Parkinson's Disease (A*)

Question 1

Give an overview of the function of the basal ganglia.

How does the function of the basal ganglia change in Parkinson’s disease?

Answer 1

• The basal ganglia is the hub for all motor activity.
• It involves a functional equilibrium between the inhibitory indirect and facilitatory direct circuits.
• In Parkinson’s disease, the dopamine insufficiency shifts the balance towards the indirect circuit, resulting in reduced movement initiation and bradykinesia.
• Currently, there is no adequate explanation for tremor or rigidity.

Question 2

What is the difference between Parkinsonism and Parkinson’s disease?

Answer 2

• Parkinsonism is a clinical syndrome involving bradykinesia, tremor, rigidity and loss of postural reflexes.
• This syndrome is present in many neurological disorders.
• Parkinson’s disease is an age-related neurodegenerative disorder, of which Parkinsonism is the main feature.
• Parkinson’s disease is one of the two types of Lewy body dementia (LBD), the other being dementia with Lewy bodies (DLB).
• Parkinson’s disease also includes non-motor symptoms such as depression, loss of smell, gastric problems and behavioural changes that reflect negative symptoms of schizophrenia (see A* card 24 for details on cognitive changes).

Question 3

What is the aetiology of Parkinson’s disease?

Answer 3

• About 10% of cases of Parkinson’s disease have autosomal dominant / recessive genetic origins (e.g. mutations in alpha-synuclein).
• These cases generally have early onset.
• There is no known cause for the other 90% of cases, which have late onset.

Question 4

List 5 atypical Parkinsonian disorders.

Answer 4

Atypical Parkinsonian disorders:

1 - Cerebellar type multiple-system atrophy.

2 - Parkinson type multiple-system atrophy.

3 - Progressive supranuclear palsy.

4 - Corticobasal ganglionic degeneration.

5 - Frontotemporal dementia.

Question 5

List 5 secondary causes of Parkinsonism.

Answer 5

Secondary causes of Parkinsonism:

1 - Drug-induced.

2 - Tumors.

3 - Infection.

4 - Vascular (stroke).

5 - Hydrocephalus.

Question 6

How can the substantia nigra be identified on an MRI in Parkinson’s disease and in a healthy brain?

What is the role of imaging in the diagnosis of Parkinson’s disease?

Answer 6

• On a normal MRI, the substantia nigra appear as two thick dark lines in the ventral midbrain.
• In Parkinson’s disease, the black lines are either missing or faded.
• Parkinson’s disease is diagnosed on the basis of clinical symptoms, not using imaging (imaging is just a research tool in Parkinson’s disease).

Question 7

List 3 histopathological features of Parkinson’s disease.

Answer 7

Histopathological features of Parkinson’s disease:

1 - Loss of cells in the substantia nigra.

2 - Lewy body inclusions in the cells of substantia nigra.

3 - Lewy neurites.

Question 8

What is the primary component of Lewy body inclusions?

What is the primary component of Lewy neurites?

How do Lewy neurites form?

Answer 8

• The primary component of Lewy body inclusions is ubiquitin, but also contains alpha synuclein.
• The primary component of Lewy neurites is alpha-synuclein.
• There is evidence that alpha-synuclein can be taken up into neurones from the extracellular environment, implying that alpha-synuclein can spread between cells like an infection. This opposes the original idea that alpha-synuclein was formed in a generative process that a cell suffers internally.

Question 9

What staging system is used for Parkinson’s disease?

What are the stages?

Why is this system controversial?

Answer 9

• Braak staging is used for staging Parkinson’s disease. The stages describe distribution of Lewy bodies:

1 and 2 - Brainstem and olfactory bulb.

3 - Substantia nigra and amygdala.

4 - Limbic system, esp. hippocampus.

5 and 6 - Higher cortical regions.

• This staging system is controversial because some patients develop motor symptoms and cognitive deficits but the lewy bodies are confined to the brainstem. The cognitive deficits in these patients are thought to be due to Alzheimer’s-like pathology.
• This suggests that it is not always spread of Lewy bodies / Lewy neurites that contributes to Parkinson’s disease.

