Antigliadin antibodies and the brain in people without celiac disease: a case-control study.

BACKGROUND: Anti-gliadin antibodies (AGA) occur in approximately 10% of the general population, produced as a response to gluten. Autoimmune gluten-related disorders can have detrimental neurological effects if not properly controlled but the relevance of such "incidental" AGA is not properly established; any harm caused would indicate the gluten-free diet as a means for affected people to protect their brain health. We explored this question by comparing brain MRI scanning, cognitive testing and other measures between healthy volunteers with and without AGA. METHODS: Healthy volunteers aged 50-70 (without celiac disease, on a gluten-containing diet) underwent blood testing to confirm AGA status. Any AGA+ subjects were matched to AGA- controls on age, sex, BMI, level of education, hypertension diagnosis and smoking history. These subgroups underwent a cognitive test battery, quality-of-life (QoL) surveys and brain MRI scanning. Groups were compared between all outcome measures. Secondary analyses correlated AGA titre with outcomes across the whole cohort. RESULTS: Groupwise comparisons of cognitive, QoL and MRI studies were all negative. Repeating these analyses as correlations with AGA titre across the cohort, a single significant result was found concerning the error rate on the subtle cognitive impairment test, in a direction indicating increased IgG AGA to predict worse performance. This did not survive multiple comparisons correction. CONCLUSIONS: Our analysis is the most comprehensive to date and utilises a number of outcome measures known to be sensitive to subtle shifts in neurophysiology and cognition. Incidental AGA does not appear to be associated with any indications of neuropsychological deficit.

Neurological Evaluation of Patients with Newly Diagnosed Coeliac Disease Presenting to Gastroenterologists: A 7-Year Follow-Up Study.

We have previously shown that 67% of patients with newly diagnosed coeliac disease (CD) presenting to gastroenterologists have evidence of neurological dysfunction. This manifested with headache and loss of co-ordination. Furthermore 60% of these patients had abnormal brain imaging. In this follow-up study, we re-examined and re-scanned 30 patients from the original cohort of 100, seven years later. There was significant reduction in the prevalence of headaches (47% to 20%) but an increase in the prevalence of incoordination (27% to 47%). Although those patients with coordination problems at baseline reported improvement on the gluten free diet (GFD), there were 7 patients reporting incoordination not present at baseline. All 7 patients had positive serology for one or more gluten-sensitivity related antibodies at follow-up. In total, 50% of the whole follow-up cohort were positive for one or more gluten-related antibodies. A comparison between the baseline and follow-up brain imaging showed a greater rate of cerebellar grey matter atrophy in the antibody positive group compared to the antibody negative group. Patients with CD who do not adhere to a strict GFD and are serological positive are at risk of developing ataxia, and have a significantly higher rate of cerebellar atrophy when compared to patients with negative serology. This highlights the importance of regular review and close monitoring.

PRESERVE: Randomized Trial of Intensive Versus Standard Blood Pressure Control in Small Vessel Disease.

[Figure: see text].

Gluten and Autism Spectrum Disorder.

An expanding body of literature is examining connections between Autism Spectrum Disorder (ASD) and dietary interventions. While a number of specialist diets have been suggested as beneficial in ASD, gluten has received particularly close attention as a potentially exacerbating factor. Reports exist suggesting a beneficial effect of the gluten-free diet (GFD) in ameliorating behavioural and intellectual problems associated with ASD, while epidemiological research has also shown a comorbidity between ASD and coeliac disease. However, both caregivers and clinicians have expressed an uncertainty of the value of people with ASD going gluten-free, and as the GFD otherwise receives considerable public attention a discussion which focuses specifically on the interaction between ASD and gluten is warranted. In this review we discuss the historical context of ASD and gluten-related studies, and expand this to include an overview of epidemiological links, hypotheses of shared pathological mechanisms, and ultimately the evidence around the use and adoption of the GFD in people with ASD.

Brain fog and non-coeliac gluten sensitivity: Proof of concept brain MRI pilot study.

