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Parkinson’s Disease - Effects In Rodent Models And MR Methods

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Parkinson's disease is a debilitating neurological condition that affects somewhere between 7 and 10 million people around the world.

This disease is characterized by extensive death of dopaminergic (DA) neurons, the presence of Lewy body inclusions that contain synuclein proteins in the substantia nigra pars compacta (SNc), and neuroinflammation.

When there is a decrease in the amount of dopamine (DA) in the striatum (STR), patients may have clinical symptoms such as akinesia, rigidity, and tremor.

A clinical diagnosis cannot be established until at least fifty percent of those neurons have been affected by the disease.

Fewer than 10 percent of instances of Parkinson's disease are caused by family mutations, despite the fact that most forms of the illness are sporadic.

COPYRIGHT_WI: Published on https://washingtonindependent.com/ebv/parkinsons-disease/ by Rian Mcconnell on 2022-08-20T23:36:30.096Z

Mutations in the leucin-rich repeat kinase 2 (LRRK2) and the α-synuclein coding gene (SNCA) are responsible for autosomal-dominant Parkinson's disease (PD), while mutations in the Parkin (PARK2), phosphatase and tensin (PTEN)-induced kinase 1 (PINK1), and DJ-1 genes are responsible for autosomal-recessive Parkinson's disease

The basal ganglia (BG) are comprised of the dorsal STR, the GP interna and externa, the SNc, the substantia nigra pars reticulata (SNr), the thalamus (TH), and the subthalamic nuclei (STN).

Excitatory glutamatergic (Glu) inputs come from the cortex, while inhibitory γ-aminobutyric acid (GABA) neurotransmitters are employed by projection neurons from the SN and GP to the TH. The dorsal STR receives these inputs.

Rodent Models

The 6-OHDA Model

In animals, the neurotoxin 6-OHDA was used as a denervation tool when it was revealed that it could induce selective degeneration of sympathetic adrenergic neurons.

This discovery came about as a result of previous research.

6-OHDA is a hydroxylated analog of DA that enters DA neurons using the same transporters that DA uses.

When it reaches the cytosol, it immediately begins to auto-oxidize, which results in the production of hydrogen peroxide.

Because 6-OHDA does not cross the blood-brain barrier (BBB), it can only be administered to the brain by stereotaxic injections.

These injections are necessary for research purposes.

The use of unilateral injections has been advocated over bilateral injections due to the increased mortality risk that is linked with the latter.

The mechanism of action is going to be different depending on where in the nigrostriatal pathway the injection is going to be placed.

Injections into the SNc or the MFB produce broad and rapid anterograde degeneration of the nigral DA neurons, as well as up to 90–100% of the SN and striatal neurons, and ultimately the whole nigrostriatal pathway. This occurs within days.

In contrast, injections into the dorsal STR cause partial lesions of the nigral DA neurons, leading to a loss of between 50 and 70% of these neurons within four to six weeks.

This leads to progressive retrograde degeneration of the nigrostriatal pathway, which more closely mimics human pathology and enables longitudinal evaluations.

When 6-OHDA is infused intrastriatal into rats, it causes a depletion of dopamine (DA) in the STR that is more than 90%.

A little black rat in the woods with a nut in its mouth
A little black rat in the woods with a nut in its mouth

The Mitochondrial Permeability Transition Pore (MPTP) Model

The selective toxicity of MPTP for the nigrostriatal tract was initially described by Langston and colleagues.

MPTP undergoes a transformation in the DA transporters to become 1-methyl-4-phenylpyridinium ion, or MPP+, and then accumulates in SNc neurons.

Since MPTP is able to traverse the BBB, it may be delivered to patients through the peripheral nervous system.

However, therapy with systemic MPTP fails in rats because conversion of MPTP to MPP+ happens at the BBB, which blocks influx into the brain; hence, treatment with systemic MPTP is used in mice instead.

Repeated intraperitoneal injections in mice result in the death of DA neurons in a manner that is both rapid and severe.

This causes the mice to exhibit symptoms that are similar to those seen in humans and include akinesia, stiffness, and tremor episodes.

Autosomal-Dominant Models

The LRRK2 gene is the one most likely to be altered in patients with autosomal dominant Parkinson's disease.

This particular kinase enzyme may be found in membranes and has a role in the activity of mitochondria, as well as autophagy and endocytosis.

Transgenic animals have very little to no DA neurodegeneration; nonetheless, the majority of them have nigrostriatal system abnormalities, α-synuclein aggregation, or decreased DA release.

This is because transgenic animals lack the gene that encodes for the DA protein.

In a similar vein, animals with a mutation in LRRK2 display alterations in behavior rather than DA neurotoxicity in the SN.

The presynaptic α-synuclein protein, which is found in high concentrations in the brain, is encoded by the SNCA gene.

It is not understood what its function is; nevertheless, it is believed to play a part in the functioning of synaptic vesicles and, therefore, in the release of neurotransmitters.