Question 10

What is the difference between frontotemporal dementia with Parkinson’s disease and Parkinson’s disease with dementia?

Answer 10

• Clinically, the difference between frontotemporal dementia with Parkinson’s disease and Parkinson’s disease with dementia is the timing of symptoms.
• If dementia symptoms appear first, it is likely frontotemporal dementia with Parkinson’s disease.
• If Parkinsonism appears first, it is likely Parkinson’s disease with dementia.
• Otherwise, the symptoms are very similar.
• In frontotemporal dementia, the dementia can be attributed to tau, whereas in Parkinson’s disease with dementia, the dementia can be attributed to alpha-synuclein (Lewy neurites).

Question 11

What is the relationship between Lewy body load and severity of dementia in Parkinson’s disease with dementia?

Answer 11

There is no correlation between Lewy body load and severity of dementia in Parkinson’s disease with dementia.

Question 12

List 7 risk factors for Parkinson’s disease.

Answer 12

Risk factors for Parkinson’s disease:

1 - Family history (in 10% of cases).

2 - Male gender.

3 - Herbicides (such as rotenone - which is used experimentally to induce alpha synuclein accumulation).

4 - Heavy metals, e.g. manganese and iron.

5 - Trauma.

6 - Emotional stress.

7 - Old age.

Question 13

What is known about the pathogenesis of Parkinson’s disease?

Answer 13

• Current understanding is that the pathogenesis is a ‘double hit’, i.e. both genetic susceptibility and exposure to an environmental factor is required.
• The consequence of this ‘double hit’ is protein misfolding and accumulation, leading to:

1 - Lewy body formation.

2 - Lewy neurite formation.

3 - Mitochondrial dysfunction.

These consequences contribute to cell death by:

1 - Promoting inflammation.

2 - Promoting excitotoxicity.

3 - Promoting oxidative stress.

• These processes can positively feedback on lewy body / neurite formation and mitochondrial dysfunction.

Question 14

List 5 advantages and 2 disadvantages of deep brain surgery for Parkinson’s disease.

Answer 14

Advantages / disadvantages for deep brain surgery for Parkinson’s disease:

Advantages:

1 - Improves the total unified Parkinson’s disease rating scale (UPDRS).

2 - Improves motor functions.

3 - Reduces complications of dopamine therapy, e.g. dyskinesias.

4 - Reduces requirement of dopamine therapy by 33%.

5 - Doesn’t affect cognition.

Disadvantages:

1 - Causes a decline in verbal fluency and vocabulary.

2 - General risk of adverse events with surgery.

Question 15

Give an example of a novel treatment for Parkinson’s disease.

How does it work?

How effective is it?

Answer 15

• Neural transplantation is a novel treatment for Parkinson’s disease.
• It involves either porcine neural xenografts or human foetal stem cell allografts being implanted into the substantia nigra.
• The treatment is successful in some patients, but success is inconsistent (in the few patients that have been trialled) and there are sometimes complications of dyskinesia after transplantation.
• There are also some cases of Lewy body formation following transplantation.
• There are also ethical concerns, e.g. over the source of donor tissue.

Question 16

A*:

What is the prevalence of Parkinson’s disease in the UK?

What is the average age of onset?

Answer 16

From National Health Service (2020):

• Approximately 145,000 people have Parkinson’s disease in the UK. NICE estimates that Parkinson’s disease affects 2% of all individuals aged 80 and above.
• This number is growing due to population ageing, as the majority of Parkinson’s disease patients first experience symptoms over the age of 50. Only in 5% of cases are symptoms experienced before the age of 40.

Question 17

A*:

Describe the treatment pathway of Parkinson’s disease.

Give examples of each drug.

Why do dopamine replacement therapies cause impulsive behaviour?

Answer 17

Treatment pathway of Parkinson’s disease:

1 - Before dopamine replacement, a MAO-B inhibitor is given.

• MAO-B inhibitors include the reversible inhibitors rasagiline and selegiline and the reversible inhibitor safinamide.

