Cadmium Induced Mental Retardation (Alzheimer’s Disease)

INTRODUCTION: Mental Retardation

Mental retardation (MR), defined as a failure to develop a sufficient cognitive and adaptive level. It is one of most common human disease. Also, 1-3 % of the human population has an IQ below 70. Recent research has discovered that MR is related to the presence of certain mineral elements in the body above-normal levels, especially cadmium and lead (Mike et al. 1983). It has been estimated that half of all cases are due to environmental factors, that include prenatal exposure of the fetus to toxic substances, environmental contaminants, infections, radiations, illness of mother (eg exposure to rubella, Cytomegalovirus) and malnutrition etc. (Birgitta et al. 2003). The prevalence of Intellectual disability (ID) also referred to as mental retardation is between 1% and 3% (Roeleveld et al. 1997; and Wen 2002). And ID is present in every social class and culture (Leonard and Wen 2002). Also, there are approximately 30% more males with MR are diagnosed than females (American Psychiatric Association 2000; Miclaren and Bryson 1987). Alzheimer’s disease (AD) is a mental retardation mostly caused by cadmium. Also, blood cadmium concentration in Alzheimer’s disease and non-demented subjects were studied. Smokers had higher cadmium level than non-smokers.

Alzheimer’s disease: A case study.

A 59 years old university teacher with Alzheimer’s disease visited our clinic and treated for five weeks from November 9 to December 15, 1995. She was suffered from memory loss and had been getting professional terms, and concepts forced her to resign at the university. She was admitted to the clinic. In day to day matters she was forgetting to switch off electronic devices and other appliances, and continuously became lost even in her own neighborhood. She suffered an acute onset of the disease and had been ill for 13 months. His history showed that first bouts of amnesia lasted three to four hours. Also, an increase in dementia and memory loss was registered. Her blood pressure rose to 150/90 mm. Also, her brother had suffered similar memory loss and died at age 57, also her mother suffered from dementia, beginning at age 52 and died at age 56. So it was discovered that this predisposition was based on genetics and not on gender.

Objectives

Routine examination of internal organs showed no pathology. No local pathology in routine neurological tests.

Mental State

Critical behavior was preserved. The acute memory loss, concerning life events, such as children and even she was unable to recall her maiden name. Also, she had difficulty with the execution of simple arithmetic operations and her logical thinking diminished.

Diagnostic

CT scan is done, which showed the atrophy of the cortex and widening of subarachnoidal spaces and also brain ventricles. Roentgenoscopy showed some reduction of blood flow in all areas. Slowing of the main cortex rhythm observed with EEG. Also, the blood test showed slightly elevated blood cholesterol.

Therapy

The patient was treated with cerebrum composition, one ampule injection three times a week. Cerebrum composition is a complex homeopathic formula produced in ampules of 2.2 ml. Also, each ampule contains in its formula as ingredients.

Result

1^st and 2^nd week: No change.

3^rd week: some improvements, and she became more physically active, but no changes in her state of memory.

4^th week: the ability to perform routine tasks improved. She was able to retell articles and her ability to perform arithmetic operations was improved.

5^th week: there were improvements in her abilities including abstract logical thinking and her mood.

CADMIUM

Strong metal cadmium appears in earth crust that spread in the environment by two processes as like human activities and by a natural process such as waste incineration, the use of phosphate fertilizers fossil fuel burning smelting procedures (Agency for Toxic Substances and Disease Registry 2008). Cadmium is found in soil, plant, animal tissues, air, and water (Friberg, et al. 1979). Cadmium is a heavy metal, has no useful natural role (WHO, 1992; NRC, 2005), and may be extremely toxic when presented into the body through absorption.

Cadmium sources:

Food Sources:

Food sources of cadmium are rice and wheat grown in the soil which is contaminated by different fertilizers such as phosphate and by wastewater.

Different fish also contains a large quantity of cadmium in their tissues such as tuna, haddock, and codfish. Oyster also contain Cd in great amount but it also has zinc which prevents it from toxicity produced by Cd.

During the processing of food, zinc is removed, which protects food from toxic effects caused by cadmium so Cd remains in food which is harmful.