When α-synuclein is overexpressed in mice, a range of problems might emerge depending on the promoters that are used for the transgenic production of the protein.

Some of them still have problems with their nigrostriatal circuitry, despite the fact that they do not have DA deterioration.

Autosomal–Recessive Models

Patients who have mutations in the Parkin (PARK2) gene, which acts as an E3 ubiquitin ligase in the ubiquitin proteasome system, suffer from a loss of function.

There is no evidence that nigrostriatal or DA lesions occur in animals lacking the parkin gene.

The overexpression of a mutated form of this gene, on the other hand, causes a decrease in the amount of dopamine (DA) that is produced in the striatum of mice, as well as the loss of synapses in the nigral region.

In a similar manner, overexpression of Parkin leads to a mild form of neurodegeneration in rats.

PINK1 is a protein kinase found in mitochondria, and it defends neurons against the damage that may be caused by mitochondrial dysfunction.

The PINK1 mutation is responsible for patients' loss of function, which is mostly shown in the kinase domain.

Although DA neuronal depletion is not seen in PINK1 knockout mice, this mutation does disrupt DA neurotransmission as well as the function of mitochondria.

Animals with a PINK1 gene deletion, on the other hand, have a loss of SN DA neurons, an accumulation of alpha-synuclein, mitochondrial abnormalities, and motor dysfunction.

Parkinson's Disease, Causes, Signs and Symptoms, Diagnosis and Treatment.

Neurodegeneration Evaluation MR Methods

Diffusion Imaging

Because of random Brownian motion, water molecules move in an unconstrained medium in a manner that is both random and free.

Its mobility may be hampered by a variety of factors, including membranes, extracellular impediment, and tissue heterogeneity.

Because technique makes use of diffusion gradients, diffusion-weighted imaging is very sensitive to the movement of water.

An effect known as anisotropy causes water molecules to diffuse along a preferred route along the fibers in white matter.

This occurs because the fiber bundles in white matter function as physical limitations.

The diffusion tensor model, which is a model of water molecule displacement, is able to provide indices such as the MD, which characterizes the overall displacement of water molecules; the fractional anisotropy (FA), which characterizes diffusion orientation; and the eigenvalues, which characterize the main directions of diffusivities, also derived as axial and radial diffusivities.

These indices can be used to characterize the overall displacement of water molecules (AD, RD).

It has been shown that modifications in AD can be used to evaluate axonal injury, whilst alterations in RD can be used to assess myelin damage.

This is despite the fact that the biological basis of anisotropy is complicated and uncertain.

In firmly oriented fiber bundles, the FA is rather high (close to 1), whereas it is relatively low in crossing fiber regions (close to 0).

Functional Imaging

The term "functional connectivity," often referred to as "synchrony," describes the temporal connections between neurophysiological activities that occur across vast distances.

fMRI may be used to detect low-frequency, spontaneous, and sometimes coherent signal changes in the brain when it is at rest.

Therefore, Rs-fMRI studies have shown co-activation in scattered networks of cortical and subcortical regions that represent functional brain networks.

Such interconnectedness could or might not have a structural connection.

The bulk of PD imaging has been done when people and animal models are at rest.

The nigrostriatal pathway's functional connectivity changes have been studied in animal models.

FC was shown to be decreased in the ipsilateral cortices and interhemispheric STR of 6-OHDA rats.

The animals were sedated either with isoflurane and medetomidine (prior research) or with medetomidine alone during imaging (later study).

Reduced FC was also seen between the contralateral TH and ipsilateral primary motor cortex (M1) in the intrastriatal 6-OHDA model with isoflurane alone.

Reduced FC was also discovered by Zhurakovskaya et al. in the corticocortical and striatocortical connections of 6-OHDA-injected rats when they were under urethane anesthesia.

Commonly, reduced FC is thought to have a direct lesioning effect.

MR Methods For Iron Accumulation Evaluation

T2∗ Imaging

The SN of MPTP and 6-OHDA-lesioned animals shows iron buildup.

Iron deposits may be found using conventional T2∗ imaging.

For instance, Olmedo et al. assessed the levels of hyposignal in the SN of 6-OHDA rats 1 and 4 weeks after injection in the MFB.

In comparison to sham rats, 6-OHDA animals showed significantly more hypointense pixels (lower T2∗ signal), which were linked to iron staining with Prussian blue after 4 weeks.

In addition, following intrastriatal injections, Virel et al. found iron accumulation in the STR of 6-OHDA rats.

In this study, greater T2∗ hypointensities (i.e., lower T2∗ signal) were seen in the ipsilateral STR starting 1 week after the lesion and persisting up to 4 weeks.

At 4 weeks, they also discovered iron accumulation indicated by Prussian blue staining, connections between such hypointensities and edematous hyperintensities, and other findings.

The SN, on the other hand, was preserved since its depletion was slower and gentler at this later period.