2 - If symptoms cannot be controlled with rasagiline, L-DOPA is given in combination with a DOPA decarboxylase (AADC) inhibitor.

• Discontinuous administration of L-DOPA is thought to contribute to L-DOPA-induced dyskinesia, as this leads to nonphysiological pulsatile behaviour of the basal ganglia. Hence, there is a need for L-DOPA treatments that provide continuous infusion, and this has been addressed by the development of subcutaneous pumps and percutaneous gastrojejunostomy tubes.
• DOPA decarboxylase (AADC) inhibitors include benserazide and carbidopa.
• DOPA decarboxylase (AADC) converts L-DOPA into dopamine. DOPA decarboxylase inhibitors increase peripheral half-life of L-DOPA (as the inhibitors are unable to cross the BBB), increasing bioavailability in the CNS and reducing dopamine production in the periphery (which would result in adverse effects - see dopamine deck for peripheral functions). These drugs are usually included in preparations of L-DOPA.

3 - As the disease progresses, Levodopa will begin to fail. When this happens, a combination therapy of Levodopa and a dopamine agonist / COMT inhibitor / MAO-B inhibitor is given.

• COMT inhibitors include entacapone, opicapone and tolcapone.
• When DOPA decarboxylase inhibitors are administered, the metabolism of L-DOPA in the periphery shifts from DOPA decarboxylase to COMT, which converts L-DOPA into 3-O-Methyldopa. hence, COMT inhibitors serve to further increase central bioavailability of L-DOPA.

4 - Dopamine agonists include rotigotine and apomorphine.

• Apomorphine is particularly useful due to its potency at both D1 and D2 receptors.
• However, dopamine agonists have a lower efficacy than L-DOPA.
• Dopamine agonists and L-DOPA are thought to cause impulsive behaviour due to their action at ventral striatal D3 receptors, resulting in overstimulation of the mesolimbic reward pathway.
• Failing drug treatment, bilateral deep brain stimulation can be carried out on the globus pallidus interna or subthalamic nucleus.

Question 18

A*:

Give an overview of the anatomy of the basal ganglia and its connections with the brain.

How does the anatomy change with Parkinson’s disease?

Answer 18

From Lanciego et al., 2012:

Anatomy of the basal ganglia and its connections with the brain:

The basal ganglia are divisible into input, intrinsic and output nuclei:

1 - Input nuclei include the striatum, which includes the ventral striatum (consisting of the nucleus accumbens) and the dorsal striatum (consisting of the caudate and putamen).

2 - Intrinsic nuclei include the globus pallidus externus, the subthalamic nucleus and the substantia nigra pars compacta.

3 - Output nuclei include the substantia nigra pars reticulata and the globus pallidus internus.

Input nuclei (striatum):

• Striatal neurones are further divisible into projection neurones (90%) and interneurones (10%).

1 - Medium-sized spiny neurones, AKA projection neurones / striatofugal neurones.

• MSNs are GABAergic multipolar neurones that have spine-covered dendritic processes.
• MSNs are further divisible into those targeting the direct or indirect pathways, as described later on.

2 - Interneurones.

