PD Plus Flashcards
How was Parkinson’s Disease originally described?
Shaking palsy (paralysis agitans) Involuntary motion, with lessened muscular power, in parts not in action even when supported, with propensity to bend the trunk forward, and to pass from a walking to a running pace: the senses and the intellect being uninjured” James Parkinson (1817) Essay on the Shaking Palsy. Turns out he was actually quite accurate, except for the ‘senses and intellect being uninjured’.
What is the epidemiology of Parkinson’s Disease?
- 1 in 1000 of the population
- 1 in 100 of those aged >60 years
- Mean age of onset at 65 years
- 4:1 male : female - for reasons we’re not really sure about
Confounders: Parkinsonism, essential tremor, comorbidity in elderly, neuroleptic drugs
Identify the key neuropathological features of Parkinson’s disease (PD)
- Degeneration of the dopamine neurones in the substantia nigra pars compacta of the midbrain. Loss of neuromelanin pigment intensity occurs first, which is a normal dopamine metabolite that should build up with time, in the locus classicus. Since neurons from the substantia nigra project to the striatum (in the basal ganglia), the putamen and caudate are implicated in the pathology as well. - You also see ventricular enlargement, but not much gyral atrophy/prominent sulci. This is why normal pressure hydrocephalus can sometimes mimic PD? - Lewy Body inclusions in the cell bodies - Lewy neurites inclusions in surviving neurones.
What are Lewy Bodies and Lewy Neurites?
A lewy body is a hyaline (smooth) circular inclusions in the neuronal cell bodies - it is a large lump of protein (α-synuclein) sitting in the cell. They pick up the pink eosinophil stains very easily and are therefore described as lamellated eosinophilic cytoplasmic inclusions. A lewy neurite is this accumulation of granular material and abnormal α-synuclein filaments, in a neurone’s neurite (a projection from the cell body). Both are found in α-synucleinopathies such as dementia with Lewy bodies, Parkinson’s disease, and multiple system atrophy.
What is the function of α-synuclein?
α-synuclein is a member of the human synuclein family along with β- synuclein and γ-synuclein. It is abundant in the brain. It has an unknown physiological function but may be involved in the regulation of synaptic plasticity and neurotransmitter release (due to its presynaptic location).
Neuritic Dystrophy Hypothesis of Lewy Neurodegeneration?
Normally, α-synuclein is transported to synaptic terminals. In the neuritic dystrophy hypothesis, normal (soluble) α-synuclein transforms into (insoluble) β-pleated sheet form. This then builds up accumulates in mitochondria and vesicles, and eventually disrupts neurofilaments and microtubules, blocking axonal transport. Eventually resulting in neuronal death.
What is Braak staging of PD based on?
These stages are based on Lewy body localisation. It suggests that Lewy body pathology does not begin in substantia nigra. The first pathology appears to begins in dorsal motor nucleus of glossopharyngeal and vagus nerves, anterior olfactory nucleus, and enteric nerve cell plexus. The pathology proceeds in rostral direction toward neocortex.
What is the difference between Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB)?
Parkinson’s Disease Dementia (PDD) is dementia resulting from PD.
Lewy Body Dementia (LBD, Dementia with Lewy Bodies) is dementia that precedes, or occurs within 1 year from motor symptoms. It involves mostly cortex pathology without subcortical involvement – there is great debate whether it is a different disease or not. Is this 1 year cut-off arbitrary?
Describe the Braak Staging of Parkinson’s Disease Pathology, and roughly to what symptoms they produce.
Based on a progressive model from brainstem to neocortex:
- Stage 1: Dorsal IX/X nucleus and/or olfactory bulb
- Stage 2: Raphe nuclei and then locus coeruleus
- Stage 3: Substantia nigra and then amygdala and hippocampus. Produces motor signs.
- Stage 4: Temporal mesocortex and allocortex. Produces cognitive signs.
- Stage 5 and 6: High order sensory association areas of the neocortex, and the prefrontal cortex.
Stage 1-2 are not associated with motor signs. May lose sense of smell. Stage 3 is associated with motor signs. Stage 4-6 is associated with cognitive and emotional signs.
What are the problems with Braak staging?
Progression of PD does not always comply with this model.
Others (including Prof Gentleman) have suggested that the dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson’s disease, as it isn’t always affected.
Some suggest that it begins in the peripheral ganglia, as α-synuclein pathology can be found in the epicardial nerve fascicles and paravertebral sympathetic ganglia.
