Preventative Concerns On Neurological Aspects Of Celiac Disease Exposure To Heavy Metals In Relation To Alzheimer’s Disease
Library Series contribution by David N. Wolfgang
Mineral under nutrition is associated with neurodevelopmental, neurological and psychiatric disorders. It may be a prerequisite for the appearance of neurotoxicity. Low income individuals who experience environmental pollution, for example, are, particularly, at risk. Under nutrition combined with chemical exposure is significant in high-income societies in old age and with respect to other variables. Most diseases are part of a pattern of conditions connected via underlying biological mechanisms and processes across a lifetime.1 Celiac disease, Alzheimer’s, among others, involve early-life exposures to environmental agents. They also involve immune-inflammatory insult or dysfunction that is evident. Focusing on the pattern of the underlying immune dysfunction, rather than the clinical symptoms of celiac disease, for example, can reduce the elevated risk of one or more diseases. This can include therapies with comprehensive immunomodulatory procedures. In the latest stages of life, disruption of immune homeostasis may differentiate dementia from normal cognitive function. Gluten sensitivity can lead to a dementia syndrome which comprises one or more conditions including ataxia, myoclonus, seizures, headaches, and neuropathy.2 This gluten sensitivity neurologic syndrome can manifest in dermatitis herpetiformis, aphthous stomatitis, fatigue, osteoporosis, and malabsorptive syndromes. 30% of patients with this syndrome will also have gluten-sensitivity enteropathy or celiac disease. Mineral intake, such as copper, bears a relationship to the capacity to safely digest food.
Copper deficiency in celiac disease can occur with deficiency of zinc, vitamin B12, and iron.3Even in patients with low serum copper indicating copper deficiency the cause of this state may not be evident. Coexistent micronutrient deficiencies may require a gastrointestinal work-up to determine the underlying cause of malabsorption. Dementia is a neurological manifestation with low copper suspected of abnormal copper metabolism. Both acquired copper deficiency and Wilson disease (copper toxicity is due to copper deposited in tissue) can have low serum copper. Incorrect treatment with copper supplementation in Wilson disease can result in irreversible neurological deterioration. With neurological signs and symptoms and low serum copper, it is important to exclude possible Wilson disease prior to copper supplementation. Diagnosis of copper deficiency, therefore, should not be based simply on the presence of low serum copper. Also to be measured, for example, are serum ceruloplasmin, serum copper, and 24-h urinary copper excretion. And free copper. There are reports of neurological manifestation and low copper that are believed to be part of the Wilson disease spectrum that may also include dementia and features of an extrapyramidal syndrome. In these disorders, abnormal copper metabolism has been suspected. The presence of coexisting neurological or hematological manifestations indicative of copper deficiency should be considered before making a diagnosis of copper deficiency, as with gastrointestinal disease (Celiac). Copper is an essential trace element and deficiency states (malnutrition) are rare only in subjects with some oral intakes, given only minute amounts are required.
FOCUS ON THE RELATIONSHIP OF THE GASTROINTESRINAL AND NERVOUS SYSTEMS
Celiac disease is common with a prevalence rate as high as 1.92. Gluten enteropathy associated with neurological complications is still at the level of case reportage as opposed to epidemiological surveys.4 With confirmed biopsy of celiac disease, antibody tests are unnecessary. However, if probability of celiac disease is low, they are helpful to avoid biopsy. Such tests are useful for screening groups of people at risk but without overt features and can aid diagnosis if biopsy results are doubtful. Also the role of gluten as a neurotoxin is being debated. The gluten ataxia hypothesis involving anti-gliadin antibodies (with or without enteropathy) wherein neurological syndromes are treated by simple dietary manipulation is controversial. These are syndromes related to gluten exposure but not directly related to celiac disease. Patients with celiac disease have been reported to have neurological disorders such as neuropathy, ataxia, dementia, chorea and epilepsy. Response to a gluten-free diet is not entirely convincing, except for a chance association. That there is underlying neuronal damage may be unclear but is pointing to be immunological or trace vitamin deficiency. Gluten neuropathy refers to patients with idiopathic neuropathy and positive antigliadin antibody with or without enteropathy.5 With autoimmune markers characteristic of celiacdisease absent, a gluten-free diet may improve neurological symptoms but it has not been shown that this alters this neurological state. Early onset dementia and cognitive decline can occasionally be due to celiac disease. The relationship between the gut and systemic autoimmune diseases and environmental factors influencing development (abnormal immune responses from exposure to environmental antigens) is evolving. This can enable development of new therapies for targeting intestinal permeability, mucosal regulatory T-cells, and neutralization of important inflammatory cytokines. The immunological basis of celiac disease increases understanding of the interplay of genetic and environmental factors in autoimmune disease.