• Striatal interneurones are further divisible into 4 types (1 cholinergic and 3 GABAergic), of which all have smooth (aspiny) dendritic processes and receive modulatory dopaminergic input from the SNc.
• Tonically active neurones (TANs) are a cholinergic type of striatal interneurone, so called for their uninterrupted pattern of action potential firing.
• The first GABAergic striatal interneurones are fast-spiking interneurones (FSIs), so called for their discontinuous and fast firing pattern. They are characterised by their expression of parvalbumin, a Ca2+-binding protein.
• The second GABAergic striatal interneurones are calretinin-positive interneurones.
• The third GABAergic striatal interneurones are nitrergic interneurones, so called for their use of nitric oxide.
• Calretinin-positive and nitrergic striatal interneurones innervate TANs and FSIs, which in turn exert a neuromodulatory effect on MSNs.
• The striatum is compartmentalised into striosomes and a matrix, both of which contain MSNs that each innervate different basal ganglia nuclei and receive afferent input from the rest of the brain.
• Striosomes are characterised by the presence of GABA, neurotensin, enkephalin and substance P. MSNs in striosomes primarily innervate the SNc.
• Striosomes receive glutamatergic afferent input from limbic cortical regions and the basolateral amygdala. They also receive some dopaminergic input from the SNc and also serotonergic input from the raphe nuclei.
• The matrix is characterised by the presence of calbindin and parvalbumin. MSNs in matrices primarily innervate the GPe, SNr and GPi.
• The matrix receives glutamatergic afferent input from the thalamus and the sensorimotor regions of the cortex. The matrix also receives most of the striatal dopaminergic input from the SNc.
• Hence, the striatum receives glutamatergic input from corticostriatal networks, the amygdala and thalamostriatal networks, dopaminergic input from nigrostriatal networks and serotonergic input from the raphe nuclei.
• Serotonergic striatal input is thought to play a role in the pathogenesis of L-Dopa-induced dyskinesia, and also in dyskinesia resulting as a complication from neural transplantation (see card 15 for details).

Intrinsic nuclei:

• The direct pathway MSNs of the striatum send direct GABAergic inhibitory efferents to the output nuclei, GPi and SNr, and express excitatory D1 receptors, substance P and dynorphin.
• The overall effect of the direct pathway is inhibition of the output nuclei.
• The indirect pathway MSNs of the striatum send GABAergic inhibitory eferents to the GPe, and express inhibitory D2 receptors and enkephalin.
• The GPe, which can be identified by its high expression of 2A adenosine receptors, sends inhibitory GABAergic efferents to the STN, and the STN sends reciprocal excitatory glutamatergic projections back to the GPe.
• The STN sends excitatory glutamatergic efferents to the output nuclei, GPi / SNr (and also reciprocal efferents to the GPe as described above). As well as receiving inhibitory GABAergic input from the GPe, the STN also receives excitatory glutamatergic input from the cortex and thalamus.
• The overall effect of the indirect pathway is excitation of the output nuclei.
• There is a constant functional equilibrium between the direct and indirect pathways.
• There is controversy regarding whether these populations of MSNs form distinct groups in the striatum (or if they are interspersed) and selectively express either D1 or D2 receptors.
• Some argue that D1 and D2 receptors are coexpressed in MSNs, and that the two populations differ in the cellular distribution of the receptors.
• However, only small numbers of striatal MSNs have actually been shown to coexpress D1 and D2 receptors (Betrán-González et al., 2008), making it likely that differences in D1R/D2R expression is the primary differentiator between direct and indirect MSNs.
• Dopamine released by the SNc shifts the equilibrium towards the direct pathway. It excites the direct pathway through excitatory D1 receptors on striatal MSNs, and inhibits the indirect pathway through inhibitory D2 receptors on striatal MSNs.
• Dopamine release by the SNc therefore results in an increase in inhibition of the output nuclei which, as described below, promotes movement.

Output nuclei:

• The output of the basal ganglia is composed of pallidothalamic (from the GPi) and nigrothalamic (from the SNr) neurones, which both innervate different regions of the ventral anterior motor thalamus:
• The pallidothalamic neurones send inhibitory GABAergic neurones to the parvicellular and densicellular regions.
• The nigrothalamic neurones send inhibitory GABAergic neurones to the magnocellular region.
• Activity of the output nuclei produces a relative hypokinesia and bradykinesia (BUT see A* card 21).

• In Parkinson’s disease, the SNc degenerates. The resulting dopamine insufficiency leads to disinhibition of the indirect pathway and a reduction in excitation of the direct pathway.
• Therefore, in Parkinson’s disease, there is a shift of the balance towards the indirect circuit, resulting in hypokinetic (poverty of involuntary motor activity) and bradykinetic (slow voluntary motor activity) motor symptoms.
• This is confounded by the fact that SNc degeneration results in sensitisation of the basal ganglia to afferent input, resulting in poor capacity to filter information from other brain regions. Dopaminergic input from nigrostriatal neurones is important for both direct neuromodulation of the basal ganglia through its effect at input nuclei and indirect modulation of the basal ganglia through TAN and FSI interneurones, which are thought to play a role in enhancing the signal-to-noise ratio of corticostriatal input.