Refined & processed food:

Refined foods have such elements such as zinc and calcium which provide protection but in some cases, these elements are removed so Cd remained in food which easily absorbed in food.

We can use Cd for plating purpose in the plants of food processing. Different processed foods such as meat, grains, carbonated drinks, coffee are a common source of cadmium that causes toxic effects in our body.

Nowadays we mostly use white rice and flour which are deficient in vitamins and minerals, this deficiency causes to enhance Cd level.

Another source of Cd toxicity is the usage of carbohydrates in large amount. Because it reduces the zinc level.

Drinking Water:

Cd is used in many industries so when industrial wastes are disposed of cadmium enters in our drinking water. In hard water, there is a large amount of calcium which protects from toxicity but soft water having low calcium contents is more harmful. Plastic and galvanized pipes are also a source of cadmium.

Batteries, Semiconductors, Electroplating, Polishes:

Information industries of different electrical goods, cadmium is used.labours of these industries have a high risk of toxicity. Dentists also use Cd in making artificial teeth and in their polishing process.

The smoke of cigarettes:

Cigarettes have high cadmium contents so when smoke is inhaled it absorbed in our lungs. One packet contains 2-4 micrograms Cd.

Other sources:

Cadmium is present in motor oil rubber goods, tiers in paints and plastic. Vehicles exhaust has a high level of Cd.

Congenital Cadmium Intoxication:

It was observed in rat pregnant mother after giving a continuous injection of cadmium, it enters into the brain of its fetus. Nowadays high amount of cadmium is being observed in babies and in young people, we can say that this high amount of source in babies is their mothers. This can cause severe birth defects and abnormalities such as learning disorders, hyperkinesis, and minimal brain dysfunction.

How to detect cadmium:

Blood Tests:

As we intake cadmium in different forms from various food sources, but its blood level is low so detection of it through blood test does not give us the clear result.

Challenge Tests:

To detect cadmium we use chelating agents. The urine sample is collected (24-hour sample) to detect Cd level in blood and arteries.but this test is not used in the detection of cadmium in bones, joints, and other tissues.

Detection from hair analysis:

There is a specific relation between cadmium level in hair and kidneys. If Cd concentration is high in hair its mean its level is also high in kidneys. Cd identification or detection is not done on the first test because Cd is bound with other elements and it takes time to release from this tight binding.

Cadmium metabolism:

Absorption:

Cadmium is highly absorbed through inhalation. Risks of cadmium toxicity in women are more than in men because metabolic rate is slower in women. Low  level of calcium, zinc, protein, and iron in body favors more absorption of cadmium in the body

Retention:

Half of the total amount of cadmium inhaled, absorbed in the body is stored in liver and kidneys. Cadmium also stored in the pancreas and salivary glands. It may also store in

Joints, periosteum or bone covering, in arteries and in all other body tissues. Cadmium moves from plasma to RBCs and binds with hemoglobin and metallothionein. Cd inhalation activates the production metallothionein, it is a protein binds with Cd and zinc. Cd varies in concentration with respect to age.

In newborn, its concentration is 15-20mg and in adults less than 1mg.

Excretion:

Metallothionein a chelating agent performs its part in excretion of Cd. This process of excretion is done through kidneys and liver but this process is very slow.10-30 years is the half-life period of cadmium.

Cadmium metabolic effects:

Energy Production:

One of the inhibitors of cellular respiration is cadmium. As it forms a strong bond with many bio-elements so it is very harmful to the human body. These biomolecules include many enzymes of the Kreb cycle.

Zinc displacement:

Harmful effects of cadmium mostly appear in kidneys, nervous system and arteries. It is observed that many birth abnormalities are caused just due to Cd.

Cadmium binds faster with metallothionein as compared to zinc and copper, so this strong binding of Cd causes a deficiency of zinc and copper. For utilization of zinc and copper it is important that these two elements bind with metallothionein but as we know cadmium binds more fastly than these two.so cadmium poisoning results into a low level of zinc and copper. Another feature is that,( poisoning caused by Cd) the replacement of zinc with cadmium in enzyme system results in the very critical situation because Cd can do homeostatic function. So that many enzymes of zinc can perform their functions with Cd so in this way the enzymatic action is not proper it becomes slow which finally results in impairment of enzymes which are dependent on zinc.