Celiac Sprue is a chronic autoimmune inflammatory enteropathy that has neurologic complications (cerebellar ataxia and peripheral neuropathy). Inhibitors of transglutaminase 2 (TG2) are expected to be of use in therapy of a number of diseases including Celiac Sprue as well as specific central nervous system disorders and cancers.6 TG2 is implicated in Alzheimer’s disease. Molecule modulators of in vivo TG2 activity, such as involvement of copper, are of pharmacological and medicinal interest. Acylidenoxoinodoles are reversible inhibitors of human TG2.This means inhibition of enzyme activity wherein the inhibiting molecular entity can associate and dissociate from a protein’s binding site.
PROTECTING AGAINST COGNITIVE IMPAIRMENT
Nutritional deficiencies, such as celiac disease, can exacerbate pathological processes in the brain leading to Alzheimer’s disease. They can cause memory loss, dementia and delirium. Celiac disease is associated with impaired brain function such as memory problems. Nutritional problems in people with Alzheimer’s disease can reflect years of subclinical malnutrition. Improvement in celiac disease can result in improvement in memory and other cognitive functions as in individuals with Alzheimer’s disease. Acquired illnesses and diseases can alter the symptomology and course of a primary disease. Though gluten sensitivity is referred to as malabsorption syndrome, neurological symptoms can be the first manifestations of the disease.7 Individuals having ataxia, polyneuropathy, other neurological abnormalities of unknown etiology, should be observed for celiac disease. Celiac disease associated encephalopathy is one of the conditions indicative of pre-senile dementia with heavy metal exposure, nutritional deficiency, malabsorption, and vitamin deficiency.8 Pre-senile dementias show heterogeneous clinical manifestations and higher number of potential reversible conditions. Neurological symptoms, such as cerebellar ataxia, can occur from antigliadin antibodies without intestinal changes. This is understood to result from cross-reaction of antibodies to neuronal tissue. Immunosuppression can be used in diet-resistant patients. Both neurodegenerationand other underlying causes, such as celiac disease, result in clinical symptoms including changes in memory, planning, orientation and processing speed. Metabolic disorders in pre-senile dementia, lead to subcortical dementia showing disturbance of vigilance and attention with memory deficits usually appearing later in the disease. Lowering availability of both iron and copper may mitigate resultant diseases and may slow the aging process. Severe copper deficiency, as in celiac disease, may cause lessened activity of copper-dependent enzymes whereas reduction of excess free copper levels may be brought down mildly but not so much as to affect copper-dependent enzymes. Evidence exists that normal levels of iron and copper contribute to various diseases of aging (oxidant stress).9 It is necessary to begin evaluation of levels of these metals that are optimal during the latter part of life. This has to be weighed against whether copper is involved in the pathogenesis of Alzheimer’s disease as there is data, for example, in which cognitive decline is correlated positively with low plasma levels of copper. Whether in Alzheimer’s disease, or related diseases of neurodegeneration, further experimentation is needed.
Figure 1 suggests an immune attack on the brain that can be similar to Alzheimer’s disease symptoms but may lead to a dementia that may or may not be (in association with celiac disease) a dementia that is actually caused by Alzheimer’s disease. (Figure 1. Memory loss and cognitive decline/dementia. Image source: http://www.gettyimages.com.)