Others suggest it could be in the in the anterior olivary nucleus of the nerves originating from the nose.
What mechanism tries to explain how environmnetal triggers can cause PD?
Retrograde transport from gut, and airborne through nose are the 2 main entry sites to the brain. This supports theories that suggest such neurodegenerative diseases may have a transmissible “prion-like” spread. Anosmia is a common early symptom of PD (and Alzheimer’s disease) – but not definitive. Constipation is another early symptom of PD.
- This could be important for early disease detection – gut or nose biopsies potentially?
- Also suggests an environmental trigger. Organophosphate exposure may explain why farmers have a greater incidence of PD
What are the causes of Parkinsonism?
- Idiopathic Parkinsonism (Parkinson’s Disease)
- Genetic
- Atypical Parkinsonism*
- Multiple system atrophy (MSA) - a α-synuclein pathology which is seen in glial cells.
- Progressive supranuclear palsy (PSP) - a tau protein pathology (nothing to do with α-synuclein)
- Corticobasal degeneration (CBD) - a tau protein pathology (nothing to do with α-synuclein)
- Vascular
- 20 other disorders
- Secondary Parkinsonism
- Drug-induced e.g. MPTP
- Head trauma
- Toxins e.g. fertilisers
Note: Parkinson’s disease is the most common form of Parkinsonism (which is a spectrum of symptoms)
*Most of the P+ syndromes are difficult to diagnose clinically – so just labelled as “atypical” PD – and specific P+ syndrome is diagnosed in post-mortem.
Discuss the clinicopathological correlates of dementia in Parkinson’s disease.
Around 80% of PD patients develop dementia
This presents as abnormalities of attention, concentration, memory, word list generation, abstraction and categorisation, judgement, problem resolution, strategy formulation and visuospatial dysfunction (such as problems with visual discrimination, visual organisation, spatial orientation, drawing and angle perception) represent core features of the dementia syndrome in PD.
Note: As opposed to mainly memory problems in AD, PD mainly has frontal pathology and hence decision making (though memory can also become involved later on).
However, the underlying pathology of cognitive deficits and dementia associated with PD has been a matter of controversy, both in terms of site and type of pathology
Recent neuropathological studies have described global Aβ [amyloid- β] deposition in the striatum in Lewy body disorders, especially in Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB)
However, PET studies using the 11C PIB ligand that binds to Aβ detects significant striatal pathology only in DLB, not PDD
To see why this was, immunohistochemistry was done post- mortem, found that in PDD, there was more diffuse amyloid pathology than clumps – so it was a problem with imaging in the point above.
This suggests that striatal Aβ pathology is common in both PDD and DLB, and may reflect the development of dementia in these conditions
Define the term “parkinsonism” and list the CNS disorders that may present in this way
Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia, rigidity, and postural instability. Parkinsonism can be caused by:
- Idiopathic Parkinson’s disease
- Drug-induced parkinsonism
- Multiple system atrophy (MSA)
- Progressive supranuclear palsy (PSP)
- Corticobasal degeneration (CBD)
- Vascular pseudo-parkinsonism
- Alzheimer’s changes
- Frontotemporal neurodegenerative disorders
- 20 other disorders
What is MSA and it’s sub-classifications?
Multiple System Atrophy is a term covering three disorders with very similar cellular pathology, so grouped together. They are all alpha-synucleinopathies:
- Olivopontocerebellar atrophy (OPCA) - When the inferior olivary nucleus in the medulla, pons and cerebellum are affected
- Shy-Drager syndrome - Characterised by autonomic dysfunction: postural hypotension, etc.
- Striatonigral degeneration - Slightly different pathology from PD (but mimics PD the most of these 3 conditions)
These are old terms used. They are now all grouped as MSA. But can be sub-classified.
Now characterised as:
- MSA-P – predominant parkinsonism
- MSA-C – cerebellar features
What are the macroscopic neuropathological features of MSA?
- Cortical atrophy (motor, premotor)
- Cerebellar atrophy (can be really quite marked)
- Shrinkage of middle cerebellar peduncle, pons and inferior olivary nucleus
- Pallor of locus coeruleus and substantia nigra
What are the microscopic neuropathological features of MSA?
- Mixed neuronal and glial pathology
- α-synuclein immunoreactive glial cytoplasmic inclusions (GCI)
- Neuronal cytoplasmic inclusions (like in PD)
- Neuronal nuclear inclusions
- Oligodendroglial nuclear inclusions (Papp-Lantos bodies)
- Neuropil threads
- ↑Hot-cross-bun sign – sign of MSA
What is CBD?
