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Iron Accumulation in Brain Detected With High-Resolution MRI Technique, Animal Study Shows

iron accumulation

An experimental model of Parkinson’s in non-human primates leads to the accumulation of iron — known to contribute to the underlying causes of the disease — in a brain area linked to motor control. This metal accumulation can be detected using a neuroimaging technique called susceptibility-weighted imaging, according to recent research.

The study, titled “The role of iron in Parkinson’s disease monkeys assessed by susceptibility weighted imaging and inductively coupled plasma mass spectrometry,” was published in Life Sciences.

Higher-than-usual iron levels have been found in a brain region — called the substantia nigra — in Parkinson’s patients. This brain area, which plays a key role in motor control, is particularly affected during the course of the neurodegenerative disease.

In non-human primates, scientists have observed that this iron accumulation is accompanied by the loss of neurons that produce the neurotransmitter dopamine. That chemical messenger is in short supply in Parkinson’s. Such high levels of iron also are thought to be correlated with an increased severity in motor deficits.

Various imaging techniques have been used to study Parkinson’s disease in distinct animal models and have been found to produce consistent results. However, such methods are rarely validated.

Now, using cynomolgus monkeys, or crab-eating macaques, researchers investigated the role of metal accumulation in the striatum and midbrain (both motor control areas) in Parkinson’s. The researchers evaluated the use of susceptibility-weighted imaging (SWI) to measure iron deposits in the brains of Parkinson’s monkeys.

SWI is a high-resolution magnetic resonance imaging (MRI) technique that is sensitive to the magnetic properties of blood, iron, and calcifications, or calcium build-up in the body. These substances disturb magnetic fields, producing a not-so-clear image in a standard MRI scenario. SWI provides a unique contrast, generating 3D high-spatial-resolution images.

The animals received a left-side carotid artery injection of MPTP, a neurotoxin that induces the death of dopamine-producing neurons and mimics Parkinson’s symptoms. The carotid artery is one of the arteries that supplies the brain with blood.

An SWI-MRI was performed before and after the monkeys had received the MPTP injections.

Around 4-to-6 days after the injection, the monkeys exhibited limb muscle stiffness and limb postural tremor, and lost the ability to move their muscles freely (called akinesia). Importantly, these effects were only observed on the body side opposite, or contralateral, to the injection’s site.

The MRI results indicated there were higher-than-usual iron deposits in the MPTP-lesion side of the substantia nigra compared with the opposite side in the same animal. Similar results were found when these animals were compared with the control group of monkeys, which had been injected with a saline solution. Despite this indication, statistical significance was not attained.

Nevertheless, “MPTP did not affect the iron levels in other brain regions of monkeys,” the researchers said.

Post-mortem analysis of brain samples revealed that MPTP treatment provoked the loss of dopamine-producing neurons in the substantia nigra. The scientists reported that approximately 67.4% of dopaminergic nerve cells were lost in the substantia nigra on the injection side, while 30.0% were lost in the contralateral (opposite) side.

Neuronal loss in the substantia nigra on the injection’s side was correlated with worse behavioral performance and with motor impairment.

Biochemical analysis showed that MPTP increased iron levels in the injection’s side of the animals’ midbrain, but not in the striatum. However, calcium and manganese levels, which have been previously linked to Parkinson’s molecular mechanism, were unaffected by MPTP treatment.

“Taken together, the results confirm the involvement of [substantia nigra] iron accumulations in the MPTP-treated monkey models for [Parkinson’s disease], and indirectly verify the usability of SWI for the measurement of iron deposition in the cerebral nuclei of [Parkinson’s disease],” the researchers concluded.

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Metabolism of Metals in Blood May Be Affected by Parkinson’s Disease, Study Says

blood and metal concentrations

Cooper concentrations are significantly affected in the blood serum of Parkinson’s patients, suggesting this metal metabolism could somewhat influence the mechanisms behind this neurodegenerative disorder, a study reports.

The results, “Assessment of copper, iron, zinc and manganese status and speciation in patients with Parkinson’s disease: A pilot study,” were published in the Journal of Trace Elements in Medicine and Biology.

Environmental factors are thought to contribute to Parkinson’s disease (PD). Metals such as copper, iron, zinc, and manganese are known to be neurotoxic. Evidence indicates that metal exposure can contribute to Parkinson’s-related neurodegeneration, mainly by modulating alpha-synuclein protein aggregation — one of the key events in the development of PD.

For instance, higher-than-usual iron levels have been found in a brain region important to motor control, called the substantia nigra, of Parkinson’s patients. This brain area is one of the most affected by the disease.