COPPER TOXICITY DURING AGING
Copper because it is so general in the population is a public health problem in diseases of aging and in the aging process. One study has shown that in the general population those in the highest fifth of copper intake, if consuming a relatively high fat diet, lose cognition at more than three times greater than the normal rate.10 Inorganic copper in drinking water and supplements is more toxic than food copper. Endocrine, metabolic, nutritional, and toxic disorders, acquired at an earlier age, may lead to dementia such as through the association with vitamin B-12 deficiency (as can occur in celiac disease) in combination with other factors such as high serum homocysteine level. One study hypothesized that common genetic pathways mediate response to different forms of brain pathology and that variation in this impacts age-related cognitive decline.11 These have a role in multiple neurodegenerative diseases, including celiac disease and dementia. Multiple pathologies can interact to produce clinical manifestations of age-related cognitive decline. ADNI (Alzheimer’s Disease Neuroimaging Initiative) formed by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and the Food and Drug Administration, pharmaceutical companies and nonprofit organizations, in 2003, has studied mild cognitive impairment in early Alzheimer’s disease.12 This initiative also includes investigation of blood levels (Chow N. Low serum levels of ApoE associate with hippocampal atrophy in the ADNI cohort, http:// www.loni.ucla.edu/~thompson/L/1148.Chow-Low_serum_ levels_of_ApoE_associate_with_hippocampal_atrophy_in_the_ ADNI_cohort_ICAD2011_poster.pdf ). Though susceptibility for inflammatory diseases are not significantly associated with cognitive decline, results did suggest intermediate phenotypes, that when combined with larger sample sizes, can be useful in dissecting susceptibility loci for age-related cognitive decline and for uncovering shared molecular pathways having a role in neuronal injury. Generally, the diet of many adults, particularly the elderly, may contain less copper than recommended. Copper malabsorption, as with celiac disease, can lead to hypocupremia.
LIFESTYLE FACTORS IN CELIAC AND ALZHEIMER’S DISEASES
Management of malnutrition associated with chronic disease (e.g. celiac disease) should become standard practice in clinical medicine.13 Compromised nutritional status has been correlated with diminished quality of life as well as increased morbidity and mortality. Severe copper deficiency can adversely affect bone health. As well as celiac disease posing risk for copper deficiency; and though controversial, low plasma copper can be linked to faster decline in cognitive ability in Alzheimer’s disease. Under these conditions, considering that a number of factors can influence bone resorption, bone metabolism can be a marker of mild decrease in copper intake (males) given a breakdown of bone with release of minerals.14 Concerns about hormone replacement therapy (increased risk for probable dementia in women 65 years and older) with bisphosphonate use have led some patients to resort to other approaches for bone health even though the link between this medication and adverse side effects is still controversial.15 This places the elderly at increased risk for fragility fractures and morbidity and mortality. In individuals with borderline deficiency states, including Celiac Sprue, fully developed clinical disease may result from stress associated with chronic infection or other acute illnesses. Lifestyle and environmental factors can influence bone health which can change over time. Risk can be diminished by pharmaceuticals but the underlying etiology requires a prevention strategy that deals with lifestyle, nutritional, and environmental determinants. These determinants can contribute to bone health compromise. Diverse health sequelae can occur in the gastrointestinal tract and also diverse systemic toxicities such as inflammation and neurological effects.16 Both infection and toxicants, including some heavy metals, can alter gut flora and modify various functions such as digestion, bioavailability/absorption, elimination, detoxification, and immune function.