AIMS: Non-Coeliac Gluten Sensitivity (NCGS) is poorly understood, particularly in terms of its neurological outcomes. We initially conducted a prospective postal survey to investigate its neurological presentation and symptom course. Results from this then motivated a follow-up pilot study utilising brain MRI to characterise potential diagnostic biomarkers for future research. METHODS: Patients with NCGS were recruited from a specialist centre and completed a prospective postal questionnaire (N = 125). This summarised symptoms experienced, their severity and their course. Onset time was compared by Chi-squared analysis to data from the same centre concerning coeliac disease patients (N = 224). Five respondents on a strict gluten-free diet who self-reported brain fog then attended a pilot study, completing MR brain imaging/questionnaires before/after a gluten challenge. "Baseline" data were assessed for abnormalities, while symptom severity and cerebral blood flow (CBF) were compared before/after challenge. RESULTS: Survey participants were aged 47 (85% female). Prevalence of neurological symptoms were: headaches (51%), brain fog (48%), balance issues (31%), tingling (19%). Median symptom resolution time was 48 hours, while onset was 90 minutes; onset pattern was not significantly different compared to CD patients (p = 0.322). Extra-intestinal symptoms worsened by 37%(±28) during a typical reaction. Predominantly non-statistical observations from the brain imaging study are discussed. CONCLUSIONS: Neurological symptoms in NCGS are common, and onset time is comparable to that in CD. Brain imaging may be a useful future means of investigating physiological injury and responses to gluten in further study.

Cognitive Impairment in Coeliac Disease with Respect to Disease Duration and Gluten-Free Diet Adherence: A Pilot Study.

Cognitive deficit has been reported in coeliac disease (CD), but previous reports often study heterogenous samples of patients at multiple stages of the disease, or lack control data. Healthy controls (N = 21), newly diagnosed CD patients (NCD; N = 19) and established CD patients (ECD; N = 35) were recruited from a specialist UK centre. Participants underwent a cognitive test battery that established seven overall domain scores. The SF-36 was administered as a quality of life (QoL) measure. Controlling for age, data were compared in between-group ANCOVAs with Tukey's post-hoc test. Any significant outcome was compared in the ECD group only, between patients who were gluten-free diet adherent vs. non-adherent (defined via Biagi score and serology results). NCD and ECD groups underperformed relative to controls, by comparable degrees, in visual (overall model: p < 0.001) and verbal (p = 0.046) memory. The ECD group only underperformed in visuoconstructive abilities (p = 0.050). Regarding QoL, the NCD group reported lower vitality (p = 0.030), while the ECD group reported more bodily pain (p = 0.009). Comparisons based on dietary adherence were non-significant. These findings confirm cognitive deficit in CD. Dysfunction appears established at the point of diagnosis, after which it (predominantly) stabilises. While a beneficial effect of dietary treatment is therefore implied, future research is needed to establish to what extent any further decline is due to gluten exposure.

Cognitive Deficit and White Matter Changes in Persons With Celiac Disease: A Population-Based Study.

BACKGROUND & AIMS: There is debate over the presence and prevalence of brain injury in patients with celiac disease. To validate previous reports, we investigated the prevalence of neuropsychological dysfunction in persons with celiac disease included in the National UK Biobank, which contains experimental medical data from 500,000 adults in the United Kingdom. METHODS: Biobank participants with celiac disease (n = 104; mean age, 63 years; 65% female) were matched with healthy individuals (controls, n = 198; mean age, 63 years; 67% female) for age, sex, level of education, body mass index, and diagnosis of hypertension. All participants were otherwise healthy. We compared scores from 5 cognitive tests and multiple choice responses to 6 questions about mental health between groups using the t test and chi-squared analyses. Groupwise analyses of magnetic resonance imaging brain data included a study of diffusion tensor imaging metrics (mean diffusivity, fractional anisotropy, radial diffusivity, axial diffusivity), voxel-based morphometry, and Mann-Whitney U comparisons of Fazekas grades. RESULTS: Compared with control individuals, participants with celiac disease had significant deficits in reaction time (P = .004), and significantly higher proportions had indications of anxiety (P = .025), depression (P = .015), thoughts of self-harm (P = .025), and health-related unhappiness (P = .010). Tract-based spatial statistics analysis showed significantly increased axial diffusivity in widespread locations, demonstrating white matter changes in the brains of participants with celiac disease. Voxel-based morphometry and Fazekas grade analyses did not differ significantly between groups. CONCLUSIONS: In an analysis of data from the UK Biobank, we found participants with celiac disease to have cognitive deficit, indications of worsened mental health, and white matter changes, based on analyses of brain images. These findings support the concept that celiac disease is associated with neurologic and psychological features.