Question 19

A*:

Give an example of a paradox that challenges the current understanding of the functioning of the basal ganglia.

Answer 19

• A paradox that challenges the current understanding of the basal ganglia is that lesioning of the basal ganglia improves drug-induced dyskinesias in humans and monkeys (Lozano et al., 1995).
• This is counterintuitive since basal ganglia output is inhibitory to movement, therefore it would be expected that lesioning of the basal ganglia would result in a disinhibition of movement, and therefore induce or worsen dyskinesia.
• Similarly, Obeso et al. (2009) found that lesioning of the output nuclei of the basal ganglia and the thalamus has been shown to improve motor symptoms in Parkinson’s disease.

Question 20

A*:

List 5 nuclei that undergo degeneration in Parkinson’s disease other than the SNc.

What is the consequence of their degeneration?

What pathological hallmarks are present in these degenerated nuclei in Parkinson’s disease?

Answer 20

Nuclei that undergo degeneration in Parkinson’s disease other than the SNc include:

1 - Locus coeruleus.

• This is the principal site of noradrenaline synthesis in the brain.
• Degeneration of the locus coeruleus is thought to be responsible for the increased risk of depression, decreased vigilance and idiopathic rapid eye movement sleep disorder (Solopchuck et al., 2018) - a sleep disorder in which individuals experience violent jerking movements during REM sleep.

2 - Nucleus basalis of Meynert.

• This is a group of cholinergic neurones that acts as a major source of cholinergic input to the cortex.
• Degeneration of the nucleus basalis of Meynert has been hypothesised to contribute to the cognitive impairment in Parkinson’s disease.

3 - Dorsal motor nucleus of the vagus.

• This is the source of parasympathetic innervation to smooth muscles of the abdomen and thorax.
• Vagal degeneration in Parkinson’s disease causes dysautonomia, resulting in cardiovascular and gastrointestinal symptoms (particularly constipation). Preservation of the nucleus ambiguus and nucleus tractus solitarius, which do not degenerate, means that some vagal efferent activity is preserved.
• Degeneration of these nuclei features the same pathological hallmarks as SNc degeneration - Lewy bodies and Lewy neurites, although these features are less apparent in these regions than in the SNc.

4 - Raphe nuclei.

• Raphe nuclei are the principal site for 5-HT synthesis in the brain.
• Initial speculation was that degeneration of raphe nuclei contribute to non-motor symptoms in PD. However, post-mortem examinations found that Raphe nuclei degeneration was associated with severity of resting tremor, but not non-motor symptoms in PD humans (Qamhawi et al., 2015). The relationship between Raphe nuclei degeneration and tremor is unknown, but it likely reflects disturbances to 5-HT activity in the thalamus, cerebellum and basal ganglia, as 5-HT systems plays a multifaceted role in the control of movement through action at these brain regions.

5 - Pedunculopontine nucleus.

• The pedunculopontine nucleus is a mainly cholinergic nucleus with a primary function in maintaining posture and bringing about voluntary control of the limbs. It therefore plays an important role in gait.
• Degeneration of the pedunculopontine nucleus is thought to contribute to postural instability and typical Parkinsonian gait in PD (Hamani et al., 2007).

Question 21

A*:

What is alpha-synuclein?

What is its function?

How does it change in Parkinson’s disease?