Susceptibility Imaging

To improve imaging of the SN nigrosomes, STN, and GP interna, two additional iron-sensitive MRI methods have been used: susceptibility-weighted imaging (SWI) and quantitative susceptibility mapping (QSM).

In SWI techniques, variations in susceptibility across tissues are identified using phase data, which is combined with magnitude data to improve image contrast.

In order to assess the increased iron accumulation in Parkinson's disease patients' deep gray nuclei, SWI was employed.

By converting phase shifts, QSM is a relatively new technique for locating magnetic susceptibility.

Elevated QSM in the SN of an MPTP mouse model has been found, despite the paucity of research on PD rodent model applications.

Additionally, this research demonstrated that QSM was a more reliable method than R2∗ for identifying iron-related changes in the SN, which was supported by a study including individuals with Parkinson's disease.

In order to image the mouse brain microstructure at an incredibly high resolution, QSM methods have advanced to the point where striatal tracts can now be recreated at a resolution of 20 m utilizing QSM images from postmortem brains.

This means that it may be used for PD model applications.

A black rat sitting on the floor while eating littel slices of food
A black rat sitting on the floor while eating littel slices of food

MR Spectroscopy For Metabolism Evaluation

Magnetic resonance spectroscopy is based on effects such as spin-spin coupling and chemical shift.

Different nuclei have different resonance frequencies depending on their chemical surroundings and nearby magnetic fields.

Their chemical shift is expressed in parts per million (ppm) with respect to the reference material, tetramethylsilane.

Parkinson's disease model brain metabolic changes have been examined using magnetic resonance spectroscopy.

For instance, higher GABA levels have been seen in the STR of MPTP mice and 6-OHDA rats who received MFB injections.

These results were consistent with research on humans, which showed that patients' pons, putamen, and SN had increased GABA levels.

The following mechanism might account for those findings: the STR receives DA projections from the SNc, and because DA inhibits GABAergic spiny neurons via D2 receptors in the STR, DA denervation should result in an overactivation of those neurons.

Similar to greater Glu levels in the SN of Parkinson's disease patients, it was shown that Glu and glutamine (Gln) levels were higher in the STR of MPTP animals.

According to Chassain et al., the increase in Glu that alters corticostriatal activity is due to an accelerated synthesis and release of Glu in the synaptic terminal of the STR.

Glu levels were shown to be lower in the STR of 6-OHDA animals that had been injected in the MFB.

People Also Ask

What Causes Parkinson's Disease?

A reduction in the number of nerve cells in the region of the brain known as the substantia nigra is the root cause of Parkinson's disease.

Dopamine is a neurotransmitter that is produced in this region of the brain by nerve cells that are important for reward and motivation.

What Is Another Name For Parkinson Disease?

Parkinson disease, also known as primary parkinsonism, paralysis agitans, or idiopathic parkinsonism, is a degenerative neurological disorder that is characterized by the onset of tremor, muscle rigidity, slowness in movement (bradykinesia), and stooped posture.

Other names for Parkinson disease include primary parkinsonism, paralysis agitans, and idiopathic parkinsonism (postural instability).

What Are The Four Cardinal Signs Of Parkinson's Disease?

Parkinson's disease (PD) is one of the most common neurological illnesses.

It is defined by four cardinal signs: tremor, bradykinesia, rigidity, and postural instability.

What's The Difference Between Parkinson's Disease And Parkinson's Syndrome?

It might be difficult to tell the difference between Parkinson's disease and other forms of Parkinsonism.

As more information about the symptoms becomes available, doctors could find they need to alter their diagnosis over time.

While Parkinson's disease (PD) often affects just one side of the body more than the other, Parkinsonisms typically do not contain tremors and do affect both sides of the body.

Conclusion

Because genetic models for the great majority of brain alterations do not include neurodegeneration, symptomatic evaluations are restricted.

At the injection site of toxic models, several kinds of degeneration may occur, such as extensive or partial, rapid or progressive, and the MR measurements may be impacted by these various forms of degeneration.

For example, vast or partial degeneration may occur.

The discrepancies that can be seen in the scientific literature are the result of a number of reasons, one of which is the accumulation of iron in the subthalamic nucleus (SN) and other regions of the brain that are thought to be involved in Parkinson's disease.

In research involving both humans and animals, multimodal imaging that takes into account both susceptibility and diffusion sequences could prove to be helpful in disentangling the connection between iron and water diffusivity.

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About The Authors

Rian Mcconnell

Rian Mcconnell - Rian is a Villanova University graduate who was born in DuBois, Pennsylvania. He graduated from Thomas Jefferson University in Philadelphia with a medical degree. His residency was at Thomas Jefferson and its associated Wills Eye Hospital, and he finished his education with fellowships in cataract and corneal surgery at the University of Connecticut. He has a vast experience in ophthalmic surgery, with a focus on cataract surgery, corneal transplantation, and laser refractive procedures. He serves on the board of Vision Health International, an agency that provides eye care and surgery to indigent patients in Central and South America, in addition to his surgical practice.

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