Gliadin antibodies in older population and neurological and psychiatric disorders

Acta Neurol Scand DOI: 10.1111/j.1600-0404.2012.01668.x
O 2012 John Wiley & Sons A/S
ACTA NEUROLOGICA
SCANDINAVICA
Gliadin antibodies in older population and
neurological and psychiatric disorders
Ruuskanen A, Kaukinen K, Collin P, Krekela I, Patrikainen H,
A. Ruuskanen1, K. Kaukinen2,
Tillonen J, Nyrke T, Laurila K, Haimila K, Partanen J, Valve R,
P. Collin2, I. Krekela3,
Maki M, Luostarinen L. Gliadin antibodies in older population and
H. Patrikainen3, J. Tillonen3,
neurological and psychiatric disorders.
T. Nyrke4, K. Laurila5, K. Haimila6,
Acta Neurol Scand: DOI: 10.1111/j.1600-0404.2012.01668.x.
(c)
J. Partanen6, R. Valve7, M. Maki5,
2012 John Wiley & Sons A/S.
L. Luostarinen1
1
Objectives - A variety of neurological and psychiatric disorders have
Department of Neurology, Paijat-Hame Central
Hospital in Lahti, Lahti, Finland; 2Department of
recently been linked to coeliac disease and gluten sensitivity. We here
Gastroenterology and Alimentary Tract Surgery,
explored whether persistently positive gliadin antibodies (AGA) and
Tampere University Hospital and Medical School,
coeliac-type HLA increase the risk of gluten sensitivity-related
University of Tampere, Tampere, Finland; 3Department
neurological and psychiatric manifestations. The study was carried out
of Gastroenterology, Paijat-Hame Central Hospital in
in an older population who had consumed gluten for decades but who
Lahti, Lahti, Finland; 4Department of Neurophysiology,
had no previous coeliac disease diagnosis. Materials and Methods -
Paijat-Hame Central Hospital in Lahti, Lahti, Finland;
The original study population comprised 4272 randomly selected older
5Pediatric Research Center, University of Tampere and
individuals, of whom 2089 had AGA and transglutaminase 2
Tampere University Hospital, Tampere, Finland;
6
antibodies (antiTG2) measured twice within a 3-year interval. Forty-
Finnish Red Cross Blood Service, Helsinki, Finland;
7
nine persistently AGA-positive but antiTG2-negative subjects with
Department of Education and Development in Lahti,
University of Helsinki, Helsinki, Finland
coeliac-type HLA and 52 randomly selected persistently AGA- and
antiTG2-negative age- and sex-matched controls were clinically
examined for neurological disorders. The Psychological General
Well-Being (PGWB) questionnaire, the SF-36 health survey
questionnaire and the Depression Scale (DEPS) were employed to
evaluate psychological well-being. The medical files of all the study
subjects were analysed for previous illnesses. Results - Persistently
AGA-positive but antiTG2-negative older subjects carrying coeliac
Key words: coeliac disease; depression; gluten
disease-type HLA did not evince significantly more neurological
sensitivity; neuropathy
symptoms or diseases than AGA-negative control subjects (P = 0.682,
K. Kaukinen, University of Tampere, Medical School,
P = 0.233). There were no statistically significant differences between
FIN-33014 University of Tampere, Tampere, Finland
AGA-positive and AGA-negative groups in psychological well-being
Tel.: +358 3 3551 8403
and quality of life when measured by PGWB (P = 0.426), SF-36
Fax: +358 3 3551 8402
questionnaires (P = 0.120) and DEPS (P = 0.683). Conclusions - At
e-mail: katri.kaukinen@uta.fi
population level, persistent AGA positivity did not indicate gluten
sensitivity-related neurological and psychiatric disorders.
Accepted for publication March 14, 2012
neuropathy, epilepsy and cognitive impairment,
Introduction
have been reported in patients with coeliac dis-
Coeliac disease is an autoimmune disorder where
ease
(1-4). Likewise, psychiatric conditions,
ingestion of dietary wheat-, rye- and barley-
including anxiety, depression and other mood
derived gluten initiates and drives chronic inflam-
alterations, have also been associated with the
mation in the small-bowel mucosa, leading even-
disease (5-8). In many cases, coeliac disease pre-
tually to villous atrophy and enteropathy in
sents without gastrointestinal symptoms and mal-
genetically
predisposed
individuals.
