Celiac.com 02/01/2021 - Non-Celiac Gluten Sensitivity (NCGS) is poorly understood, particularly in terms of its neurological effects. A team of researchers looking into the matter first conducted a prospective postal survey to investigate its neurological presentation and symptom course. Based on the results of the survey, they conducted a brain MRI study to follow-up, and to note potential diagnostic biomarkers for future research.

The research team included Iain D. Croall, Nigel Hoggard, Imran Aziz, Marios Hadjivassiliou, and David S. Sanders. They are variously affiliated with the Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield/INSIGENO, Sheffield, United Kingdom; the Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, United Kingdom; and the Academic Departments of Neurosciences and Neuroradiology, Sheffield Teaching Hospitals NHS Trust, Sheffield, United Kingdom.

The team recruited 125 patients with NCGS from a clinical center. Each patient completed a prospective postal questionnaire summarizing the symptoms, their severity and their course. The team used Chi-squared analysis to compare onset time to data from 224 celiac disease patients from the same centre. 

Five gluten-free respondents who self-reported brain fog then received MR brain imaging and questionnaires, both before and after a gluten challenge. The team recorded this “baseline” data, and looked for abnormalities. They then compared symptom severity and cerebral blood flow (CBF) both before and after the gluten challenge.

Neurological symptoms included headaches in more than half of patients, brain fog in just under half,  balance issues in about one-third of patients, and tingling in about 20%. Symptoms typically began with 90 minutes, and resolved within 48 hours. The pattern of symptom onset was similar to that seen in celiac patients. Extra-intestinal symptoms worsened by nearly 40% during a typical reaction. 

The combined survey and brain imaging analysis showed that non-trivial neurological symptoms are common, and may be studied within 2 hours following gluten ingestion. The team suggests that further brain imaging studies may help reveal physiological damage, and the physiological response to gluten.

The researchers stress the need for diagnostic biomarkers for NCGS, and notes that  there is limited research showing AGA is raised in NCGS patients compared to the general population 

This first-of-a-kind neuro-imaging study revealed numerous clinical variables, which may be helpful for further studying the pathophysiology of NCGS. The positivity rate in patients for this study was about 18%, compared to just under 13% for healthy volunteers, which is an insignificant difference. 

This generally supports previous literature showing that AGA is not a good way to diagnose typical NCGS.  A better understanding of how gliadin positivity interacts with neurological outcomes may be helpful, as research indicates that these antibodies may harm the brain.

Read more at PLOS.org

Celiac.com 01/25/2021 - What's the connection between celiac disease, and cognitive impairment? Does the connection change over time? Does following a gluten-free diet help reduce cognitive impairment? There really hasn't been much good study data on this so far.

One of the main problems, according to researchers, previous reports of cognitive deficit in celiac disease often study widely variable groups of patients at multiple stages of the disease, and/or lack control data. 

To better understand the connection between cognitive impairment and celiac disease duration and gluten-free diet adherence, a team of researchers recently set out to examine groups of newly diagnosed and long-standing celiac disease patients.

The research team included Iain D Croall, Claire Tooth, Annalena Venneri, Charlotte Poyser, David S Sanders, Nigel Hoggard and Marios Hadjivassiliou. They are variously affiliated with the Department of Neuroscience, the Department of Infection, Immunity & Cardiovascular Disease, and the Institute for Silico Medicine, at the University of Sheffield in Sheffield, UK; the Department of Psychological Services, Royal Hallamshire Hospital, STH, Sheffield, UK; the South West Yorkshire Partnership NHS Foundation Trust in Wakefield, UK; the Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals National Health Service Foundation Trust, Sheffield, UK; and the Department of Neurology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals National Health Service Foundation Trust in Sheffield, UK.

The team recruited 21 healthy control subjects, along with 19 newly diagnosed celiac patients (NCD) and 35 established celiac patients (ECD). Each participant took cognitive tests that established seven baseline domain scores. Patients also responded to SF-36 quality of life (QoL) questionnaires. The team then controlled for age, and compared data in between-group ANCOVAs with Tukey’s post-hoc test. 

The team then compared significant outcomes in the ECD group between fully gluten-free patients patients who not fully gluten-free diet, as defined by Biagi scores and blood tests. 

In visual, verbal, and memory tasks, the NCD and ECD groups underperformed relative to controls, by comparable measures. The ECD group only underperformed in visual-constructive tasks. 