Answer 21

• Alpha-synuclein is a protein localised mostly to presynaptic terminals, but is also present in small quantities in neuronal nuclei.
• Because of its presynaptic localisation, much research into the function of alpha-synuclein has focussed on its role in presynaptic neurotransmitter release.
• Research into the role of alpha-synuclein in neurotransmitter release has been complicated by observations that alpha-synuclein has a differential effect on presynaptic neurotransmitter release in dopaminergic and glutamatergic synapses (Bendor et al., 2013). In alpha-synuclein knockout mice, nigrostriatal neurones show depleted dopamine reserves, and also display faster recovery following high frequency stimulation, whereas similar investigations using glutamatergic synapses identified significantly weaker effects.
• Although these findings are suggestive of an inhibitory role of alpha-synuclein in presynaptic neurotransmitter release, other findings are suggestive of a facilitatory role. For example, a recent study by Somayaji et al. (2020) found that the presynaptic release-modifying effect of alpha-synuclein is facilitatory during burst activity, but inhibitory during slow release. Hence, the role of alpha synuclein in presynaptic neurotransmitter release is unclear and requires further characterisation.
• Other than presynaptic neurotransmitter release, alpha-synuclein has been implicated in various cellular functions, such as regulating plasma membrane lipids, altering gene expression and influencing mitochondrial function.
• In the absence of pathology, alpha-synuclein adopts an alpha helix secondary structure, but becomes misfolded in Parkinson’s disease to form an oligomeric beta-pleated sheet. These mutant alpha-synuclein proteins show impaired degradation, lose their presynaptic localisation and begin to spread to other regions of the CNS in a manner similar to that of a prion. This prion hypothesis of Parkinson’s disease suggests that mutant alpha-synuclein spreads between cells by way of exosomes, which, in the absence of pathology, would otherwise be destined for degradation by lysosomes. The disturbed degradation process leads to the accumulation of misfolded alpha-synuclein, as well as other cellular proteins such as ubiquitin, resulting in formation of Lewy bodies and Lewy neurites. Ses A* card 22 for details on spread from the enteric nervous system!
• This leads to mitochondrial dysfunction, and ultimately, cell death by promoting excitotoxicity, inflammation and oxidative stress - processes which are able to positively feedback on lewy body / neurite formation and mitochondrial dysfunction.
• Currently, it is thought that this gain-of-function mutation of alpha synuclein is the primary pathological event in Parkinson’s disease. Significantly less importance is attributed to the loss of normal function of alpha-synuclein, however this may be an oversight. Degeneration of nigrostriatal neurones can be seen in alpha-synuclein knockout mice (Robertson et al., 2004) and in mice treated with alpha-synuclein shRNA (which acts to decrease expression of alpha-synuclein) (Khodr et al., 2011). Furthermore, as previously described, alpha-synuclein may be implicated in a range of important cellular functions. Whether alpha-synuclein is necessary for cell survival is of great importance to Parkinson’s disease treatment, therefore further work is necessary to elucidate its physiological functions. This will provide a background to help indicate the pathological mechanisms that occur in Parkinson’s disease.

Question 22

A*:

What is truncal vagotomy?

Describe the effect of truncal vagotomy on Parkinson’s disease risk.

What might explain this effect?

What are the symptoms of truncal vagotomy?

Answer 22

• Truncal vagotomy is a surgical procedure involving resection of the vagus as it emerges as the anterior and posterior trunks inferior to the diaphragm.
• A recent study by Liu et al. (2017) found that truncal vagotomy is associated with a reduced risk of Parkinson’s disease.
• It has been hypothesised that degeneration in Parkinson’s disease begins in the enteric nervous system, and that Lewy pathology spreads via the vagus nerve to the CNS where it causes a range of motor and non-motor symptoms.
• In mice, administration of rotenone, a herbicide used experimentally to induce alpha-synuclein accumulation, was able to induce PD-like symptoms and trigger degeneration of the dorsal motor nucleus of the vagus and SNc.
• Therefore, truncal vagotomy disconnects the CNS from the spreading Lewy pathology, preventing onset of symptoms.
• However, truncal vagotomy can cause chronic gastrointestinal symptoms such as vomiting and diarrhoea, and can also cause abdominal pain.

Question 23

From NO and purinergic signalling A* cards:

Briefly describe a potential purinergic target for Parkinson’s disease.

How can this target be used to treat Parkinson’s disease?