Gluten-
absorption and may therefore go undiagnosed for
induced immune responses may extend beyond
many years. The untreated condition may eventu-
the intestine and the disease may also manifest
ally lead to chronic ill-health and a diminished
itself with various non-specific and extra-intesti-
sense of psychological well-being (9, 10).
nal symptoms (1). A wide range of neurological
Recent
evidence
shows
that
gluten-related
disorders, including cerebellar ataxia, peripheral
problems are not restricted to classical coeliac
1

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Ruuskanen et al.
disease enteropathy. The term gluten sensitivity
well-being and depression in this older cohort. To
has been launched to take into account the vari-
find previously undiagnosed and subclinical con-
ous extraintestinal gluten-dependent manifesta-
ditions, we personally thoroughly examined all
tions, even in patients with an apparently normal
study subjects. Randomly selected persistently
intestinal mucosa (1). As a marker of gluten sen-
AGA- and antiTG2-negative subjects of the same
sitivity, increased levels of antibodies against
age and gender were invited as controls. This
wheat gluten, gliadin have been found in a vari-
study enlightens further and more precisely the
ety of neurological disorders of unknown aetiol-
issues of our previous study based on medical
ogy, cerebellar ataxia and peripheral neuropathy
files (11).
being the most common problems (1). Further-
more, increased immune sensitivity to dietary
Materials and methods
gluten proteins has been reported in psychiatric
conditions such as depression, schizophrenia and
Patients, controls and study design
bipolar disorder (11-13). Many of these gliadin
antibody (AGA)-positive subjects remain negative
The Good Ageing in the Lahti Region (GOAL)
for coeliac disease-specific transglutaminase 2
survey on ageing and well-being (18) provided a
antibodies (antiTG2). However, in gluten ataxia,
basis for the current case-control study. The ori-
even though AGA-positive and antiTG2-negative
ginal study population comprised 4272 randomly
subjects often have normal small-bowel mucosal
selected individuals born in the years 1946-50,
villous morphology, the majority have coeliac dis-
1936-40 and 1926-30, representing the general
ease-type HLA DQ2 or DQ8, antibodies against
population in the respective age groups (Fig. 1).
neuronal transglutaminase (transglutaminase 6)
Of those approached, 2815 agreed to participate
and signs of minor small-bowel mucosal inflam-
and filled in questionnaires on their health condi-
mation indicative of early stage coeliac disease
tion, present and past diseases and special diets.
(1). This suggests that these gluten ataxia cases
Sera were collected for the analysis of IgA- and
belong to the same gluten-induced disease spec-
IgG-class AGA and IgA-class antiTG2 in 2002
trum as coeliac disease patients showing classical
(11), and 3 years later, all eligible subjects
enteropathy. As the above-mentioned neurologi-
(n = 2216) were asked to undergo a new serologi-
cal and psychiatric gluten-sensitive disorders are
cal test. Serum samples were available in both
potentially treatable with a gluten-free diet (1, 14
-16), active case-finding by coeliac serology has
been suggested. So far, however, association
between AGA and neurological and psychiatric
disorders has been studied in specialized centres
in selected patient series, which may overestimate
the association between AGA and various neuro-
logical and psychiatric conditions. The clinical
relevance of AGA positivity at population level
thus needs to be elucidated.
We have recently shown AGA positivity to be
common (14%) in the older Finnish population,
and the positivity was persistent in 81% (11, 17).
Even though this was rarely indicative of overt
coeliac disease, it was often associated with minor
small-bowel mucosal inflammation in subjects
carrying coeliac-type HLA (17). The hypothesis
in this study was that as gluten sensitivity is
markedly genetically predisposed and takes years
to develop, we could detect gluten sensitivity-
related neurological and psychiatric manifesta-
tions in older subjects with persistently positive
AGA and coeliac-type HLA, as they will have
consumed gluten for decades. We now sought to
establish whether persistent AGA positivity with-
Figure 1. Flowchart of the study. AGA, antigliadin antibod-
out positive antiTG2 is related to neurological
ies; antiTG2, antibodies against tranglutaminase-2; CD, coe-
problems, decreased self-perceived psychological
liac disease; *no previous CD diagnosis.