A Population Survey of Dietary Attitudes towards Gluten.

It is unclear how the prevalence of people who believe the gluten-free diet (GFD) to be generally healthy ("Lifestylers") is impacting the overall rates of self-reported gluten sensitivity (GS). We repeated a population survey from 2012 in order to examine how attitudes towards GS have changed over time. Our survey (N = 1004) was administered in Sheffield (UK) in 2015, replicating the 2012 experiment. The questionnaire included a food frequency survey and assessed self-reported GS as well as associated variables (prevalence, current diet, pre-existing conditions, etc.). The overall rates of key variables and chi-squared analysis in comparison to the previous survey were as follows: self-reported GS was 32.8% (previously 12.9%, p < 0.001), pre-existing coeliac disease (CD) was 1.2% (previously 0.8%, p = 0.370), following a GFD was 3.7% (previously 3.7%, p = 0.997). Self-reported GS was positively associated with some pre-existing conditions, including anxiety, depression, chronic fatigue, headaches, and other food allergies/intolerances (including irritable bowel syndrome (IBS); chi-squared analyses, all p < 0.001). Over a 3-year period, the fraction of people who self-reported GS increased by over 250%. Despite this, arguably more meaningful indications of underlying physiological GS remained comparable. This research suggests that the public perception of gluten is causing a marked increase in the number of people who erroneously believe they are sensitive to it.

Neurologic Deficits in Patients With Newly Diagnosed Celiac Disease Are Frequent and Linked With Autoimmunity to Transglutaminase 6.

BACKGROUND & AIMS: Celiac disease is an autoimmune disorder induced by ingestion of gluten that affects 1% of the population and is characterized by gastrointestinal symptoms, weight loss, and anemia. We evaluated the presence of neurologic deficits and investigated whether the presence of antibodies to Transglutaminase 6 (TG6) increases the risk of neurologic defects in patients with a new diagnosis of celiac disease. METHODS: We performed a prospective cohort study at a secondary-care gastroenterology center of 100 consecutive patients who received a new diagnosis of celiac disease based on gastroscopy and duodenal biopsy. We collected data on neurologic history, and patients were evaluated in a clinical examination along with magnetic resonance imaging of the brain, magnetic resonance (MR) spectroscopy of the cerebellum, and measurements of antibodies against TG6 in serum samples. The first 52 patients recruited underwent repeat MR spectroscopy at 1 year after a gluten-free diet (GFD). The primary aim was to establish if detection of antibodies against TG6 can be used to identify patients with celiac disease and neurologic dysfunction. RESULTS: Gait instability was reported in 24% of the patients, persisting sensory symptoms in 12%, and frequent headaches in 42%. Gait ataxia was found in 29% of patients, nystagmus in 11%, and distal sensory loss in 10%. Sixty percent of patients had abnormal results from magnetic resonance imaging, 47% had abnormal results from MR spectroscopy of the cerebellum, and 25% had brain white matter lesions beyond that expected for their age group. Antibodies against TG6 were detected in serum samples from 40% of patients-these patients had significant atrophy of subcortical brain regions compared with patients without TG6 autoantibodies. In patients with abnormal results from MR spectroscopy of the cerebellum, those on the GFD had improvements detected in the repeat MR spectroscopy 1 year later. CONCLUSIONS: In a prospective cohort study of patients with a new diagnosis of celiac disease at a gastroenterology clinic, neurologic deficits were common and 40% had circulating antibodies against TG6. We observed a significant reduction in volume of specific brain regions in patients with TG6 autoantibodies, providing evidence for a link between autoimmunity to TG6 and brain atrophy in patients with celiac disease. There is a need for early diagnosis, increased awareness of the neurologic manifestations among clinicians, and reinforcement of adherence to a strict GFD by patients to avoid permanent neurologic disability.