Renal Effects caused by Cd:

As cadmium is stored in kidneys, this storage causes the malfunctioning of renal.

When renal not performs well it strongly affects the concentration level of calcium-vitamin D phosphorus and sodium level. These low levels of elements result in different problems such as renal hypertension, proteinuria, glycosuria, and other disorders of metabolism.

Carcinogenesis and Teratogenesis:

It is observed now that calcium causes cancer. Abnormalities occurring at the birth time are usually due to low level of zinc. Mostly mice and rat are being observed suffering from these abnormalities caused by Cd.

Metabolism dysfunction due to a high level of Cd:

Metabolism dysfunction due are categorized into different types which are as follow

Nervous System:

Neurotransmitters:

Cd by disturbing calcium metabolism stops the release of acetylcholine.zinc stops the action of cholinesterase but cadmium enhances the action of this enzyme. Cadmium also stops the adenylate cyclase monoamine action.

Other damage caused by cadmium:

Cadmium also harmful for nerve cells and also for nerve fibers. It induces the hemorrhages in the autonomic ganglia. It can also cause Peripheral neuropathy.

Muscular-Skeletal System:

Cadmium alters the different metabolic pathways as do with zinc and calcium.

This alteration results in osteoporosis and arthritic disorders in case of protein. In the case of zinc deficiency, neuromuscular dysfunctions occurred.

Cardiovascular:

Decreased strength and flexibility in arteries is mainly due to the low level of zinc. This deficiencies also caused the narrowing of arteries.

Digestive System:

Cadmium interaction with different enzymes such as zinc-dependent enzymes may result in improper digestion.

Endocrine/Metabolic System:

Zinc is necessary for growth. Growth disorders and failures may be caused by cadmium.

Dental:

Disorder of Calcium and vitamin D metabolism results in deformities of teeth and dental caries.

Mental/Psychological:

Hyperactivity and learning disorders are caused by cadmium. Acetylcholine release is disturbed by Cd results in hyperkinetic behavior.

Metabolic Dysfunctions Associated With Cadmium Toxicity

Alcoholism:

This is linked with a deficiency of zinc and with the low level of calcium. We can say that Cd causes alcoholism because it is the main reason for zinc deficiency.

Loss of hair (Alopecia):

This phenomenon is mainly associated with zinc deficiency results due to inhalation and absorption of cadmium.

Anemia:

Early symptoms showing cadmium poisoning is anemia.

Atherosclerosis:

Proper metabolism of fats is done in the presence of zinc. But when this optimal level is disturbed.atherosclerosis occurs.

Arteriosclerosis:

As zinc is necessary for the flexibility of arteries. But by replacement of zinc with Cd results into disorders of arteries. Due to the low level of zinc arteries have high risks to rupture and becomes less flexible. In this critical situation, the body accumulates calcium which may provide strength to the walls of arteries.

Arthritis, Osteo, and Rheumatoid:

Zinc replacement causes by Cd disturbed the protein formation. So in this way less and improper protein formation occurs resulting in pain and inflammation of joints.

Bone Repair, Inhibited:

Cadmium can replace calcium in our bones.

When any damage occurs in bone or breakage zinc is the element requires for bone repair.

Cerebral Hemorrhage:

Cerebral hemorrhage caused due to cadmium toxicity. Weakness and loss of flexibility of cerebral arteries caused by cadmium.

Liver Cirrhosis:

Liver cirrhosis is caused by low level of zinc-induced by cadmium detoxification in the liver.

Diabetes:

The complete process of insulin from production stage to transport and usage zinc is very essential. But with the interference of Cd zinc metabolism is disturbed which leads to induce diabetes.

Emphysema:

It is the condition in which fragile alveoli of lungs are broken and alveoli get brittle. This condition is caused when zinc is replaced by cadmium in collagen.

Enlarged Heart:

Cadmium is the most common element causing various heart disease. As it causes the reduced flexibility of arteries, in addition to this, it causes the enlargement of heart size and high blood pressure.