In terms of QoL measures, the NCD patients reported lower vitality, while the ECD patients reported more bodily pain. Comparisons based on dietary adherence were non-significant. 

The team's findings confirm cognitive deficit in celiac patients, which seems to exist at the time of diagnosis, after which it seems to level off. 

While it seems that a gluten-free diet may be that cause of the leveling off, more research is needed to establish the degree to which this is true, and to what extent any further decline might result from ongoing gluten exposure.

Read the team's paper entitled, Brain fog and non-coeliac gluten sensitivity: Proof of concept brain MRI pilot study, in Nutrients 2020, 12(7), 2028

Celiac.com 04/23/2018 - A team of researchers recently set out to learn whether celiac disease patients commonly suffer cognitive impairment at the time they are diagnosed, and to compare their cognitive performance with non-celiac subjects with similar chronic symptoms and to a group of healthy control subjects.

The research team included G Longarini, P Richly, MP Temprano, AF Costa, H Vázquez, ML Moreno, S Niveloni, P López, E Smecuol, R Mazure, A González, E Mauriño, and JC Bai. They are variously associated with the Small Bowel Section, Department of Medicine, Dr. C. Bonorino Udaondo Gastroenterology Hospital; Neurocience Cognitive and Traslational Institute (INECO), Favaloro Fundation, CONICET, Buenos Aires; the Brain Health Center (CESAL), Quilmes, Argentina; the Research Council, MSAL, CABA; and with the Research Institute, School of Medicine, Universidad del Salvador.

The team enrolled fifty adults with symptoms and indications of celiac disease in a prospective cohort without regard to the final diagnosis.  At baseline, all individuals underwent cognitive functional and psychological evaluation. The team then compared celiac disease patients with subjects without celiac disease, and with healthy controls matched by sex, age, and education.

Celiac disease patients had similar cognitive performance and anxiety, but no significant differences in depression scores compared with disease controls.

A total of thirty-three subjects were diagnosed with celiac disease. Compared with the 26 healthy control subjects, the 17 celiac disease subjects, and the 17 disease control subjects, who mostly had irritable bowel syndrome, showed impaired cognitive performance (P=0.02 and P=0.04, respectively), functional impairment (P<0.01), and higher depression (P<0.01). 

From their data, the team noted that any abnormal cognitive functions they saw in adults with newly diagnosed celiac disease did not seem not to be a result of the disease itself. 

Their results indicate that cognitive dysfunction in celiac patients could be related to long-term symptoms from chronic disease, in general.

Source:

• J Clin Gastroenterol. 2018 Mar 1. doi: 10.1097/MCG.0000000000001018.

Celiac.com 01/01/2018 - A team of researchers recently set out to conduct a genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment.

The research team included Max Lam, Joey W. Trampush, Jin Yu, Emma Knowles, Gail Davies, David C. Liewald, John M. Starr, Srdjan Djurovic, Ingrid Melle, Kjetil Sundet, Andrea Christoforou, Ivar Reinvang, Pamela DeRosse, Astri J. Lundervold, Vidar M. Steen, Thomas Espeseth, Katri Räikkönen, Elisabeth Widen, Aarno Palotie, Johan G. Eriksson, Ina Giegling, Bettina Konte, Panos Roussos, Stella Giakoumaki, Katherine E. Burdick, Antony Payton, William Ollier, Ornit Chiba-Falek, Deborah K. Attix, Anna C. Need, Elizabeth T. Cirulli, Aristotle N. Voineskos, Nikos C. Stefanis, Dimitrios Avramopoulos, Alex Hatzimanolis, Dan E. Arking, Nikolaos Smyrnis, Robert M. Bilder, Nelson A. Freimer, Tyrone D. Cannon, Edythe London, Russell A. Poldrack, Fred W. Sabb, Eliza Congdon, Emily Drabant Conley, Matthew A. Scult, Dwight Dickinson, Richard E. Straub, Gary Donohoe, Derek Morris, Aiden Corvin, Michael Gill, Ahmad R. Hariri, Daniel R. Weinberger, Neil Pendleton, Panos Bitsios, Dan Rujescu, Jari Lahti, Stephanie Le Hellard, Matthew C. Keller, Ole A. Andreassen, Ian J. Deary, David C. Glahn, Anil K. Malhotra, and Todd Lencz. They are variously associated with the dozens of research facilities listed below.