2

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Gluten and neurological and psychiatric disorders
2002 and 2005 for 2089 cases (Fig. 1). Altogether
serum and urine protein fractions, antineuronal
203 persistently (both in 2002 and 2005) AGA-
and antiganglioside antibodies were measured
positive but antiTG2-negative subjects without
and if possible, cerebrospinal fluid analysed for
known coeliac disease were offered HLA testing,
cells, glucose, protein, albumin, immunoglobulins,
and 53 of the 130 tested had coeliac-type HLA.
IgG index, antineuronal antibodies and antibod-
Eventually, 49 of those persistently AGA-positive
ies against Borrelia burdorferie. In addition, when
and genetically predisposed individuals consented
ataxia was detected, vitamin-E, gene tests for
to undergo a general and thorough neurological
MIRAS/POLG1, Friedrich`s ataxia and FragileX
examination (study group, cases; median age
were performed.
69 years, range 57-80 years; 45% women); fur-
thermore, 36 of them were willing to undergo
Psychiatric conditions and psychological well-being
endoscopy and small-bowel biopsy. Equal num-
bers of randomly selected persistently AGA- and
Present and past histories of psychological condi-
antiTG2-negative subjects of the same age and
tions were inquired into during the clinical exami-
gender were invited to attend a clinical examina-
nation. Psychological well-being and quality of life
tion (control group; median age 69 years, range
were evaluated applying questionnaires widely
57-81 years; 44% women). All cases and controls
used in coeliac disease and of proven validity and
were examined and interviewed in similar manner
reliability (10, 21, 22). The Psychological General
by the same investigator; however, for ethical rea-
Well-Being (PGWB) questionnaire contained 22
sons, HLA-typing and endoscopy were not per-
items comprising six subdimensions: anxiety,
formed on control subjects (17).
depression, well-being, self-control, general health
For further comparisons, data on clinical histo-
and vitality, scoring being based on a six-grade
ries of 77 persistently AGA-positive subjects with-
Likert scale, higher scores indicating better psy-
out coeliac-type HLA (median age 67 years, range
chological well-being (21). The SF-36 health survey
56-80 years; 48% women) were extracted from the
questionnaire, containing eight subdimensions
medical records of Paijat-Hame Central Hospital.
(mental health, physical functioning, role limita-
tions because of physical problems, bodily pain,
general health, vitality, social functioning and role
Neurological examination
limitations because of emotional problems), was
The occurrence of neurological symptoms and
used to assess health-related quality of life. The
diseases was recorded and the medical files of the
raw scores on all 36 items were rescored from 0 to
subjects were analysed. On examination, we
100, higher scores indicating better health and
focused especially on finding previously undiag-
quality of life (10).
nosed and subclinical disorders. Gait, balance,
The Depression Scale (DEPS) has been widely
muscle strength, deep tendon reflexes, vibration,
applied as a self-rating depression questionnaire
pin-prick and light touch senses and the functions
and is suitable in recognizing depression in pri-
of cranial nerves were evaluated. Cognition was
mary care patients (23). The DEPS includes ten
assessed by clinical interview and a combination
items covering the core symptoms of depression
of the Mini Mental State Examination (MMSE)
with four alternatives in scoring: 0 = not at all,
and the clock-drawing test (19). All evaluations
1 = a little, 2 = quite a lot and 3 = extremely. A
were made by the same, non-blinded investigator
higher score indicates more severe symptoms (24)
(AR), but in borderline cases another (blinded)
and the cut-off level for depressive symptoms is
investigator (LL) co-evaluated the subject. If any
nine (23).
relevant clinical symptoms or signs were detected,
further studies such as electroneuromyography
Serology and HLA-typing
(ENMG), skin biopsy, lumbar puncture, radio-
logical scans, neuropsychological and laboratory
Serum IgA- and IgG-class AGA were measured
tests were performed according to clinical needs
by enzyme-linked immunosorbent assay (ELISA)
and good clinical practice. When neuropathy was
(25); the results were obtained from the standard
suspected, ENMG using a structured study pro-
curve established according to dilutions of posi-
tocol and a three mm punch skin biopsy 5-10 cm
tive reference serum and converted to concentra-
above the lateral malleolus to detect small-fibre
tions of arbitrary ELISA units per millilitre (EU/
neuropathy (20) was carried out. In cases where
ml). The limits of positivity were set at 0.20 and
neuropathy was diagnosed, full blood count, liver
20 EU/ml, respectively. Serum IgA-class antibod-
and thyroid function tests, blood glucose, serum
ies against TG2 and IgA- and IgG-class antibod-
creatinine, vitamin-B12, -B6, -B1, folic acid levels,
ies against TG6 were detected by ELISA using
3

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Ruuskanen et al.