Genetic variation in PLEKHG1 is associated with white matter hyperintensities (n = 11,226).

OBJECTIVE: To identify novel genetic associations with white matter hyperintensities (WMH). METHODS: We performed a genome-wide association meta-analysis of WMH volumes in 11,226 individuals, including 8,429 population-based individuals from UK Biobank and 2,797 stroke patients. Replication of novel loci was performed in an independent dataset of 1,202 individuals. In all studies, WMH were quantified using validated automated or semi-automated methods. Imputation was to either the Haplotype Reference Consortium or 1,000 Genomes Phase 3 panels. RESULTS: We identified a locus at genome-wide significance in an intron of PLEKHG1 (rs275350, ß [SE] = 0.071 [0.013]; p = 1.6 × 10-8), a Rho guanine nucleotide exchange factor that is involved in reorientation of cells in the vascular endothelium. This association was validated in an independent sample (overall p value, 2.4 × 10-9). The same single nucleotide polymorphism was associated with all ischemic stroke (odds ratio [OR] [95% confidence interval (CI)] 1.07 [1.03-1.12], p = 0.00051), most strongly with the small vessel subtype (OR [95% CI] 1.09 [1.00-1.19], p = 0.044). Previous associations at 17q25 and 2p16 reached genome-wide significance in this analysis (rs3744020; ß [SE] = 0.106 [0.016]; p = 1.2 × 10-11 and rs7596872; ß [SE] = 0.143 [0.021]; p = 3.4 × 10-12). All identified associations with WMH to date explained 1.16% of the trait variance in UK Biobank, equivalent to 6.4% of the narrow-sense heritability. CONCLUSIONS: Genetic variation in PLEKHG1 is associated with WMH and ischemic stroke, most strongly with the small vessel subtype, suggesting it acts by promoting small vessel arteriopathy.

Effect of Standard vs Intensive Blood Pressure Control on Cerebral Blood Flow in Small Vessel Disease: The PRESERVE Randomized Clinical Trial.

Importance: Blood pressure (BP) lowering is considered neuroprotective in patients with cerebral small vessel disease; however, more intensive regimens may increase cerebral hypoperfusion. This study examined the effect of standard vs intensive BP treatment on cerebral perfusion in patients with severe small vessel disease. Objective: To investigate whether standard vs intensive BP lowering over 3 months causes decreased cerebral perfusion in small vessel disease. Design, Setting, and Participants: This randomized clinical trial took place at 2 English university medical centers. Patients were randomized via a central online system (in a 1:1 ratio). Seventy patients with hypertension and with magnetic resonance imaging-confirmed symptomatic lacunar infarct and confluent white matter hyperintensities were recruited between February 29, 2012, and October 21, 2015, and randomized (36 in the standard group and 34 in the intensive group). Analyzable data were available in 62 patients, 33 in the standard group and 29 in the intensive group, for intent-to-treat analysis. This experiment examines the 3-month follow-up period. Interventions: Patients were randomized to standard (systolic, 130-140 mm Hg) or intensive (systolic, <125 mm Hg) BP targets, to be achieved through medication changes. Main Outcomes and Measures: Cerebral perfusion was measured using arterial spin labeling; the primary end point was change in global perfusion between baseline and 3 months, compared between treatment groups by analysis of variance. Linear regression compared change in perfusion against change in BP. Magnetic resonance imaging scan analysis was masked to treatment group. Results: Among 62 analyzable patients, the mean age was 69.3 years, and 60% (n = 37) were male. The mean (SD) systolic BP decreased by 8 (12) mm Hg in the standard group and by 27 (17) mm Hg in the intensive group (P < .001), with mean (SD) achieved pressures of 141 (13) and 126 (10) mm Hg, respectively. Change in global perfusion did not differ between treatment groups: the mean (SD) change was -0.5 (9.4) mL/min/100 g in the standard group vs 0.7 (8.6) mL/min/100 g in the intensive group (partial η2, 0.004; 95% CI, -3.551 to 5.818; P = .63). No differences were observed when the analysis examined gray or white matter only or was confined to those achieving target BP. The number of adverse events did not differ between treatment groups, with a mean (SD) of 0.21 (0.65) for the standard group and 0.32 (0.75) for the intensive group (P = .44). Conclusions and Relevance: Intensive BP lowering did not reduce cerebral perfusion in severe small vessel disease. Trial Registration: isrctn.org Identifier: ISRCTN37694103.