Fertility, Decreased:

Cadmium induces the deficiency of zinc which regulates the fertility of males. Due to this sexual potency is decreased.

Hemochromatosis:

Hemochromatosis is the situation of high accumulation of iron in the body tissues. This occurs when the liver fails to detoxify iron. Loss of this detoxification of iron is due to cadmium. One reason for hemochromatosis may be decreased level of calcium and copper.

Hypercholesterolemia and Hyperlipidemia:

Low level of zinc leads to increase the level of cholesterol. This increased level of cholesterol may affect the normal function of the liver.

Hypertension:

Cadmium is one of the reasons for hypertension and high blood pressure.

Hypoglycemia:

Zinc deficiency may leads to hypoglycemia.

Lung Disease:

Cadmium is harmful to lungs as it inhaled with the cigarette smoke it affects the elasticity of lung tissues.

A migraine Headache:

By interfering with zinc metabolism, cadmium toxicity may allow tissue copper buildup to occur, resulting eventually in the causation of migraine headaches.

Schizophrenia:

Zinc is an essential element which stabilizes the CNS and it is a neurotransmitter.

Low level of it may cause the mood disorders and this low level allow copper to accumulate in the brain. This accumulation of copper is one of the reasons for schizophrenia.

Vascular Disease – Strokes (cerebral vascular disease):

Due to the replacement of zinc with the cadmium arteries loss their flexibility and have high risks of rupturing, in this situation body covers the arteries with fatty acids or calcium which provide protection to walls of arteries. If a small part of plaque breaks, it can block the arteries causing a vascular stroke.

ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is a neurodegenerative infection that is categorized by dementia as the main medical feature of Alzheimer’s disease. Mostly affects the mature and has become one of the foremost mortal infections. Classic neurotic structures of AD contain β-amyloid protein (Aβ) confession in the brain that forms. Forgetful plates (SPs), neurofibrillary twists (NFTs) and neuronal apoptosis. Cadmium (Cd) is an injurious hint element that reasons living abnormalities and morphological of the central nervous system (CNS) mental retardation and memory loss (Wu et al. 2001). Concentrations of Cadmium and Cd/Zn are expressively higher in the hair of AD patients and blood than in vigorous people.

However, the association between Cadmium and Aβ has occasionally has been studied. Identification of three loci—on chromosomes 6p21, 10q24, 11q23—that produced helpful effects in three or more self-governing studies, in addition to the deep-rooted Alzheimer’s disease relationship with the gene encoding Apolipoprotein E (APOE) (Bertram et al., 2004). There is a noticeable damage to noradrenergic, cholinergic, and dopaminergic neurons in the AD. The decrease of turgid A deposits with trashes of monoclonal antibodies against A  that absence the Fc portion recommends a non-Fc-mediated appliance of consent.

While current proof proposes that Alzheimer’s disease is a varied disorder including numerous diverse genotypic and phenotypic expressions, Alzheimer’s disease can be categorized clinically by an advanced deficiency in mental retardation purpose throughout mid- to late-adult life with the primary symptoms naturally being sure practices of language and memory losses.

Brains from Alzheimer’s (AD) disease patients expression numerous neuropathological features, with intracellular and extracellular amyloid- (A ) peptide-containing plaques neurofibrillary masses of unusually astrocytic gliosis, phosphorylated, inflammation and reactive microglia as well as synaptic and neuronal victims. The straight combination of AβP into neuronal membranes of memorialized hypothalamic neurons (GT1-7 cells) related with the development of calcium-permeable pores, and also, the elevation of the intracellular calcium concentrations in the GT1-7 cells the distraction of calcium homeostasis by AβP-channels may be the cause of molecular basis of the neurotoxicity of AβP, and the expansion of AD. It is also introduced that the ingredients of membrane lipids can show vital roles in the process of this network development. Our theory may also clarify the appliance of growth of other ‘conformational diseases’, such as type 2 diabetes mellitus or prion disease which part some collective characterize with the AD Enlarged confession of Aβ in those cases resonant the hazard allele. However, the hereditary indication is presently not enough to specify whether βAPP mismetabolism, straight or secondary Aβ neurotoxicity (or its derivatives) are dominant to the AD procedure. The happenings of protein phosphatases strength reduced in the affected neurons in Alzheimer’s disease AD brain, permitting the irregular hyperphosphorylation of tau. Neurofibrillary deterioration can perhaps be subdued by growing the activities of protein phosphatases in the brain of patients with Alzheimer’s disease.