human recombinant TG2 (Celikey, Phadia, GmbH,
Results
Freiburg, Germany) and TG6 (E003 and E004
Neuronal transglutaminase ELISA kits; Zedira,
Based on the interview and follow-up examina-
Darmstadt, Germany) as antigens according to
tion persistently AGA-positive but antiTG2-nega-
the manufacturer's instructions. Concentrations
tive older subjects carrying coeliac disease-type
over 5.0 U/ml, over 21 U/ml and over 38 U/ml
HLA did not have more neurological diseases or
were considered positive for IgA-class antiTG2,
symptoms than AGA-negative control subjects
IgA- and IgG-class antiTG6 antibodies, respec-
(Table 1). Four AGA-positive and three AGA-
tively, as recommended by the manufacturers.
negative subjects suffered from polyneuropathy
The study subjects were genotyped for HLA-
(Table 2). Only one AGA-positive subject, a
DQB1*02, DQB1*0302 and DQA1*05 alleles
79-year-old men, had ataxia. He had suffered an
using the DELFIA Coeliac Disease Hybridization
ischaemic stroke 6 years previously with residual
Assay (Perkin-Elmer Life and Analytical Sci-
mild aphasia and mild right-sided hemiparesis. In
ences, Turku, Finland). The genotypes DQB1*02
brain magnetic resonance imaging, profound
and DQA1*05 correspond to the serological
cerebral and cerebellar atrophy was found along
HLA type DQ2 and DQB1*0302 to HLA-DQ8.
with cerebral ischaemic white matter lesions. His
These genotypes together or DQB1*02 alone are
erythrocyte folic acid concentrations were low,
found in 96-100% of patients with coeliac disease
but he refused duodenal biopsy and a treatment
and in this study were considered to constitute
trial with a gluten-free diet. Furthermore, in the
coeliac-type HLA (17).
examination, mild cognitive problems were sus-
pected in three AGA-positive and two AGA-neg-
ative subjects, but none evidenced dementia in
Upper gastrointestinal endoscopy and small-bowel mucosal
further neuropsychological evaluations. In the
biopsies
AGA-positive group, neurological findings were
Four small-bowel mucosal biopsy samples were
not related to small-bowel mucosal coeliac dis-
taken by upper gastrointestinal endoscopy from
ease-type morphological or inflammatory changes
the distal part of the duodenum. The biopsies
(data not shown).
were processed and evaluated as described in our
Altogether 12 (25%) of the 48 persistently
previous studies (17, 26). Only one of 36 persis-
AGA-positive but antiTG2-negative subjects with
tently AGA-positive but antiTG2-negative sub-
coeliac-type HLA had antibodies against TG6;
jects was found to have villous atrophy with
seven were IgA-class, three IgG-class antiTG6-
crypt hyperplasia indicative of overt coeliac dis-
positive and two were positive in both IgA and
ease. In addition, 19 (54%) had signs of minor
IgG classes. Two of the antiTG6-positive cases
coeliac disease-type small-bowel mucosal inflam-
had polyneuropathy and small-fibre neuropathy
mation (increased density of CD3+ or cd+ IELs
(Table 2), while the rest evinced no neurological
or the presence of small-bowel mucosal TG2-tar-
dysfunction.
geted IgA deposits) (17). In this study, these
biopsy findings were compared to the occurrence
Table 1 Neurological disorders in persistently gliadin antibody (AGA)-positive
of neurological and psychological conditions.
subjects with coeliac-type HLA and in persistently AGA-negative controls
revealed in interview and follow-up examination. All were also transglutaminase
2-antibody-negative and did not have diagnosed coeliac disease
Statistics
Quantitative data were expressed as medians or
Persistently
AGA-positive
Persistently
means and 95% confidence intervals (CI). Statisti-
and HLA-positive
AGA-negative
cal differences between study groups were evalu-
n =49
n = 52
P-value
ated using Pearson's chi-square test, Fisher's exact
Neurological symptoms, n (%)
18 (37)
17 (33)
0.682
test, t-test or Mann-Whitney U-test, as appropri-
Neurological disease, n (%)
8 (16)
14 (27)
0.233
ate. Values of P < 0.05 were considered significant.