Answer 23

• A potential purinergic target for Parkinson’s disease is A2A receptors.
• A2A receptors are found abundantly in the basal ganglia, but particularly in striatal medium spiny neurones of the indirect pathway. This is a circuit in the basal ganglia that inhibits movement.
• In the striatum, A2A receptors are colocalized with D2 receptors, with which they form dimers. A2A receptors tonically inhibit D2 receptors.
• Since D2 receptors inhibit the indirect pathway of the basal ganglia, promoting movement, and A2A receptor activation inhibits D2 receptor activation, A2A receptor activation is inhibitory to movement.
• Istradefylline is an A2A receptor antagonist. Administration of istradefylline is associated with a significant increase in unified Parkinson’s disease ranking scale.
• This could be used in combination with dopamine replacement therapy to reduce the required dose of L-DOPA, which has numerous side effects.
• Aryati et al., 2019.

Question 24

A*:

What are the behavioural deficits in Parkinson’s disease?

What underpins these behavioural deficits?

Answer 24

• Patients suffering from parkinson’s disease show behavioural deficits that reflect the negative symptoms of schizophrenia. This includes:

1 - Reduced expression of emotion.

2 - Social withdrawal.

3 - Poverty of speech (absence of useful information in speech).

• One possible explanation for the behavioural deficits in Parkinson’s disease is through defective functioning of the basal ganglia.
• As well as playing a key role in motor function, the basal ganglia play an important role in filtering nonmotor information. Indeed, nonmotor deficits in schizophrenia can also be attributed to deficits in glutamatergic and dopaminergic signalling in the basal ganglia.
• The sensory filter comprises a network of neurones forming the cortico-thalamo-striatal loop:
• All sensory information destined for the cortex first passes through the thalamus.
• To enable the thalamus to filter unimportant sensory information, the cortex relays information back to the thalamus via the basal ganglia.
• This information reaches the basal ganglia by way of excitatory glutamatergic fibres, which innervate neurones in the striatum constituting both direct and indirect pathways (the glutamatergic networks innervating the basal ganglia have been previously described). Also previously described is the modulatory dopaminergic input to the striatum from the SNc.
• The direct pathway forms excitatory synapses with the thalamus. Stimulation of the thalamus by the direct pathway ‘opens’ the sensory filter.
• The indirect pathway forms inhibitory synapses with the thalamus. Stimulation of the thalamus by the indirect pathway ‘closes’ the sensory filter.
• In schizophrenia, negative symptoms are thought to arise from hypofunction of the direct pathway (‘closing’ the sensory filter) and positive symptoms are thought to arise from hypofunction of the indirect pathway (‘opening’ the sensory filter).
• Since there is a shift towards the indirect pathway in Parkinson’s disease, there is greater inhibition of the thalamus by the indirect pathway, and diminished excitation of the thalamus by the direct pathway.
• This leads to ‘closing’ of the sensory filter, resulting in behavioural symptoms that reflect the negative symptoms of schizophrenia.
• However, this view is challenged by the fact that dopamine replacement therapy, although beneficial for motor symptoms, does not alleviate most nonmotor symptoms. A growing body of research indicates that dysregulation of glutamate transmission is responsible for the cognitive deficits in Parkinson’s disease (see card below for d-serine).

Question 25

A*:

What is the rationale behind targeting glutamatergic neurones for the treatment of Parkinson’s disease?

List 4 emerging glutamatergic treatments for Parkinson’s disease.

Answer 25

• As previously discussed, the basal ganglia participate in a complex network of glutamatergic neurones, facilitating communication with cortical and subcortical structures. Various studies have indicated dysregulation of these glutamatergic networks in both motor and non-motor symptoms of PD. Hence, there may be therapeutic potential in manipulating these networks in order to fine tune neurotransmission in the basal ganglia. Furthermore, in addition to the cellular stresses caused by Lewy body formation, some have speculated that hyperfunction of glutamatergic innervation of the basal ganglia contributes to excitotoxicity, accelerating neurodegeneration. In contrast to L-DOPA therapy, this novel drug class has the potential to improve both motor and non-motor symptoms of PD, and does not pose the risk of treatment-induced dyskinesia.