High levels of zinc and copper have also been found in the cerebrospinal fluid (surrounds the brain and spinal cord) of people with Parkinson’s. In addition, severe manganese overexposure can cause Parkinson’s-like symptoms. Manganese is a compound present in ground water.

Although metal exposure is known to play some role in neurodegeneration, available data on their trace amounts in Parkinson’s patients are rather contradictory.

A team of researchers in Russia assessed the levels of iron, copper, zinc, and manganese in the hair, blood serum, and urine of 13 patients, as well as the species of these metals in patients’ serum.

These 13 people (nine women and four men; mean age of 73.6) and 14 gender-matched healthy controls had their serum, urine, and hair metal content analyzed. Scientists also assessed the specific forms/species of iron, copper, zinc, and manganese that were present in participants’ serum samples.

Several exclusion criteria were used in the study to “decrease the impact of side factors.” Namely, these factors are the presence of other neurological disorders; being a vegetarian; endocrine (hormone imbalance) disorders; recurrent gastrointestinal problems; acute infectious, surgical and traumatic diseases;  metallic implants; smoking and alcohol use; and occupational or environmental exposure to metals.

While no significant differences were found in hair, urine and serum metal levels between these two groups, “a trend towards decreased hair (−22%) and urine (−41%) copper levels was observed in PD patients as compared to controls,” the researchers wrote.

Hair iron and manganese levels showed a tendency to rise in the Parkinson’s group: iron concentrations in patients exceeded those of controls by 24% and manganese levels by 21%.

Urine iron and zinc levels were 38% and 47% lower in the patient than control group. Blood serum metal levels were almost similar across the two.

In circulation, cooper is usually carried by ceruloplasmin, the major copper-carrying protein in the blood. This protein also plays a role in iron metabolism. In Parkinson’s, the binding of copper to ceruloplasmin is reduced, this way increasing the pool of free cooper available in the blood. Free cooper is thought to play a significant role in neurodegeneration, mainly by promoting oxidative stress: cellular damage as a consequence of high levels of oxidant molecules.

According to the researchers, “reduced ceruloplasmin levels may ultimately lead to increased iron sequestration in brain structures including substantia nigra.”

Speciation analysis — a process by which one can identify the quantities and concentrations of individual elements in a sample — revealed a significant decrease in the molecular binding of copper to ceruloplasmin, resulting in “a nearly ten-fold increase in serum free copper levels in PD patients.”

These results need to be interpreted carefully, as the levels of free copper in both groups were still within normal range, the researchers said.

Though metal speciation appears to be significantly affected in the serum of Parkinson’s patients, how these molecular changes impact the patients’ disease course remains to be understood.

The scientists believe that their “findings are indicative of the potential role of metal metabolism and PD pathogenesis [its origin and progression], although the exact mechanisms of such associations require further detailed studies.”

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High Levels of Zinc Found in Hair of Parkinson’s Patients with Depression, Psychiatric Symptoms, Study Says

zinc, depression, Parkinson's

Parkinson’s disease patients with either depression or psychiatric symptoms such as hallucinations, confusion, or illusion may have higher levels of the mineral zinc in their hair, researchers report.

Their study, “Higher zinc concentrations in hair of Parkinson’s disease are associated with psychotic complications and depression,” was published in the Journal of Neural Transmission.

Besides the typical motor symptoms, Parkinson’s patients may also experience non-motor symptoms such as cognitive impairment, sleep difficulties, depression, anxiety, and psychosis. Psychosis, although not fully understood, is common in Parkinson’s, particularly in its later stages. Symptoms include minor illusions, vivid dreams, occasional visual hallucinations, paranoia, and panic attacks.

Evidence indicates an imbalance of metal compounds is somewhat associated with Parkinson’s disease mechanism. In fact, too much iron has been found within patients’ substantia nigra and striatum — two brain regions involved in motor control that are extensively damaged in Parkinson’s — as well as in other peripheral tissues.

In this neurodegenerative disorder, calcium has also been suggested to play a role by promoting cellular death, while zinc may influence non-motor features of the disease.

These minerals are strongly correlated to psychiatric complaints and mood disorders in Parkinson’s, but the exact relationship between calcium, iron, and zinc levels in Parkinson’s patients with psychiatric complaints remains to be clarified.

Therefore, researchers at the University of Copenhagen in Denmark, along with collaborators in Brazil and Ireland, set out to investigate the link between these metal compounds and the co-occurrence of depression, anxiety, and psychotic symptoms in Parkinson’s disease.