Polyneuropathy
4 (8)
3 (6)
0.710
The statistics were calculated with SPSS 15.0
Small-fibre neuropathy
3 (6)
1 (2)
0.353
(SPSS Inc., Chicago, IL, USA).
Ataxia
1 (2)
0 (0)
0.485
Nerve root lesion
1 (2)
5 (10)
0.363
Migraine
2 (4)
1 (2)
0.610
Essential tremor
1 (2)
2 (4)
1.000
Ethical considerations
Ischaemic stroke
3 (6)
7 (13)
0.320
The study was accepted by the research ethics
Epilepsy
0 (0)
1 (2)
1.000
Intracranial
1 (2)
0 (0)
0.485
committee of Paijat-Hame Central Hospital. All
haemorrhage
participants gave written informed consent.
4

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Gluten and neurological and psychiatric disorders
Table 2 Clinical details of cases evincing polyneuropathy
Small-bowel
Medical history and
Sex age
AntiTG6 +/A
mucosal biopsy
Type of neuropathy
Clinical findings
laboratory findings
Persistently AGA-positive with coeliac-type HLA
F 78
IgA+
nd
Axonal polyneuropathy and
Absent achilles tendon
High vitamin-B6
small-fibre neuropathy
reflexes, mild balance problem
M 80
IgG+
Normal
Axonal polyneuropathy and
Ostostatic hypotension, absent
Antiganglioside antibodies
small-fibre neuropathy
achilles tendon reflexes,
positive, prostate cancer
reduced sensation of touch
F 80
-
Minor mucosal
Axonal polyneuropathy
Absent achilles tendon reflexes,
Deficiency of
inflammation
mild balance problem, reduced
vitamin-D and folic acid
sensation of touch,
mild muscle weakness
M 79
-
Normal
Axonal polyneuropathy and
Absent achilles tendon reflexes,
Deficiency of vitamin-E and
small-fibre neuropathy
mild balance problem
vitamin-B12, DM II, prostate
cancer
Persistently AGA-negative
M 79
nd
nd
Polyneuropathy*
Mild balance problem, reduced
Prostate cancer, polymyalgia
sensation of vibration and touch,
rheumatica
absent achilles tendon reflexes
M 69
nd
nd
Axonal polyneuropathy and
Mildly unsteady gait, mildly
small-fibre neuropathy
reduced sensation of vibration
M 59
nd
nd
Axonal polyneuropathy
Mild balance problem, reduced
Primary hyperparathyreosis,
sensation of vibration,
DM II
absent achilles tendon reflexes
Nd, not done; antiTG6, transglutaminase 6 antibodies; DM II, diabetes mellitus type-II.
*Diagnosed 2 years before entering the study; skin biopsy not performed.
Only one subject in the AGA-negative control
Table 3 Mean and 95% confidence intervals of Psychological General Well-
group reported depression in her past history; no
Being (PGWB) and SF-36 scores in persistently gliadin antibody (AGA)-positive
other previously diagnosed psychiatric disorders
subjects with coeliac-type HLA and AGA-negative subjects. All were also
transglutaminase 2-antibody-negative and did not have diagnosed coeliac
were reported in the study or control groups.
disease
There were no statistically significant differences
between AGA-positive and AGA-negative sub-
Persistently
jects in psychological well-being or quality of life
AGA-positive
Persistently
as measured by PGWB and SF-36 questionnaires
and HLA-positive
AGA-negative
n = 49
n = 52
P-value
(Table 3). Furthermore, persistently AGA-posi-
tive subjects with coeliac-type HLA did not suffer
PGWB*
from depression more often than persistently
Anxiety
25.0 (24.0-26.0)
26.0 (24.9-27.0)
0.195
Depression
16.8 (16.3-17.2)
16.8 (16.3-17.4)
0.852
AGA-negative controls as assessed by DEPS
Well-being
17.7 (16.9-18.5)
17.6 (16.6-18.5)
0.848
score (mean 4.6 [95% CI 3.4-5.8] vs 4.3 [3.4-5.2],
Self-control
15.6 (15.1-16.1)
15.8 (15.2-16.4)
0.598
P = 0.683). There were no differences in DEPS
General health
13.8 (13.1-14.6)
13.2 (12.3-14.1)
0.323
scores between the persistently AGA-positive sub-
Vitality
18.9 (18.0-19.7)
19.5 (18.7-20.3)
0.293
Total
107.6 (103.9-111.2)
109.8 (105.7-114.0)
0.426
jects who had coeliac-type small-bowel mucosal
SF-36*
minor changes, those who had entirely normal
Mental health
76.6 (69.0-84.2)
83.5 (79.3-87.7)
0.120
small-bowel mucosa or those who did not
Physical functioning
80.3 (75.2-85.4)
77.2 (71.5-82.9)
0.437
undergo small-bowel biopsy (P = 0.898).