Emerging glutamatergic treatments for Parkinson’s disease:

1 - D-serine has been shown to significantly improve both motor and nonmotor symptoms of Parkinson’s as an adjuvant therapy, and is currently in stage 4 clinical trials.

• This may be explained by the finding that animal models of Parkinson’s disease show reduced D-serine in the substantia nigra. and similar findings have been made in the cerebrospinal fluid of Parkinson’s disease patients.
• These findings may open avenues for other NMDA-based treatments, such as glycine, sarcosine and the partial agonist, D-cycloserine.

2 - NR2B antagonists.

• Dysfunction of the nigrostriatal neurones in Parkinson’s is thought to increase glutamatergic transmission through NMDA receptors with NR2B subunits. Restoration of physiological levels of glutamatergic transmission at these receptors by way of NR2B antagonists initially showed efficacy for treating symptoms of Parkinson’s disease in animal models, but showed limited efficacy for the treatment of Parkinson’s disease in clinical trials. NR2B antagonists did significantly improve treatment-induced dyskinesia, however since these drugs have a tendency to cause amnesia and dissociation, these drugs are unlikely to be pursued.

3 - AMPA PAMs.

Potentiation of glutamatergic signalling at AMPA receptors has been shown to drive synthesis of BDNF. Hence, it has been hypothesised that administration of AMPA positive allosteric modulators (PAMs) can enhance proliferation and cause neuroprotection in the substantia nigra. This has been evidenced by studies which have shown that the neuroprotective effect of AMPA PAMs can be reversed by administration of a BDNF inhibitor. In spite of the excitotoxic effect produced by other potentiators of ionotropic glutamate receptors, AMPA PAMs have been shown to protect against excitotoxicity - a mechanism thought to play a major role in the loss of nigral cells in Parkinson’s. One group demonstrated that a class of AMPA PAMs, biarylpropylsulfonamides, exerted a neuroprotective effect in nigral cells derived from rodents which were infused with 6-OHDA - a substance used experimentally to cause neurodegeneration. Due to their modulatory action at allosteric sites, AMPA PAMs are also less likely than orthosteric agonists to cause unwanted side effects. Despite the potential clinical benefit of AMPA PAMs for Parkinson’s, most research effort into these drugs has been focussed on Alzheimer’s disease and schizophrenia, hence few drugs have seen clinical trials for Parkinson’s disease.

*a note on the advantages of PAMs over orthosteric agonists (from schizophrenia / glutamate decks): ‘Today, the focus on targeting mGluRs has changed from orthosteric agonists to PAMs, as these only exert an effect when present with an endogenous agonist (and therefore show better safety profiles), generally show greater specificity for the receptor compared to orthosteric ligands (and therefore show fewer side effects) and have reduced potential for desensitisation.’

4 - mGlu4 positive allosteric modulators (PAMs) have shown efficacy in recent years for treating the motor symptoms of Parkinson’s disease. The drugs have potential to reduce the required dosage of L-DOPA, thereby protecting against L-DOPA-induced dyskinesia. Despite success in preclinical models, only one mGlu4 PAM, foliglurax, has entered clinical trials due to its favourable pharmacokinetic properties. Research into foligurax was discontinued as it did not meet efficacy endpoints. The therapeutic potential behind targeting mGlu4 receptors lies in their ability to reduce neurotransmission in the indirect pathway of the basal ganglia. This pathway is inhibitory to movement, therefore inhibition of the pathway by potentiation of mGlu4 transmission has potential for treating the hypokinetic (poverty of involuntary motor activity) and bradykinetic (slow voluntary motor activity) motor symptoms of Parkinson’s disease. Generally, mGlu4 PAMs show high specificity for the mGlu4 receptor, therefore the drugs have been well-tolerated in preclinical models and in the foligurax trial. All other previously developed mGlu4 PAMs have been shown to produce either anxiolytic or antidepressant effects in preclinical models using the elevated plus maze and forced swim tests. Hence, the development of mGlu4 PAMs with more desirable pharmacokinetic properties is warranted.