain

Background: Exploring biological variables that may serve as indicators of the development and progression of cognitive decline is currently a high-priority research area. Recent studies have demonstrated that during normal aging, individuals experience increased inflammation throughout the brain and body, which may be linked to cognitive impairment and reduced gray matter volume in the brain. Neurofilament light polypeptide (NfL), which is released into the circulation following neuronal damage, has been proposed as a biomarker for neurodegenerative diseases, and may also have utility in the context of normal aging. The present study tested associations between age, peripheral levels of the pro-inflammatory cytokine IL-6, peripheral NfL, brain volume, and cognitive performance in a sample of healthy adults over 60 years old.Methods: Of the 273 individuals who participated in this study, 173 had useable neuroimaging data, a subset of whom had useable blood data (used for quantifying IL-6 and NfL) and completed a cognitive task. Gray matter (GM) thickness values were extracted from brain areas of interest using Freesurfer. Regression models were used to test relationships between IL-6, NfL, GM, and cognitive performance. To test putative functional relationships between these variables, exploratory path analytic models were estimated, in which the relationship between age, IL-6, and working memory performance were linked via four different operationalizations of brain health: (1) a latent GM variable composed of several regions linked to cognitive impairment, (2) NfL alone, (3) NfL combined with the GM latent variable, and (4) the hippocampus alone.Results: Regression models showed that IL-6 and NfL were significantly negatively associated with GM volume and that GM was positively associated with cognitive performance. The path analytic models indicated that age and cognitive performance are linked by GM in the hippocampus as well as several other regions previously associated with cognitive impairment, but not by NfL alone. Peripheral IL-6 was not associated with age in any of the path models.Conclusions: Results suggest that among healthy older adults, there are several GM regions that link age and cognitive performance. Notably, NfL alone is not a sufficient marker of brain changes associated with aging, inflammation, and cognitive performance.

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Oroxylum Indicum ameliorates chemotherapy induced cognitive impairment

PLoS ONE ◽

10.1371/journal.pone.0252522 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252522

Author(s):

Satyanarayana R. Pondugula ◽

Mohammed Majrashi ◽

Mohammed Almaghrabi ◽

Sindhu Ramesh ◽

Kodye L. Abbott ◽

...

Keyword(s):

Cognitive Impairment ◽

Cognitive Performance ◽

Mitochondrial Function ◽

Chemical Constituents ◽

Lipid Peroxide ◽

Chemotherapeutic Agents ◽

Glutathione Depletion ◽

Spatial Learning And Memory ◽

Oroxylum Indicum ◽

The Brain

While chemotherapy is the most effective therapeutic approach for treating a variety of cancer patients, commonly used chemotherapeutic agents, often induce several adverse effects. Escalating evidence indicates that chemotherapeutics, particularly doxorubicin (DOX) and cyclophosphamide (CPS), induce cognitive impairment associated with central nervous system toxicity. This study was performed to determine neuroprotective effects of Oroxylum indicum extract (OIE) in regard to preventing chemotherapy induced cognitive impairment (CICI) occurring after 4 cycles of DOX (2mg/kg) and CPS (50mg/kg) combination chemotherapy in male C57BL/6J mice. OIE significantly prevented the chemotherapy impaired short-term cognitive performance, exploratory behavior associated with cognitive performance, cognitive performance, and spatial learning and memory in the Y-maze, Open-Field, Novel Object Recognition, and Morris Water Maze tests, respectively. These data suggest that OIE protects from the CICI. OIE decreased the reactive oxygen species and lipid peroxide generated by the chemotherapy treatment in the brain, while also blocking the chemotherapy-induced glutathione depletion. These results establish that OIE exhibits potent antioxidant activity in chemotherapy treated mice. Notably, OIE significantly increased the Complex-I and Complex-IV activities in the brain, indicating that OIE enhances mitochondrial function in the brain. In silico analysis of the major active chemical constituents (Oroxylin A, Baicalein and Chrysin) of OIE indicated that OIE has a favorable absorption, distribution, metabolism and excretion (ADME) profile. Taken together, our results are consistent with the conclusion that OIE prevents CICI by counteracting oxidative stress and perhaps by improving mitochondrial function.