Social functioning
87.5 (82.6-92.4)
91.9 (87.7-96.1)
0.180
Role limitations
75.0 (65.3-84.7)
83.3 (74.5-92.1)
0.218
According to the hospital records, persistently
because of emotional
AGA-positive subjects without coeliac-type HLA
problems
did not have more often neurological diseases (18
Role limitations
70.7 (60.5-81.0)
66.2 (55.0-77.3)
0.557
of 77, 23%) than persistently AGA-positive cases
because of physical
problems
with coeliac-type HLA (16%, Table 1) or persis-
Vitality
68.3 (62.3-74.3)
72.9 (67.9-77.9)
0.247
tently
AGA-negative
cases
(27%)
(difference
General health
60.5 (55.9-65.0)
59.4 (54.5-64.3)
0.759
between the groups, P = 0.430). Three AGA-
Bodily pain
78.7 (73.5-83.9)
79.0 (73.3-84.6)
0.953
positive subjects who did not have coeliac-type
HLA suffered from polyneuropathy; none had
*Higher score indicates better quality of life.
5

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Ruuskanen et al.
ataxia. AGA-positive but coeliac-type HLA-nega-
(11) and small-bowel mucosal inflammation (22).
tive subjects did not have more often depression
Here, however, we found no difference in the
(8%) than AGA-negative control group (P =
occurrence of depression or in psychological well-
0.241).
being between AGA-positive subjects and AGA-
negative controls. Psychiatric disorders associated
with AGA might not be coeliac-type HLA-depen-
Discussion
dent (32). It has recently been shown that gluten
While in more selected patient materials, AGA
sensitivity extends beyond coeliac-type HLA (33,
has proved a good biomarker for gluten-sensitive
34), and this should be noted in further studies.
neurological and psychiatric conditions (1, 12, 13,
Moreover, in this study, we asked participants to
26), at population level persistent AGA positivity
contact us and attend for laboratory and clinical
could not uncover these disorders in older sub-
examination. This may have left depressed and
jects who have in fact been exposed to gluten for
poorly functioning subjects out of the study,
decades. By thorough clinical examination, we
which could explain the difference in results from
found new neurological conditions equally in
our previous study based on medical records of
both AGA-positive and AGA-negative groups,
the same background population (11).
which would indicate that AGA is unspecific for
As far as we know this is the first large study
coeliac disease and gluten-related neurological or
focusing on gluten-sensitive neurologic and psy-
psychiatric conditions.
chiatric conditions in a randomly selected adult
Although we could not show persistently AGA-
population. The study population was represen-
positive subjects to have more neurological disor-
tative of the general Finnish older population
ders than controls, it is interesting that some
and was not originally selected for screening of
AGA-positive subjects with neurological disorders
coeliac disease. The strength of this study is that
yielded laboratory results previously reported to
the controls were selected from the same back-
be associated with coeliac disease and its neurolog-
ground population and they were studied in the
ical manifestations (Table 2). One neuropathy
same way. As this was a population-based
patient had antiganglioside antibodies (27) and
study, intervention by gluten-free diet was not
two were antiTG6-positive (28). Altogether three
possible.
had malabsorption of vitamins and one of these
To conclude, gluten sensitivity-related neuro-
three evinced minor small-bowel mucosal inflam-
logical and psychiatric manifestations do not
mation. Although other conditions such as diabe-
seem to constitute any major health problem at
tes or cancer may have caused the neurological
the older population level. In this context, posi-
disorders in these individuals, we cannot rule out
tive AGA without coeliac disease is not a bad
the possibility that gluten sensitivity may have
prognostic sign. Further studies are needed to
played a role and predisposed the patients to
assess the value of AGA analysis in the diagnos-
develop neuropathy or ataxia more easily.
tic work-up of patients with neuropathy, ataxia
While in previous studies, antiTG6 has proved
or psychiatric problems.