Their study provided a large-scale GWAS of cognitive performance, combined with GWAS of educational attainment; 70 independent genomic loci associated with individual differences in cognition. The study found that implicated genes suggest potential treatment targets for cognitive enhancement. The team also observed genetic overlap between cognitive ability and multiple health-related phenotypes.

For their genome-wide association study (GWAS) of general cognitive ability ("g"), the team evaluated 107,207 subjects. They further enhanced their data pool by combining results with a large-scale GWAS of educational attainment. They also identified 70 independent genomic loci associated with general cognitive ability.

Observing the outcomes, the team saw substantial enrichment for genes triggering Mendelian disorders with an intellectual disability phenotype. Analysis of competitive pathways pointed to neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor.

According to the researchers: "we observed modest, yet nominally significant, inverse correlations between cognition and autoimmune diseases such as eczema and Crohn's disease, attaining Bonferroni significance for rheumatoid arthritis (rg for MTAG results = −0.2086; p = 1.60E−08). There was also a Bonferroni-significant positive genetic correlation with celiac disease (rg for MTAG results = 0.1922; p = 0.0001)."
Full analysis of both the transcriptome and epigenome showed that the implicated loci were enriched for genes expressed across all brain regions; mostly in the cerebellum.

Interestingly, only genes expressed in neurons were enriched, not those expressed in oligodendrocytes or astrocytes.

Lastly, the team observed genetic correlations between cognitive ability and various phenotypes, including psychiatric disorders, autoimmune disorders, longevity, and maternal age at first birth.

Source:

• Cell.com. DOI: http://dx.doi.org/10.1016/j.celrep.2017.11.028 

The research team members are variously associated with the following:

• Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada
• Institute of Mental Health, Singapore, Singapore
• BrainWorkup, LLC, Los Angeles, CA, USA
• Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA
• Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA
• Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, NY, USA
• Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA
• Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
• Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
• Mental Illness Research, Education, and Clinical Center (VISN 2), James J. Peters VA Medical Center, Bronx, NY, USA
• Department of Neurology, Bryan Alzheimer's Disease Research Center and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA
• Department of Psychiatry and Behavioral Sciences, Division of Medical Psychology, Duke University Medical Center, Durham, NC, USA
• Laboratory of NeuroGenetics, Department of Psychology & Neuroscience, Duke University, Durham, NC, USA
• Human Longevity Inc., Durham, NC, USA
• Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
• Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
• Department of Psychology, Yale University, New Haven, CT, USA
• Department of Psychology, Stanford University, Palo Alto, CA, USA
• Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institute of Health, Bethesda, MD, USA
• Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA
• Neuroimaging, Cognition & Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland
• Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
• Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
• Department of Psychology, University of Edinburgh, Edinburgh, UK
• Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK
• Division of Brain Sciences, Department of Medicine, Imperial College, London, UK
• Centre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, UK
• Centre for Integrated Genomic Medical Research, Institute of Population Health, University of Manchester, Manchester, UK
• Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Manchester, UK
• Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway
• Department of Medical Genetics, Oslo University Hospital, University of Bergen, Oslo, Norway
• NORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway
• Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
• Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
• Department of Psychology, University of Oslo, Oslo, Norway
• Department of Psychology, University of Edinburgh, Edinburgh, UK
• Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
• Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
• Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
• Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK
• Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland
• Department of General Practice, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
• National Institute for Health and Welfare, Helsinki, Finland
• Folkhälsan Research Center, Helsinki, Finland
• Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland
• Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany
• Department of Psychology, University of Crete, Crete, Greece
• Department of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, Greece
• University Mental Health Research Institute, Athens, Greece
• Neurobiology Research Institute, Theodor-Theohari Cozzika Foundation, Athens, Greece
• Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece
• Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
• McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
• UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA
• 23andMe, Inc., Mountain View, CA, USA

The researchers included S. Casella, B. Zanini, F. Lanzarotto, C. Ricci, A. Marengoni, G. Romanelli, A. Lanzini, of the Gastroenterology Unit of the Department of Medicine at University and Spedali Civili in Brescia, Italy.

The researchers wanted to evaluate functional and cognitive performances in celiac disease, and in control patients, older than 65 years.

For their study, they recruited 18 celiac disease patients aged 75-years or older (±4 years, group A) who had been on a gluten free diet for an average of 5.5 years (±3 years), along with a control group of 18 patients matched for sex and age, averaging 76 years of age (±4 years, group .