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The Inflammasome Adaptor Protein ASC in Mild Cognitive Impairment and Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21134674 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4674 ◽

Cited By ~ 4

Author(s):

Xavier O. Scott ◽

Marisa E. Stephens ◽

Marie C. Desir ◽

W. Dalton Dietrich ◽

Robert W. Keane ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Memory Loss ◽

Adaptor Protein ◽

Therapeutic Window ◽

Likelihood Ratios ◽

Predictive Values ◽

Protein Levels

Mild cognitive impairment (MCI) is characterized by memory loss in the absence of dementia and is considered the translational stage between normal aging and early Alzheimer’s disease (AD). Patients with MCI have a greater risk of advancing to AD. Thus, identifying early markers of MCI has the potential to increase the therapeutic window to treat and manage the disease. Protein levels of the inflammasome signaling proteins apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and interleukin (IL)-18 were analyzed in the serum of patients with MCI, AD and healthy age-matched donors as possible biomarkers, as well as levels of soluble amyloid precursor proteins α/β (sAPP α/β) and neurofilament light (NfL). Cut-off points and positive and negative predictive values, as well as receiver operator characteristic (ROC) curves, likelihood ratios and accuracy were determined for these proteins. Although the levels of ASC were higher in MCI and AD than in age-matched controls, protein levels of ASC were higher in MCI than in AD cases. For control vs. MCI, the area under the curve (AUC) for ASC was 0.974, with a cut-off point of 264.9 pg/mL. These data were comparable to the AUC for sAPP α and β of 0.9687 and 0.9068, respectively, as well as 0.7734 for NfL. Moreover, similar results were obtained for control vs. AD and MCI vs. AD. These results indicate that ASC is a promising biomarker of MCI and AD.

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Mitochondrial Protection and Against Glutamate Neurotoxicity via Shh/Ptch1 Signaling Pathway to Ameliorate Cognitive Dysfunction by Kaixin San in Multi-Infarct Dementia Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5590745 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Xiaoqiong Li ◽

Wen Wen ◽

Ping Li ◽

Ying Fu ◽

Hao Chen ◽

...

Keyword(s):

Signaling Pathway ◽

Brain Tissue ◽

Energy Charge ◽

Memory Loss ◽

The Elderly ◽

Protective Effects ◽

Protein Levels ◽

Glutamate Neurotoxicity ◽

Mitochondrial Functions ◽

The Brain

Multi-infarct dementia (MID), a prominent subtype of vascular dementia (VD), is responsible for at least 15 to 20 percent of dementia in the elderly. Mitochondrial dysfunctions and glutamate neurotoxicity due to chronic hypoperfusion and oxidative stress were regarded as the major risk factors in the pathogenesis. Kaixin San (KXS), a classic prescription of Beiji Qianjin Yaofang, was applied to treatment for “amnesia” and has been demonstrated to alleviate the cognitive deficit in a variety of dementias, including MID. However, little is known whether mitochondria and glutamate are associated with the protection of KXS in MID treatment. The aim of this study was to investigate the role of KXS in improving the cognitive function of MID rats through strengthening mitochondrial functions and antagonizing glutamate neurotoxicity via the Shh/Ptch1 signaling pathway. Our data showed that KXS significantly ameliorated memory impairment and hippocampal neuron damage in MID rats. Moreover, KXS improved hippocampal mitochondrial functions by reducing the degree of mitochondrial swelling, increasing the mitochondrial membrane potential (MMP), and elevating the energy charge (EC) and ATP content in MID rats. As expected, the concentration of glutamate and the expression of p-NMDAR1 were significantly reduced by KXS in the brain tissue of MID rats. Furthermore, our results showed that KXS noticeably activated the Shh/Ptch1 signaling pathway which was demonstrated by remarkable elevations of Ptch1, Smo, and Gli1 protein levels in the brain tissue of MID rats. Intriguingly, the inhibition of the Shh signaling pathway with cyclopamine significantly inhibited the protective effects of KXS on glutamate-induced neurotoxicity in PC12 cells. To sum up, these findings suggested that KXS protected MID rats from memory loss by rescuing mitochondrial functions as well as against glutamate neurotoxicity through activating Shh/Ptch1 signaling pathway.