specific to gluten-sensitive neurological manifesta-
tions (1, 28), in our series, it was not associated
Acknowledgements
with neurological symptoms or disorders. Meth-
odological differences might partly explain this,
This study and the Coeliac Disease Study Group have been
because we used a commercial test while others
financially supported by the Competitive Research Funding
of the Tampere Hospital District and Pa
have used in-house assays (28) and it is conceiv-
ijat-Hame Central
Hospital, The Academy of Finland and The Sigrid Juselius
able that the antigens used in the different tests
Foundation.
may vary (29). Similarly, minor variability has
previously been reported between commercial
antiTG2 ELISA tests from different manufactur-
Conflicts of interest
ers (30). Of note, in coeliac disease, we have
None.
learned that antiTG2 positivity often predicts or
anticipates the development of small-bowel muco-
References
sal atrophy and full-blown coeliac disease (31). It
remains to be seen whether the antiTG6-positive
1. HADJIVASSILIOU M, SANDERS DS, GRUNEWALD RA, et al.
subjects found in this study develop gluten-depen-
Gluten sensitivity: from gut to brain. Lancet Neurol
dent neurological disorders in the follow-up.
2010;9:318-30.
2. C
Depression and mood alterations have been
RONIN CC, JACKSON LM, FEIGHERY C, et al. Coeliac dis-
ease and epilepsy. QJM 1998;91:303-8.
linked to coeliac disease (5-8), AGA positivity
6

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Gluten and neurological and psychiatric disorders
3. LUOSTARINEN L, PIRTTILA T, COLLIN P. Coeliac disease
20. KOSKINEN M, HIETAHARJU A, KYLANIEMI M, et al. A
presenting
with
neurological
disorders.
Eur
Neurol
quantitative method for the assessment of intraepidermal
1999;42:132-5.
nerve
fibers
in
small-fiber
neuropathy.
J
Neurol
4. HU WT, MURRAY JA, GREENAWAY MC, et al. Cognitive
2005;252:789-94.
impairment and celiac disease. Arch Neurol 2006;63:1440
21. DIMENAS E, GLISE H, HALLERBACK B, et al. Quality of life
-6.
in patients with upper gastrointestinal symptoms. An
5. HALLERT C, DEREFELDT T. Psychic disturbances in adult
improved evaluation of treatment regimens? Scand J
coeliac disease. I. Clinical observations. Scand J Gastro-
Gastroenterol 1993;28:681-7.
enterol 1982;17:17-9.
22. KURPPA K, COLLIN P, SIEVANEN H, et al. Gastrointestinal
6. CIACCI C, IAVARONE A, MAZZACCA G, et al. Depressive
symptoms, quality of life and bone mineral density in
symptoms in adult coeliac disease. Scand J Gastroenterol
mild enteropathic coeliac disease: a prospective clinical
1998;33:247-50.
trial. Scand J Gastroenterol 2010;45:305-14.
7. ADDOLORATO G, CAPRISTO E, GHITTONI G, et al. Anxiety
23. POUTANEN O, KOIVISTO AM, KAARIA S, et al. The validity
but not depression decreases in coeliac patients after one-
of the Depression Scale (DEPS) to assess the severity of
year gluten-free diet: a longitudinal study. Scand J Gas-
depression
in
primary
care
patients.
Fam
Pract
troenterol 2001;36:502-6.
2010;27:527-34.
8. LUDVIGSSON JF, REUTRORS J, OSBY U, et al. Coeliac dis-
24. SALOKANGAS RK, POUTANEN O, STENGARD E. Screening
ease and risk of mood disorders-a general population-
for depression in primary care. Development and valida-
based cohort study. J Affect Disord 2007;99:117-26.
tion of the depression scale, a screening instrument for
9. UKKOLA A, MAKI M, KURPPA K, et al. Diet improves
depression. Acta Psychiatr Scand 1995;92:10-6.
perception of health and well-being in symptomatic, but
25. VAINIO E, KALIMO K, REUNALA T, et al. Circulating IgA-
not asymptomatic, patients with celiac disease. Clin Gas-
and IgG-class antigliadin antibodies in dermatitis herpeti-
troenterol Hepatol 2010;9:118-23.
formis detected by enzyme-linked immunosorbent assay.
