Celiac and the BrainDr Iain Croall

About me

Academic researcher –“cognitive neuroscientist”

Sheffield Institute of Gluten-Related Disorders since 2017

My main interest is how the brain is affected in gluten-related disorders

Experiment #1 - What sort of neurological symptoms do people with celiac disease have?

100 newly-diagnosed patients (via gastroenterology) consecutively enrolled.

All subjects underwent:

Neurological examination

Blood testing for TG6

MRI scanning including:

Structural scans (T1W)

Spectroscopy scans to characterise cerebellar biochemistry

Full Sample (areas of orbiting

circles are proportionate

to this)

24% Balance Problems

42% Frequent headaches

12% Sensory symptoms

10% Signs of peripheral

neuropathy

29% Walking difficulty

11% Nystagmus

= on examination = self-reported

Excluding headaches, half of the patients had a neurological symptom

Full Sample 46% Abnormal NAA/Cr values

57% abnormal hemisphere

82% abnormal vermis

36% both

MR Spectroscopy findings

Are people with TG6 at higher risk of neurological consequences?

CerebellumSubcortical structures

* *

Cerebral Sub-Cortical GM Cerebellar GM

p=0.050p=0.016

40% of subjects were TG6 positive

Are people with TG6 at higher risk of neurological consequences?

Does TG6 positivity predict brain atrophy?

From Netter, F. (2010), Atlas of Human Anatomy

Motor and sensory

Conclusions

Neurological symptoms are common in typical, newly-diagnosed celiac disease

Centre around headaches, balance and sensory problems

They are accompanied by some evidence on brain scans of brain changes

TG6 may be a useful tool to identify people more at risk

The gluten free diet is effective at preventing any further harm

OR… there are no problems

at all?

Studies with ascertainment or recruitment bias?

Studies with ascertainment or recruitment bias?

Studies lacking experimental sensitivity?

“Validation” needed - UK

Biobank

UK biobank is a “health resource” funded by the Wellcome Trust

Initially collected eclectic healthcare data on 500,000 participants

More recently it has begun MRI scanning 100,000 of these (ongoing)

Independently-collected data; diagnoses will be representative of “typical” celiac disease

Experiment #2 – can we still

see these sorts of

findings in other people’s

data?

Volunteers with celiac disease identified: (N=104)

Otherwise healthy

Was not taking “psychoactive” medication at the time of data collection

Also had brain imaging data available

Cases matched in a 1:2 ratio to healthy controls on: (N=198)

Age

Sex

B.M.I.

Highest level of education

Diagnosis of hypertension

Methods

Case vs control analyses:

Key scores from 5 cognitive tests

Responses given to 6 multiple-choice questions exploring aspects of mental health

Brain imaging analyses…

Methods

Case vs control analyses:

Key scores from 5 cognitive tests

Responses given to 6 multiple-choice questions exploring aspects of mental health

Brain imaging analyses…

Tract-based spatial statistics (TBSS)

Group demographics

Results – Cognition and Mood

Reaction time sig. slower (p= 0.004)

• “Ever felt worried, tense, or anxious for most of a month or longer?”

31.5% vs 18.0% (p=0.025)

• “Ever had prolonged feelings of sadness or depression?”

58.4% vs. 41.4% (p=0.015)

• “Ever contemplated self-harm?”19.5% vs 9.0% (p=0.025)

• Celiac patients sig. more likely to be “unhappy” with their own health. (p=0.010)

Results –White matter

changes in patients with celiac disease

Conclusions

Using independently-acquired data, patients with “typical” celiac disease show signs of cognitive & mental health problems, and brain white matter changes

This validates previous research showing the condition to involve neurological consequences which are measurable and meaningful

Comparable to “subjective cognitive impairment”, which similarly involves white matter injury, cognitive problems and lowered quality of life

Findings should help resolve this argument, validate patient experience, and help clinicians give properly targeted care

Would gluten-sensitive

people without celiac disease benefit from a

gluten-free diet?

Dementia

Preventing dementia

Dementia is the biggest healthcare issue we face, causing the most deaths of any disease and costing the UK £26 billion a year (and Canada $10.4 billion).

“Modifiable risk factors” are lifestyle choices the general population can make to prevent dementia.

These can be easily implemented through things like primary care and public awareness campaigns

Modifiable risk factors in

dementia

Gluten?

Gluten antibodies

and the brain

Celiac Disease

Brain white matter injury, impaired cognition, increased risk of vascular dementia

Antigliadin, Anti-Transglutaminase 2, Anti-endomysial

Neurological non-celiac gluten sensitivity

Gluten ataxia, Gluten encephalopathyCognitive impairment, headaches

Antigliadin

Gluten Encephalopathy

Antigliadin reacts with brain blood

vessels

Pratesi et al. (2019). Serum IgA antibodies from patients with coeliac disease react strongly with human brain blood-vessel structures, Scand J Gastroenterol., 33(8), 817-821

Antigliadin reacts with a

protein in neurons

Alaedini et al. (2007). Immune cross-reactivity in celiac disease: anti-gliadin antibodies bind to neuronal synapsin I, J Immunol., 178(10), 6590-6595

Antigliadin reacts

cerebellar brain cells

Hadjivassiliou et al. (2007). The humoral response in the pathogenesis of gluten ataxia., Neurology, 58(8), 1221-1226

Gluten-free diet

eliminates antigliadin

Caio et al. (2017). Effect of gluten free diet on immune response to gliadin in patients with non-celiac gluten sensitivity, BMC Gastroenterol., 14:26

Antigliadin titre diminishing over 6 months in NCGS patients after starting a GFD (most dropped to “negative” levels – red line)

One in ten people have antigliadin

Benign

vs

Undiscovered effects

GLUten as a risk factor for

DEMentia: GLUDEM

This is the first study to directly investigate if there is any evidence of brain injury in people who have gliadin antibodies

We hypothesise that 10% of the population is accumulating neurological harm

We’ve got a screening tool that works

We’ve got an intervention that works

Primary care would be an ideal context to implement prevention

Blood screening for AGA

Recruit 390 participants

39 AGA positive

39 AGA negative

MatchedCollect measurements to

broadly describe brain and cognitive health

Outcomes and AnalysisWhite matter lesionsBrain atrophyBrain biochemistryPrimary: Diffusion tensor imaging Cognitive performanceQuality of life

So far…

Recruitment began in November 2019. Projected to run for 2 years.

75 participants recruited, blood tests completed on 64

9 gliadin-positive people identified so far – 14.1% positivity rate

So far…Positive study findings would be evidence that gluten could be a modifiable dementia risk factor for 10% of

the general population

Bringing it all together…

The brain does appear to be affected in celiac disease

This research should help this view be more fully adopted by the clinical community

The gluten-free diet is still the best way (and effective!) to prevent any further harm

Future research is investigating what other types of gluten sensitivity exist, where a GFD would be advisable.

Prof. Nigel HoggardProf. Marios HadjivassiliouProf. David Sanders

Acknowledgments