celiac and the brain · celiac disease benefit from a gluten-free diet? dementia. preventing...
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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