10. HALLERT C, GRANNO C, GRANT C, et al. Quality of life
Arch Dermatol Res 1983;275:15-8.
of adult coeliac patients treated for 10 years. Scand J
26. HADJIVASSILIOU M, MAKI M, SANDERS DS, et al. Autoan-
Gastroenterol 1998;33:933-8.
tibody targeting of brain and intestinal transglutaminase
11. RUUSKANEN A, KAUKINEN K, COLLIN P, et al. Positive
in gluten ataxia. Neurology 2006;66:373-7.
serum antigliadin antibodies without celiac disease in the
27. VOLTA U, DE GIORGIO R, GRANITO A, et al. Anti-ganglio-
elderly population: does it matter? Scand J Gastroenterol
side antibodies in coeliac disease with neurological disor-
2010;45:1197-202.
ders. Dig Liver Dis 2006;38:183-7.
12. CASCELLA NG, KRYSZAK D, BHATTI B, et al. Prevalence of
28. HADJIVASSILIOU M, AESCHLIMANN P, STRIGUN A, et al.
celiac disease and gluten sensitivity in the United States
Autoantibodies in gluten ataxia recognize a novel neuro-
clinical antipsychotic trials of intervention effectiveness
nal transglutaminase. Ann Neurol 2008;64:332-43.
study population. Schizophr Bull 2011;37:94-100.
29. LINDFORS K, KOSKINEN O, LAURILA K, et al. IgA-class
13. DICKERSON F, STALLINGS C, ORIGONI A, et al. Markers of
autoantibodies against neuronal transglutaminase, TG6
gluten sensitivity and celiac disease in bipolar disorder.
in celiac disease: no evidence for gluten dependency. Clin
Bipolar Disord 2011;13:52-8.
Chim Acta 2011;412:1187-90.
14. HADJIVASSILIOU M, DAVIES-JONES GA, SANDERS DS, et al.
30. VAN MEENSEL B, HIELE M, OFFMAN I, et al. Diagnostic
Dietary treatment of gluten ataxia. J Neurol Neurosurg
accuracy of ten second-generation (human) tissue trans-
Psychiatry 2003;74:1221-4.
glutaminase antibody assays in celiac disease. Clin Chem
15. PYNNONEN PA, ISOMETSA ET, VERKASALO MA, et al. Glu-
2004;50:2125-35.
ten-free diet may alleviate depressive and behavioural
31. SALMI TT, COLLIN P, JARVINEN O, et al. Immunoglobulin
symptoms in adolescents with coeliac disease: a prospec-
A autoantibodies against transglutaminase 2 in the small
tive
follow-up
case-series
study.
BMC
Psychiatry
intestinal mucosa predict forthcoming coeliac disease.
2005;5:14.
Aliment Pharmacol Ther 2006;24:541-52.
16. SOUAYAH N, CHIN RL, BRANNAGAN TH, et al. Effect of
32. SAMAROO D, DICKERSON F, KASARDA DD, et al. Novel
intravenous immunoglobulin on cerebellar ataxia and
immune response to gluten in individuals with schizo-
neuropathic pain associated with celiac disease. Eur J
phrenia. Schizophr Res 2010;118:248-55.
Neurol 2008;15:1300-3.
33. BIESIEKIERSKI JR, NEWNHAM ED, IRVING PM, et al. Glu-
17. RUUSKANEN A, LUOSTARINEN L, COLLIN P, et al. Persis-
ten causes gastrointestinal symptoms in subjects without
tently positive gliadin antibodies without transglutamin-
celiac disease: a double-blind randomized placebo-con-
ase antibodies in the elderly: Gluten intolerance beyond
trolled trial. Am J Gastroenterol 2011;106:508-14; quiz
coeliac disease. Dig Liver Dis 2011;43:772-8.
515.
18. GOAL. Good Aging in the Lahti region = GOAL.
34. SAPONE A, LAMMERS KM, CASOLARO V, et al. Divergence
http://www.palmenia.helsinki.fi/ikihyva/inenglish.html.
of gut permeability and mucosal immune gene expression
19. CACHO J, BENITO-LEON J, GARCIA-GARCIA R, et al. Does
in two gluten-associated conditions: celiac disease and
the combination of the MMSE and clock drawing test
gluten sensitivity. BMC Med 2011;9:23.
(mini-clock) improve the detection of mild Alzheimer's
disease and mild cognitive impairment? J Alzheimers Dis
2010;22:889-96.
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