Mental/Psychological

Cadmium is associated with hyperactivity and learning disability, most likely due to a cadmium-induced zinc deficiency. Inhibition of acetylcholine release may also result in hyperkinetic behavior.

Cerebral Hemorrhage

Weakness and hardening of cerebral arteries, due to cadmium toxicity, results in an increased tendency for cerebral hemorrhage

Hypertension

High levels of cadmium are considered to be an important causative factor in hypertension. Cadmium, by impairing kidney function and causing hardening of the arteries, can result in high blood pressure.

Population-based study

Aims of investigations

What is the concentration of cadmium in the blood of normal aging and AD? And to find if there any relation between the concentration of cadmium in blood and cognitive functions.

Blood sampling from subjects

The subjects were from a population-based study, which has been reported in detail elsewhere (Fratigilation et al., 1991, 1992). The project was based on all inhabitants who born 1912 and before and living in areas of Stockholm called kungsholmen in October 1987. There were 2368 individuals 1800 females and 568 males. The whole population was assessed with the Mini-Mental State Examination. Ten ml blood was collected from 29 subjects (21 females and 8 males). The sample collectors were non-smokers. Before collection of blood, the skin of the patient was cleaned with the help of mediswab. Which containing iso-propanol venojet VT 100-H with green stoppers. The tubes turned 10-15 times for mixing. Then 1 ml was transferred to an acid washed tubes with Pasteur pipette and frozen at -20 ^oC and stored at -80 ^oC ^.after 1 week. (Basun et al. , 1994).

Result

Smokers had more cadmium concentration in their blood than non-smokers.

Molecular Mechanism of Cadmium-induced Mental Retardation.

Intellectual disability (ID) is a common neurodevelopmental disorder that is characterized by an intelligence-quotient (IQ) of 70 or below. And also a deficiency in at least two behaviors of adaptive functioning especially when diagnosed at 18 years of age(American Psychiatric Association2000). Especially the deficiency of adaptive functioning includes self-care, judgment, communication, reasoning, and memory loss etc.

Approximately 30% more males are diagnosed with an Intellectual disability than females.

Cadmium (Cd), a toxic heavy metal, which released from cigarette smoking, smelting and the refining of metals, and also burning of chemical fuels also others include municipal wastes. Cadmium can be absorbed in both animals and leads to its accumulation. As cadmium has its half life 15-20 years so it accumulated in the human body in major organs such as kidneys, liver, and even brain and leads to their damages, and its accumulation becomes the cause of or leads to carcinogenesis, immunodepression, and neurodegenerative disorders.

Cadmium can accumulate in the brain also clinical data have shown that Cd in the brain contributes to neurological disorders such as learning disabilities, hyperactivity in children, neurobehavioral defects in

attention, psychomotor speed, and also memory in the workers exposed to Cd. Cd is a possible factor which can cause neurodegenerative disorders, e.g,  amyotrophic lateral sclerosis Alzheimer’s disease, and Parkinson’s disease. Calcium is an intracellular signal which is responsible for

controlling many cellular processes which includes cell survival/death, proliferation, and differentiation.

Elevation of the Cytoplasmic Ca⁺² level activates the MAPK and m-TOR.

Also, it is observed that cadmium can disturb the intracellular Ca⁺² ions concentration and eventually leads to apoptosis in a variety of cells such as hepatic, kidneys, thyroid cancer cells and also in brain cells which eventually becomes the cause of Mental Retardation. The elevation Ca⁺² ions level activate the Mitogen-activated protein kinase MAPK cascade, which is involved in cell signaling and also involve in cell apoptosis, C⁺² increased level also activate mammalian Target of rapamycin mTOR and also (P13k)-Akt pathway, ( Baoshan et al. 2011). The activation of MAPK and mTOR control cell death and survival depending upon the stimuli. Also, Cd-induced neuronal apoptosis is partially associated with the activation of t signaling pathways involving the c-Jun N-terminal kinase (JNK) and Akt/mTOR, as well as extracellular signal-regulated kinase 1/2 (Erk1/2) in neuronal (PC12 and SH-SY5Y) cells (Chen 2008).