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An evaluation on changes in Hippocampus size for Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and Alzheimer’s disease (AD) patients using Fuzzy Membership Function

10.31222/osf.io/6cj7v ◽

2021 ◽

Author(s):

Ruhul Amin Hazarika ◽

Arnab Kumar Maji ◽

Debdatta Kandar ◽

Prasun Chakrabarti ◽

Tulika Chakrabarti ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Memory Loss ◽

Fuzzy Membership Function ◽

Average Difference ◽

Mr Images ◽

Cognitively Normal ◽

The Brain

Background: Alzheimer’s disease (AD) is a neurological disorder where the hippocampus in the brain gets affected severely. Hippocampus is a part of the limbic system, which is mainly responsible for forming memories. The transition from Cognitively Normal (CN) to AD is having one intermittent stage, popularly known as Mild Cognitive Impairment (MCI). In this study, segmentation operation has been performed first to separate the hippocampus, and then an analysis has been made on the basis of changes in area and atrophy in the hippocampus. A total of “2008” numbers of MR images have been analyzed for three different subject groups consist of “210” different subjects (Male:105, Female: 105) namely, CN, MCI, and AD.Objective: The objective of this study is to analyze the size and atrophy of the hippocampus due to AD and MCI in comparison with CN patients.Material and Methods: All the experiments have done using MATLAB tools. All the data used is acquired from the online dataset “Alzheimer’s Disease Neuroimaging Initiative (ADNI)”.Results: From the study, it is found that the average difference in the size of the hippocampus between CN and MCI is 17.05%, between CN and AD is 31.90%, and between MCI and AD is 18.24%. The average atrophy per year in the hippocampus is found to be as 4.62% for AD, 2.33% for MCI, and 1.10% for CN subjects.Conclusions: From the study, it is observed that, for AD patients, hippocampus atrophy is highest, and hence they experience the highest memory loss followed by the MCI and CN patients.

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An evaluation on changes in Hippocampus size for Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and Alzheimer’s disease (AD) patients using Fuzzy Membership Function

10.31219/osf.io/wujfn ◽

2021 ◽

Author(s):

Ruhul Amin Hazarika ◽

Arnab Kumar Maji ◽

Debdatta Kandar ◽

Prasun Chakrabarti ◽

Tulika Chakrabarti ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Memory Loss ◽

Fuzzy Membership Function ◽

Average Difference ◽

Mr Images ◽

Cognitively Normal ◽

The Brain

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Mild cognitive impairment: when nutrition helps brain energy rescue—a report from the EuGMS 2020 Congress

European Geriatric Medicine ◽

10.1007/s41999-021-00534-z ◽

2021 ◽

Author(s):

Stephen C. Cunnane ◽

Cornel C. Sieber ◽

Russell H. Swerdlow ◽

Alfonso J. Cruz-Jentoft

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Performance ◽

Alternative Energy ◽

Nutritional Intervention ◽

Older Individuals ◽

Nutritional Interventions ◽

The Brain ◽

Brain Energy

Abstract Background Mild cognitive impairment (MCI) is characterized by a decline in cognition and mainly affects older individuals above the age of 60. The global incidence of MCI varies, but it is often underdiagnosed and untreated. There is a distinct lack of approved pharmacologic options to treat MCI. There is, however, evidence to support the efficacy of nutritional interventions, such as ketogenic supplements/diets, which offer ketones as an alternative energy source to brain cells. This article explores the effect of ketones on metabolic activity in the brain and the mechanisms by which ketogenic medium-chain triglycerides (kMCTs) induce ketosis in patients with MCI. Key takeaways This article reviews the effect of ketogenic supplements/diets on brain metabolism, including evidence supporting the efficacy of ketones as an efficient fuel for the brain. It discusses the use of oral nutritional ketogenic supplements, with particular reference to the 6-month randomized controlled BENEFIC trial, which showed that consumption of a kMCT drink, BrainXpert Energy Complex, improved cognitive performance in individuals with MCI compared with placebo. Conclusion While there is a need for more long-term studies, results from the BENEFIC trial revealed the benefits of a brain-specific ketogenic supplement, as a nutritional intervention, on cognitive performance in individuals with MCI.

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Starving the brain: Structural abnormalities and cognitive impairment in adolescents with anorexia nervosa

Seminars in Clinical Neuropsychiatry ◽

10.1053/scnp.2001.22263 ◽

2001 ◽

Vol 6 (2) ◽

pp. 146-152 ◽

Cited By ~ 57

Author(s):

Debra K. Katzman ◽

Bruce Christensen ◽

Arlene R. Young ◽

Robert B. Zipursky

Keyword(s):

Anorexia Nervosa ◽

Cognitive Impairment ◽

Structural Abnormalities ◽

The Brain

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Brain FDG PET for the Etiological Diagnosis of Clinically Uncertain Cognitive Impairment During Delirium in Remission

Journal of Alzheimer s Disease ◽

10.3233/jad-200530 ◽

2020 ◽

Vol 77 (4) ◽

pp. 1609-1622

Author(s):

Franziska Mathies ◽

Catharina Lange ◽

Anja Mäurer ◽

Ivayla Apostolova ◽

Susanne Klutmann ◽

...