Twenty-two patients (15 men and seven women, with a mean age of 69.8 years), who were registered in the 13th Regional Health Board in Jequié, Bahia (Brazil), had their mood and psychiatric complications assessed by clinically validated scales. Using the participants’ hair samples, scientists also quantified calcium, iron, and zinc levels.

To do so, the investigators applied a technique called flame atomic absorption spectroscopy (FAAS), which uses the absorption of electromagnetic radiation to measure the concentration of gas-phase atoms. The results were compared to 33 healthy individuals.

Significantly higher zinc levels were found to be correlated with depression or with one or more psychotic complications, including hallucinations, illusion, paranoid ideation (when the patient believes he or she is being harassed or persecuted), altered dream phenomenon, and confusion, compared with patients without these symptoms and healthy controls.

Altered concentrations of calcium and iron were not associated with Parkinson’s-related psychiatric disturbances.

Although the sample size was small, the study seemed to suggest that zinc levels could be a biomarker for psychiatric manifestations in Parkinson’s, and as such, a potential target for novel disease management therapies.

“FAAS is simple to implement, and low in cost, and as it can be used with a biological sample easy to obtain, such as hair, this methodology offers the real advantage of being feasible for a wide range of clinics to implement,” the team said, adding that further research and larger studies are still warranted.

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Lowering Iron Levels in Brain May Help Treat Parkinson’s, Trial in People with PKAN Says

deferiprone study

Binding to, or chelating, toxic levels of iron in the brain can slow the progression of a neurodegenerative disorder known as pantothenate kinase-associated neurodegeneration (PKAN), results from a Phase 3 trial show.

These findings may be relevant for other neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s and multiple sclerosis, which are also associated with high levels of iron in the brain, its researchers say.

The results, ”Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study,” were published in the journal The Lancet Neurology.

Iron is required for normal physiological functions; however, excessive levels can be toxic and abnormal high levels of iron are seen in several neurodegenerative diseases, from PKAN to Parkinson’s, Alzheimer’s, and MS.

Researchers conducted a Phase 3 trial (NCT01741532), called TIRCON, to evaluate the safety and efficacy of deferiprone in treating PKAN, a form of neurodegeneration that results in severe, involuntary muscle contractions (dystonia).

Deferiprone is an oral iron chelator approved to treat conditions linked with iron overload after blood transfusions in people with thalassemia, an inherited blood disorder characterized by lower levels of hemoglobin and fewer red blood cells.

The trial enrolled 88 patients with pantothenate kinase-associated neurodegeneration from four hospitals in Germany, Italy, England and the US. The participants, ages 4 and older, were randomized to deferiprone at 30 mg/kg a day (divided into two equal doses) or a placebo. Treatment was maintained for 18 months followed by an 18-month open-label extension phase, the TIRCON-Extension trial (NCT02174848).

Using magnetic resonance imaging (MRI) scans of the brain, researchers observed that treatment with deferiprone significantly lowered concentrations of iron in a specific part of the brain, called the globus pallidus, after 18 months compared to levels in the placebo group.

The globus pallidus is a region that is connect to several brain regions, and supports functions that include motivation, cognition and action.

These findings are in line with a previous Phase2/3 (NCT00943748) clinical trial’s results in Parkinson’s patients treated with deferiprone.

Treatment with deferiprone also decreased the number of PKAN patients who required other medications to control dystonia (11% compared to 21% in the placebo group). Slight, but not significant, improvements in disease progression with deferiprone treatment after 18 months were also seen compared to placebo. This was assessed using the Barry-Albright Dystonia (BAD) scale, which tests the severity of dystonia in eight different body regions.

This improvement appeared to be greater in a subset of later-onset patients with atypical pantothenate kinase-associated neurodegeneration, who had almost a 50% slower disease progression rate when treated with deferiprone compared to placebo. In placebo group patients who switched to deferiprone treatment in the TIRCON-extension trial, disease progression slowed by more than 60%.

Deferiprone appeared to be well-tolerated, with placebo and treatment groups reporting similar side effects. Anemia was the exception, as 21% of deferiprone treated patients reporting this side effect compared to no patients in the placebo group.

“The finding that brain iron can be markedly lowered by a chelator may have important implications also for age-associated neurodegenerative conditions such as Parkinson’s disease,” Thomas Klopstock, the Ludwig-Maximilians-University of Munich and the study’s first author, said in a news release.

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Osteonectin Protein May Play Role in Parkinson’s, Other Neurodegenerative Diseases

osteonectin

A protein called osteonectin may be implicated in Parkinson’s and other neurodegenerative diseases, according to a computer-based analysis.