Cd-induced neuronal toxicity is as a result of induction of Reactive Oxygen Species (ROS).

Under pathological conditions, the excessive amounts of ROS induced by Cd can modify lipids, proteins, and DNA, alter their functions, and also activate the related signaling pathways, so the Cd-induced neurotoxicity is due to generation or induction of ROS. Cd can activate the MAPK pathway by the generation of ROS and which activate Erkt1/2 and JNK and leading to apoptosis of neural cells.

TREATMENTS

The AD is the main leading cause of dementia, affecting more than 26 million people around worldwide. To enter clinical trials in humans Aβ immunotherapy has started from preclinical studies in transgenic mouse models of the AD. Nevertheless, studies of active and passive Aβ immunotherapies are continuing to go forward, with an estimated total enrollment of more than 9,000 patients. According to the results from preclinical and clinical studies, if patients are immunized before disease onset or in the earliest stages of the disorder it is believed that Aβ immunotherapy has strong potential for preventing AD.

Alzheimer’s disease is a progressive neurodegenerative ailment of the mature, categorized by extensive loss vital cholinergic purpose. Also, the only indicative management verified operative, to date is the use of cholinesterase (ChE) inhibitors to enhance living cholinergic action. And the Cholinesterase inhibitors act on the enzymes that hydrolyze acetylcholine (ACh) and following synaptic release. Investigational proof from the use of agents with enriched choosiness for ChE inhibitors such as rivastigmine and BuChE (cymserine, MF-8622), which have a double-inhibitory action on both BuChE and AChE, designate potential relaxing positive points of preventing both BuChE and AChE in Alzheimer’s disease and associated dementias.

Future directions

For the treatment of Alzheimer disease, many potential therapeutic agents are currently under investigation. Enzymes involved in the formation of β-amyloid and Amyloid precursor protein are thought to contribute to genetic forms of Alzheimer disease; so, interventions to reduce amyloid plaque burden by altering the amyloid metabolism are now being evaluated. To promote clearance of β-amyloid from the central nervous system Immunotherapy is being assessed. Other treatments include resveratrol, (a compound present in the skin of red grapes), which have beneficial effects on aging in mice, and, an N-methyl-D-aspartate receptor antagonist that may also weakly inhibit the acetylcholinesterase, and which may improve cognitive performance and is currently in the trial phase. Agents targeted against tau are also other possible options. Also due to high prevalence, of the fragile X syndrome most therapeutic studies have focused on it. Recently, it was discovered minimally affected individuals with an unmethylated full mutation still produce the FMR1 proteins. So it was concluded that the silencing of the FMR1 gene is caused by the methylation. Due to the extreme genetic heterogeneity, the development of rational therapies for mental retardation disorders is more difficult than for any other type of disorder. Perhaps to develop therapy a more realistic approach would be to increase our insights that, in how mutations in these mental retardation genes lead to disease. Common pathways might be involved in more than a single disorder. Therefore, increasing our vision of the molecular causes of the mental retardation might lead to realistic therapies for mental retardation diseases in the future.

CONCLUSION

Cadmium a heavy toxic metal which released from different human activities such as smelting and refining of metals and other main source is food, it can be introduced into human body either by direct Cd contaminated environment e.g in workers or by food. As it has a large half life so leading to its accumulation in the different major organs and leads to their damage. Also can accumulate in the brain and lead to apoptosis of neurons, by activating the MAPK and m-TOR pathways. Cd can activate MAPK and m-TOR by disturbing the intercellular Ca⁺² ions level in the cytoplasm and activated MAPK can, in turn, activate the JNK pathway, and leads to neurons cells apoptosis. Also, Cd-induced neuronal toxicity is due to oxidative stress by the induction of ROS by Cd. Consequently, Cd-elevated [Ca²⁺] ions induce ROS and also activates MAPK and mTOR pathways which lead to neuronal cell death.