Lifestyle can contribute to cardiovascular disease, cancer, and obesity/metabolic syndrome/diabetes. Similarly, gene-environment interaction, such as Apolipoprotein-E4 interactions with heavy metals, is associated with Alzheimer’s disease. Multiple related conditions including metabolic syndrome and Alzheimer’s may be associated with lower socioeconomic circumstances such as poor diet, housing and increased stress, as well as air pollution, heavy metals, and endocrine disrupting chemicals, for example. Early life exposure to a range of toxicants, including heavy metals, POPs, and pesticides can have immediate effects such as problems with learning , attention, and increased predisposition to Alzheimer’s. There are mult-system complaints with patients significantly disabled increasingly commonly presenting themselves to clinicians. AGEs can invoke an immunoglobulin G (IgG) response that has been correlated in a number of studies to IgE production.17 They are also linked with heightened immunogenicity, aging, and age-enhanced disease states such as diabetic complications, atherosclerosis, hemodialysis-related amyloidosis, and Alzheimer’s disease. Celiacdisease, which is not mediated by IgE, is nevertheless an allergic reaction that is lifelong. TILT (toxicant induced loss of tolerance in response to a significant initiating toxic exposure) has been suggested as a pervasive mechanism of illness which involves several organ systems concurrently.18 TILT results in sensitivity-related illness (SRI). Celiac disease is an example of lack of adequate uptake of required nutrients from GI inflammation with SRI leading to varied clinical signs/symptoms. Cognitive dysfunction and disability have been noted with intolerance to environmental chemicals. Heavy metals, including copper, can induce autoimmunity. TILT also relates to acquired allergy, food intolerance and chemical hypersensitivity. This encompasses chemical, inhalant, or food antigens. TILT and resultant sensitivity-related illness can evoke wide-ranging physical or neuropsychological manifestations. This mirrors escalating rates of toxicant exposure and bioaccumulation into the population. There is emerging evidence that toxic environmental factors including infection and xenobiotics, for example, can potentially initiate pathogenesis of immune intolerance of self or autoimmunity. This has been linked to exposures such as assorted heavy metals. That auto-antibodies against human tissue antigens can often be detected following toxicant exposure and before onset of clinical autoimmunity can account for why industrial regions, especially Northern Europe and North America, show the highest rates of most autoimmune diseases.
Figure 2 is in line with the search for safe and effective therapies in a gluten-free diet comparable to a normal social lifestyle.19 Essentially, celiac disease autoimmunity results from enzyme tTG generating additional antigenic epitopes through cross-linking gliadin peptides to itself and/or to other protein substrates, thus stimulating mucosal T cells to produce autoantibodies against tTG and gliadin. Involvement of tTG in celiac disease pathogenesis may also arise from a distinct interdependent pathway via a gliadin-derived peptide deamidation reaction as depicted in Figure 2. It is thought that tTG may account for deamidation of specific glutamineresidues within naturally digested gluten peptides, particularly at low pH, potentiating T cell activation. In fact, there are several active gluten peptides with a large degree of heterogeneity of responses. It is also the case that gluten contains peptides that can stimulate cells of the innate immune system.
THOUGHTS TO CONSIDER ON CELIAC DISEASE CONJUNCTION WITH ALZHEIMER’S DISEASE
Copper deficiency is a serious risk for neurological disease which can underlie the relationship between celiac disease, brain atrophy, and dementia. There are immunologic mechanisms involving copper deficiency that can manifest in Alzheimer’s disease in association with celiac disease. Patients should be tested for this type of deficiency. The increasing use of serological screening tests makes it easier to identify extra-intestinal manifestations including short stature, anaemia unresponsive to iron therapy, osteoporosis, ataxia, peripheral neuropathies, hypertransaminasemia, and unexplained infertility in celiac disease.20 There are potential therapies available for Celiac Sprue and certain central nervous system degenerative disorders, such as Alzheimer’s disease, with involvement of copper status. Blockage, for example, of the transamidating activity of tTG is a tool that may prevent immune activation. A similar approach has been investigated in Alzheimer diseases wherein tTG is involved. tTG inhibitory drugs are predicted to have a wide medical application. There are avenues for therapeutic intervention directed at targeting each factor involved in celiac disease onset. Understanding of the hierarchy of pathogenic gliadin epitopes and core region is necessary before a peptide-based therapy can occur. Another therapeutic approach is correction of intestinal barrier defect against gluten entry. Copper has effects on transglutaminase enzymes (tTG) which can have involvement in both Celiac and Alzheimer’s diseases.21 A large proportion of transglutaminase is present in a number of component.
- Dietart R R, DeWitt J C, Germolec D R, Zelikoff J T. Breaking Patterns of Environmentally Influenced Disease for Health Risk Reduction: Immune Perspectives. Environmental Health Perspectives. 2010;118(8):1091-1099.
- Rosenbloom M H, Smith S, Akdal G, Geschwind M D. Immunologically Mediated Dementias. Current Neurology and Neuroscience Reports. 2009;9:359-367.