The study, “In silico method for identification of novel copper and iron metabolism proteins in various neurodegenerative disorders,” was published  in the journal NeuroToxicology.

Excessive production of copper and iron leads to oxidative stress, which particularly affects the central nervous system. Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals or reactive oxygen species are harmful to the cells and are associated with a number of diseases, including Parkinson’s.

Altered copper and iron levels have been associated with neurodegenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s. Alpha-synuclein, the main component of Lewy bodies in Parkinson’s is itself a copper-binding protein, whose aggregation is promoted by both copper and iron.

However, the exact role of copper and iron toxicity in nerve cell death and disease progression remains unclear. A further challenge is the extensive network of interactions between metals and proteins, which changes with age, disease and treatment.

In this study, researchers used an approach called network biology to assess all proteins implicated in copper and iron metabolism with the goal of determining their interactions in different neurodegenerative diseases.

In total, the in silico (computer-based) assessment initially included 204 proteins implicated in copper, and 441 in iron metabolism. But these numbers increased to 1,175 and 2,529, respectively, after obtaining the protein-protein interaction networks. Also, there were 1,350 interactions related to copper and 7,233 related to iron proteins.

After searching for connections that could be part of a protein complex or pathway and merging the interaction networks of copper and iron to find common proteins, the investigators assessed their association with different diseases.

The results revealed that osteonectin and the clotting proteins factor V and VII could be involved in different neurodegenerative diseases. Specifically, osteonectin, a protein found at increased levels in cancer and with a protective role against oxidative stress, may be implicated in Parkinson’s, Alzheimer’s, and Huntington’s diseases, and neurodegeneration with brain iron accumulation disorders.

Expression of the SPARC gene, which codes for osteonectin, is found in different brain regions and has been associated with protection from neuroinflammation.

In turn, factor V may be involved in Brunner syndrome, obsessive-compulsive disorder, febrile seizures and schizophrenia, and factor VII in L1 syndrome and congenital hydrocephalus.

The literature on the links between clotting proteins and neurodegenerative diseases is scarce, researchers noted, although variants in F5, the gene coding for factor V, have been associated with Alzheimer’s.

“In conclusion, the present study shows the first evidence in silico that SPARC/osteonectin, Coagulation factor V and VII proteins may have plausible role in the pathogenesis of various neurodegenerative diseases,” researchers wrote.

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L‐DOPA Treatment Prevents Age-related Iron Accumulation, Mouse Study Finds

iron accumulation

Levodopa (L-DOPA) therapy is neuroprotective and prevents age-related iron accumulation in the substantia nigra, a brain region involved in Parkinson’s disease.

The study with that finding, “L-DOPA modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha-synuclein mouse models of Parkinson’s disease,” was published in the Journal of Neurochemistry.

L-DOPA is sill the primary pharmacological treatment for Parkinson’s disease motor symptoms. However, while the therapy provides symptom relief immediately following the onset of motor symptoms, during later stages of the disease certain non L-DOPA-responsive symptoms emerge that contribute to the rapid decline in quality of life.

Conflicting evidence also suggests the therapy may further damage dopamine-producing neurons due to the overproduction of reactive oxygen species, a molecular phenomenon known as oxidative stress.

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or reactive oxygen species, are harmful to the cells and are associated with a number of diseases, including Parkinson’s disease.

Several studies have established an association between iron build-up and both aging and neurodegenerative disorders like Parkinson’s disease. Apart from loss of dopamine-producing neurons, Parkinson’s also is characterized by pronounced iron accumulation in two brain regions: the globus pallidus and the substantia nigra.

It has been suggested that free iron molecules can induce dopamine oxidation and thus contribute to Parkinson’s disease development. Nonetheless, the exact mechanism of iron-induced dopaminergic degeneration is still unclear.

“Considering the substantial conflicts in the literature regarding whether L -DOPA is either neurotoxic or protective, and that [iron] has multiple well-established roles in both normal [dopamine] metabolism and neurotoxic oxidation,” researchers from the University of Melbourne, Australia, examined the effects of L -DOPA administration in three mouse models of Parkinson’s disease.

Mice fed with an iron solution from 10 to 17 days of age — mimicking early-life iron overexposure to accelerated age-related accumulation; a mouse model of Parkinson’s disease which over-expresses human A53T mutation (hA53T) in the alpha-synuclein protein, mimicking disrupted dopamine metabolism; and a mouse model combining these two experimental paradigms, i.e., hA53T transgenic iron-fed mice.