Using DTI to assess white matter microstructure in cerebral small vessel disease (SVD) in multicentre studies.

Diffusion tensor imaging (DTI) metrics such as fractional anisotropy (FA) and mean diffusivity (MD) have been proposed as clinical trial markers of cerebral small vessel disease (SVD) due to their associations with outcomes such as cognition. However, studies investigating this have been predominantly single-centre. As clinical trials are likely to be multisite, further studies are required to determine whether associations with cognition of similar strengths can be detected in a multicentre setting. One hundred and nine patients (mean age =68 years) with symptomatic lacunar infarction and confluent white matter hyperintensities (WMH) on MRI was recruited across six sites as part of the PRESERVE DTI substudy. After handling missing data, 3T-MRI scanning was available from five sites on five scanner models (Siemens and Philips), alongside neuropsychological and quality of life (QoL) assessments. FA median and MD peak height were extracted from DTI histogram analysis. Multiple linear regressions were performed, including normalized brain volume, WMH lesion load, and n° lacunes as covariates, to investigate the association of FA and MD with cognition and QoL. DTI metrics from all white matter were significantly associated with global cognition (standardized ß =0.268), mental flexibility (ß =0.306), verbal fluency (ß =0.376), and Montreal Cognitive Assessment (MoCA) (ß =0.273). The magnitudes of these associations were comparable with those previously reported from single-centre studies found in a systematic literature review. In this multicentre study, we confirmed associations between DTI parameters and cognition, which were similar in strength to those found in previous single-centre studies. The present study supports the use of DTI metrics as biomarkers of disease progression in multicentre studies.

White matter correlates of cognitive dysfunction after mild traumatic brain injury.

OBJECTIVE: To relate neurophysiologic changes after mild/moderate traumatic brain injury to cognitive deficit in a longitudinal diffusion tensor imaging investigation. METHODS: Fifty-three patients were scanned an average of 6 days postinjury (range = 1-14 days). Twenty-three patients were rescanned 1 year later. Thirty-three matched control subjects were recruited. At the time of scanning, participants completed cognitive testing. Tract-Based Spatial Statistics was used to conduct voxel-wise analysis on diffusion changes and to explore regressions between diffusion metrics and cognitive performance. RESULTS: Acutely, increased axial diffusivity drove a fractional anisotropy (FA) increase, while decreased radial diffusivity drove a negative regression between FA and Verbal Letter Fluency across widespread white matter regions, but particularly in the ascending fibers of the corpus callosum. Raised FA is hypothesized to be caused by astrogliosis and compaction of axonal neurofilament, which would also affect cognitive functioning. Chronically, FA was decreased, suggesting myelin sheath disintegration, but still regressed negatively with Verbal Letter Fluency in the anterior forceps. CONCLUSIONS: Acute mild/moderate traumatic brain injury is characterized by increased tissue FA, which represents a clear neurobiological link between cognitive dysfunction and white matter injury after mild/moderate injury.