- Kumar N, Butz J A. Clinical significance of the laboratory determination of low serum copper in adults. Clin Chem Lab Med. 2007;45(10):1402-1410.
- Wills A J. The neurology of enteric disease: Neurological complications of gastrointestinal, hepatic and pancreatic disease. J Neural Neurosurg Psychiatry. 2006:77;805-810.
- Barton SH, Murray JA. Celiac Disease and Autoimmunity in the Gut and Elsewhere. Gastroenterol Clin North Am. 2008;37(2):1-17
- Klock C, Jin X, Choi K, Khosla C, Madrid P B, Spencer A, Raimundo B, C, Boardman P, Lanza G, Griffin J H. Acylideneoxoindoles: A new class of reversible inhibitors of human transglutaminase 2. Biorganic & Medicinal Chemistry Letters. 2011;21:2692-2696.
- Tunc T, Okuyucu E, Ucler S, Sonmez T. Coskun O, Selvi E, Inan L E. Subclinical celiac disease with cerebellar ataxia. Acta neurol belg. 2004;104:64-86.
- Heinemann U, Gawinecka J, Schmidt C, Zerr I. Differential Diagnosis of Rapid Progressive Dementia. European Neurological Review. 2012;5(2):21-29.
- Brewer G J. Iron and Copper Toxicity in Diseases of Aging, Particularly Atherosclerosis and Alzheimer’s disease. 2007;232:323-335.
- Brewer GJ. Risks of Copper and Iron Toxicity during Aging in Humans. Chem Res Toxicol. 2012;26:319-326.
- DeJager P L, Shulman J M, Chibbnik L B, Keenan B T, Raj T, Wilson R S, Yu L, Leurgans S E, Tran D, Aubin, C, Anderson C D, Biffi A, Corneveaux J J, Huentelman M J, Alzheimer’s Disease Neuroimaging Initiative, Rosand J, Daly M J, Myers A J, Reiman E M, Bennett D A, Evans D A. A genome-wide scan for common variants affecting the rate of age-related cognitive decline. Neurobiology of Aging. 2012;33:1017.e1-1017.e15.
- Jager PLD, Shulman JM, Chibnik LB, Keenan BT, Raj T, Wilson RS, Yu L, Leurgans SE, Tran D, Aubin C, Anderson CD, Biffi A, Corneveaux JJ, Huentelman MJ, Alzheimer’s Disease Neuroimaging Initiative, Rosand J, Daly MJ, Myers AJ, Reiman EM, Bennett DA, Evans DA. A genome-wide scan for common variants affecting the rate of age-related cognitive decline. Neurobiology of Aging. 2012;33:1017.e1-1017.e15.
- Genuis S J, Bouchard T P. Combination of Micronutrients for Bone (COMB) Study: Bone Density after Micronutrient Intervention. Journal of Environmental and Public Health. 2012:1-10.
- Danzeisen R, Araya M, Harrison B, Keen C, Solioz M, Thiele D, McArdle, HJ. How reliable and robust are current biomarkers for copper status? British Journal of Nutrition. 2007;98:676683.
- Genuis SJ, Bouchard.Sears M E, Genuis S J. Environmental Determinants of Chronic Disease and Medical Approaches: Recognition, Avoidance, Supportive Therapy, and Detoxification. Journal of Environmental and Public Health. 2011;2012:1-15.
- Maleki SJ, Hurlburt BK. Food Allergy: Recent Advances in Food Allergy Research. Chapter 15. Department of Food Processing and Sensory Quality, Southern Regional Research Center, Agricultural Research Service, U. S. Department of Agriculture, New Orleans, LA.
- Genuis S J. Sensitivity-related illness: The escalating pandemic of allergy, food intolerance and chemical sensitivity. Science of the Total Environment. 2010;408:6047-6061.
- Caputo I, Lepretti M, Martucciello S, Esposito C. Enzymatic Strategies to Detoxify Gluten: Implications for Celiac Disease. Enzyme Research. 2010:1-9.
- Caputo I et al.Kuo T-F, Tatsukawa H, Kojima S. New insights into the functions and localization of nuclear transglutaminase 2. The FEBS Journal. 3022:4756- 4767.