Keyword(s):

Cognitive Impairment ◽

Fdg Pet ◽

False Negative ◽

Ground Truth ◽

Etiological Diagnosis ◽

Geriatric Unit ◽

Positron Emission ◽

The Brain ◽

Hospitalized Geriatric Patients

Background: Positron emission tomography (PET) of the brain with 2-[F-18]-fluoro-2-deoxy-D-glucose (FDG) is widely used for the etiological diagnosis of clinically uncertain cognitive impairment (CUCI). Acute full-blown delirium can cause reversible alterations of FDG uptake that mimic neurodegenerative disease. Objective: This study tested whether delirium in remission affects the performance of FDG PET for differentiation between neurodegenerative and non-neurodegenerative etiology of CUCI. Methods: The study included 88 patients (82.0±5.7 y) with newly detected CUCI during hospitalization in a geriatric unit. Twenty-seven (31%) of the patients were diagnosed with delirium during their current hospital stay, which, however, at time of enrollment was in remission so that delirium was not considered the primary cause of the CUCI. Cases were categorized as neurodegenerative or non-neurodegenerative etiology based on visual inspection of FDG PET. The diagnosis at clinical follow-up after ≥12 months served as ground truth to evaluate the diagnostic performance of FDG PET. Results: FDG PET was categorized as neurodegenerative in 51 (58%) of the patients. Follow-up after 16±3 months was obtained in 68 (77%) of the patients. The clinical follow-up diagnosis confirmed the FDG PET-based categorization in 60 patients (88%, 4 false negative and 4 false positive cases with respect to detection of neurodegeneration). The fraction of correct PET-based categorization did not differ between patients with delirium in remission and patients without delirium (86% versus 89%, p = 0.666). Conclusion: Brain FDG PET is useful for the etiological diagnosis of CUCI in hospitalized geriatric patients, as well as in patients with delirium in remission.

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A Chemical Perspective to the Anti-Amyloid Action of Compounds and a Nanoparticle Based Assay for Screening Amyloid Inhibitors

10.26434/chemrxiv.7819661 ◽

2020 ◽

Author(s):

Nidhi Gour ◽

Bharti Koshti

Keyword(s):

Memory Loss ◽

Cost Effective ◽

Structural Motif ◽

Rapid Screening ◽

Stacking Interactions ◽

Aromatic Rings ◽

Amyloid Fibers ◽

Aromatic Stacking ◽

Cost Effective Technique ◽

The Brain

Aggregation of amyloid beeta 1-42 (Aβ42) peptide causes the formation of clustered deposits knows as amyloid plaques in the brain which leads to neuronal dysfunction and memory loss and associated with many neurological disorders including Alzheimer’s and Parkinson’s. Aβ42 has core structural motif with phenylalanine at the 19 and 20 positions. The diphenylalanine (FF) residue plays a crucial role in the formation of amyloid fibers and serves as model peptide for studying Aβ42 aggregation. FF self-assembles to well-ordered tubular morphology via aromatic pi-pi stackings. Our studies, suggest that the aromatic rings present in the anti-amyloidogenic compounds may interact with the pi-pi stacking interactions present in the FF. Even the compounds which do not have aromatic rings, like cyclodextrin and cucurbituril show anti-amyloid property due to the binding of aromatic ring inside the guest cavity. Hence, our studies also suggest that compounds which may have a functional moiety capable of interacting with the aromatic stacking interactions might be tested for their anti-amyloidogenic properties. Further, in this manuscript, we have proposed two novel nanoparticle based assays for the rapid screening of amyloid inhibitors. In the first assay, interaction between biotin-tagged FF peptide and the streptavidin labelled gold nanoparticles (s-AuNPs) were used. In another assay, thiol-Au interactions were used to develop an assay for detection of amyloid inhibitors. It is envisaged that the proposed analytical method will provide a simple, facile and cost effective technique for the screening of amyloid inhibitors and may be of immense practical implications to find the therapeutic remedies for the diseases associated with the protein aggregation.

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