The team then administered a number of functional and cognitive neuropsychological tests. They recorded the results as "row scores" and as "equivalent scores" by relating "raw scores" to reference rank categories.

For the functional tests, they found that the Barthel Index of functional performance was similar for both groups.

However, for the cognitive tests, they found that the "raw score" was significantly lower in celiac disease than controls. The cognitive tests included Mini Mental Test Examination (p=0.02), Trail Making Test (p=0.001), Semantic Fluency (p=0.03), Digit Symbol Test (p=0.007), Ideo-motor apraxia (p

The also found that the "equivalent score" was also lower in celiac disease than controls for tests of Semantic memory. The results showed that cognitive performance is worse in elderly patients with celiac disease than in healthy control patients, despite prolonged treatment with a gluten-free diet.

They write that "awareness on the increasing phenomenon of late-onset celiac disease is important to minimize diagnostic delay and prolonged exposure to gluten that may adversely and irreversibly affect cognitive function."

Source:

• Open Original Shared Link

Celiac.com 11/05/2010 - To address study data suggesting that people with intellectual disabilities, especially men, suffer high rates of celiac disease, a team of researchers recently set out to assess rates of celiac disease in patients with intellectual disabilities.

The research team included Manouchehr Khoshbaten, Mohammad Rostami Nejad, Shaheed Beheshti, Nasrin Sharifi, Majid Torabi, David Al Dulaimi, Kamran Rostami, and Chris J. Mulder

They are affiliated with the Liver and Gastrointestinal Diseases Research Centre at Emam Reza Educational Hospital in Tabriz, Iran, the Research Center of Gastroenterology and Liver Diseases at University M.C. in Tehran, Iran, the Liver Tabriz Welfare Organization in Iran, Nutritional Research Center at Tabriz University of Medical Sciences in Iran, the School of Medicine at at University Hospital Birmingham, UK, and with the Department of Gastroenterology at VU University Medical Center in Amsterdam, The Netherlands, and with the Department of Gastroenterology, at Alexander Hospital in Redditch, UK.

A number of studies suggest that people with intellectual disabilities, especially men, suffer high rates of celiac disease. To more deeply examine the issue, the research team found 196 patients with intellectual disabilities who were being treated in rehabilitation centers in Iran's province of East Azerbaijan.

The team paired these patients with 196 healthy control subjects, and screened both groups for celiac disease using anti-tissue transglutaminase IgA antibodies (tTGA), total serum IgA levels, and Marsh-Rostami criteria to assess histological results.

Two patients (1%) showed positive tTG screens, while and duodenal biopsies revealed Marsh I levels in one patient, and Marsh 0 in the second.

Three patients showed IgA deficiency, while one showed a positive tTGA screen. Biopsies from this patient revealed a level of Marsh IIIc.

From the control group, just one subject showed positive tTGA, while five cases were IgA deficient.  Two of the five IgA deficient patients registered positive tTG screens, but both showed normal histology.

These results show the rates of celiac disease in patients with intellectual disabilities to be 1% with biopsy confirmation, and "no significant differences in frequency of the tTGA positive participants between the study and control groups."

Interestingly, in contrast to the higher rates of gluten sensitivity in male patients affected with intellectual disabilities, male and female patients in this study showed nearly equal rates.

This study shows no difference in rates of celiac disease in patients with intellectual disability compared to those with no intellectual disability, "unless the patients have symptoms or known risk factors for celiac disease such as epilepsy or Down’s syndrome."

Thus, the study suggests, general celiac screening of people with intellectual disabilities is unnecessary.

Source:

• Open Original Shared Link

Arch Neurol. Oct 2006;63:1440-1446
Cognitive Impairment and Celiac Disease
William T. Hu, MD, PhD; Joseph A. Murray, MD; Melanie C. Greenaway, PhD;
Joseph E. Parisi, MD; Keith A. Josephs, MST, MD

This was a limited study. While it looked at folate and vitamins B12 and E, one major oversite of celiac disease research continues to be a dearth of knowledge about levels of essential fatty acids in celiac disease patients. Fat malabsorption is a primary symptom of celiac disease, and the consequences continue to be ignored. Meanwhile, an accumulation of evidence supports the critical role of omega-3 fatty acids in maintaining cognitive and mental health. Omega-3 supplementation has even reversed conditions such as schizophrenia in individuals, begging the question of whether it is gluten toxicity or a fatty acid deficiency that may cause schizophrenia in some celiacs.

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