Animals were given L-DOPA in their drinking water from three to eight months of age. Researchers analyzed the therapy’s effect on brain iron levels, nerve cell numbers and motor function prior to the equivalent onset of clinical symptoms, in comparison to mice fed with clioquinol spiked food for the same period of time.

Clioquinol is a compound that binds to iron molecules suppressing their (harmful) chemical activity. Studies demonstrate clioquinol is beneficial in animal models of three neurodegenerative disorders: Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.

Results revealed L-DOPA did not increase neurotoxicity in any of the mouse models and prevented age-related iron accumulation in the substantia nigra, much like clioquinol.

In addition, researchers observed a potential neuroprotective effect, as in both the iron overload and the hA53T mouse models L-DOPA treatment significantly reduced iron levels in the substantia nigra, decreased protein carbonyls (biomarkers of oxidative stress), and prevented neurodegeneration.

“Chronic L -DOPA treatment showed no evidence of increased oxidative stress in [normal mice] midbrain and [normalized] motor performance, when excess [iron] was present,” researchers wrote.

Additionally, L-DOPA did not increase protein oxidation levels in hA53T mice, with or without excess iron accumulation in the substantia nigra, and showed evidence of neuroprotection.

At eight months, total iron levels did not increase in hA53T mice that did not receive L-DOPA, suggesting the mutant alpha-synuclein does not itself trigger harmful iron accumulation.

“When challenged with excess [iron] during a critical window of neurodevelopment [10-17 days of age], hA53T mice showed the expected increase in nigral [iron]. Interestingly, excess [iron] did not worsen or accelerate neuropathology,” researchers wrote.

Similar to clioquinol, L -DOPA was able to mitigate oxidative damage from excessive iron accumulation. This effect was not as pronounced in hA53T expressing mice, which are more susceptible to oxidative damage from iron exposure.

These findings suggest that alpha-synuclein dysfunction could be behind iron-mediated dopamine oxidation, with the latter being an early sign of parkinsonian neurodegeneration.

“We found no evidence in any of our model systems that L-DOPA treatment accentuated neurodegeneration, suggesting [dopamine] replacement therapy does not contribute to oxidative stress in the Parkinson’s disease brain,” researchers concluded.

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Nicotine May Protect the Brain from Toxic Trace Metals Linked to Parkinson’s, Cell Study Finds

nicotine study

Nicotine may protect the brain from manganese and iron metal trace elements thought to be involved in the onset of Parkinson’s disease, a study based on a disease cell model reported.

The study, “Nicotine protects against manganese and iron-induced toxicity in SH-SY5Y cells: Implication for Parkinson’s disease,” was published in Neurochemistry International.

Parkinson’s is characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — leading to motor and cognitive impairments.

Although the exact causes of Parkinson’s are not yet fully understood, scientists believe the accumulation of metal trace elements, such as manganese and iron, could play a role in its onset. At low concentrations, these elements are crucial for cell growth and physiological functions; indeed, they are important for all growth and healthy workings of the body. But at high levels, they become toxic, and have been associated with several neurodegenerative disorders, including Parkinson’s.

Nicotine, a potent stimulant originally found in plants that activates the nicotinic acetylcholine receptor (nAChR) in the brain, has been shown to protect dopaminergic neurons from damage caused by different types of toxins. However, no study had addressed possible neuroprotective effects of nicotine against specific metal trace elements.

The new study from Howard University College of Medicine examined the effects of nicotine on toxic manganese and iron elements in a neuroblastoma cell line (SH-SY5Y), a standard in vitro model to study Parkinson’s disease cells, due to their dopaminergic activity.

When researchers exposed SH-SY5Y cells to high concentrations of manganese or iron for a day, toxicity levels increased by 30% and 35%, respectively. Pretreatment with nicotine was seen to completely prevent these toxic effects.

As expected, nicotine’s neuroprotective properties against toxic trace elements were lost when researchers used different types of nicotinic receptor antagonists (molecules that block the activity of nAChRs). This was true for “dihydro-beta erythroidine (DHBE), a selective alpha4-beta2 subtype antagonist and methyllycaconitine (MLA), a selective alpha7 antagonist,” the study noted.  

“In summary, the results of this study provide evidence for neuroprotective effects of nicotine against toxicity induced by Mn [manganese] or Fe [iron] in a cellular model of PD [Parkinson’s disease],” the researchers wrote.

“Moreover, both high and low affinity nicotinic receptors (i.e., alpha4-beta2 and alpha7 subtypes) appear to mediate the effects of nicotine. Thus, utility of nicotine or nicotinic agonists in trace element-induced Parkinson-like syndrome may be suggested,” they concluded.

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