Corticobasal Degeneration (CBD) is a progressive neurodegenerative disorder.
4R Tauopathy not alpha-synucleinopathy
What are the symptoms of CBD?
Symptoms include rigidity, clumsiness, stiffness and jerking of arm, and “alien limb”. Clinically distinguished from PD mainly due to Alien limb syndrome/phenomenon – limb moves without the consciousness of the patient – disconnect between cognition and motor movement
Affects cerebral cortex (fronto-parietal atrophy), deep cerebellar nuclei and substantia nigra
What are the neuropathological features of CBD?
- Glial and neuronal inclusions
- Neuropil threads particularly prominent
Microscopically distinguished by:
- Diagnosis is made via presence of astrocytic plaques which contain tau protein. (picture on right)
- Background is pretty much all neuropil threads (neuropil threads are particular prominent in CBD - filled with hyperphosphorylated tau) - picture on left
What is the most common form of atypical parkinsonism?
Progressive Supranuclear Palsy (PSP)
What is PSP?
Progressive Supranuclear Palsy (PSP) is the most common form of atypical parkinsonism. PSP is also a 4R tauopathy.
What are the symptoms of PSP?
Symptoms:
- Supranuclear gaze palsy. I.e. vertical gaze palsy
- Postural instability
- Not being able to look down, with poor posture leads to lots of falls down stairs.
What are the neuropathaological features of PSP?
PSP - Macroscopic pathology:
- Atrophy of basal ganglia, subthalamus & brainstem
- Discolouration of the subthalamic nucleus
PSP - Microscopic pathology:
- Neuronal loss and gliosis (the defining lesions are the tufted astrocytes - different from astrocytic plaques as they are individual astrocytes with tau, rather than many astrocytes)
- Neuronal and glial tau-positive inclusions. E.g. there are coiled bodies with tails, which are tau in oligodendrocytes.
Describe the Tau gene
Tau is a cytoskeletal protein coded by a single gene on chromosome 17q21. It has 16 exons, however, alternative splicing gives rise to 6 isoforms.
What are the different tau isoforms?
Can be either 3R or 4R tau, which are named according to the number of microtubule binding domains it has.
There are 2 further inserts (N) with unknown function
There are 6 isoforms:
- 4R/0N
- 4R/1N
- 4R/2N
- 3R/0N
- 3R/1N
- 3R/2N
The shortest form is 3R/0N, and is foetal – we still have some of this circulating but not so much
What is the function of the tau protein?
Binds and stabilises microtubules.
Promotes microtubule polymerisation
4R tau is more efficient at these functions.
Other MAPs (Microtubule Associated Proteins) have similar functions and that’s probably why knockout has no overt phenotype
What is known about tau phosphorylation?
- Tau function is dependent on phosphorylation status
- There are 79 potential serine (ser) or threonine (thr) sites and they’re clustered around microtubule binding sites
- Increased phosphorylation reduces microtubule binding and reduces the normal physiology
- There needs to be a balance between kinases (e.g. GSK-3β and CDK5) and phosphatases
How can tau aggregation patterns aid in molecular diagnosis of dementias?
Idealised western-blot. All of us are walking around with all six isoforms of the soluble protein. Pathological, aggregated tau is insoluble. Different diseases produce different patterns:
- In Alzheimer’s Dementia, you can see how all six forms of tau (after dephosphoralisation) are involved in pathology.
- In CBD and PSP, there are only two bands on the western blot. After dephosphorlyation, you see only three tau isoforms are involved in pathology, which are all 4R tau.
- In PiD (Pick’s Disease) you see it involves 3R tau. Pick’s disease is a fronto-temporal dementia that therefore has parkinsonism.
How is tau implicated in Parkinson’s Disease?
Parkinson’s Disease is not considered a tauopathy. However GWAS on PD patients have shown 2 hotspots: α-synuclein and tau.
Tauopathy in PD is surprising - perhaps a fault of study design? Perhaps some of the patients may have had PSP rather than PD and included in GWAS?
Either way, this raises questions because when you look at a PD patient’s brain, you can see α-synuclein pathology sometimes along with tau patholog.
In some cases the tau can just be age-related or due to early Alzheimer’s type tau.
In other cases it can be because PD is co-existing with PSP in that individual.
How could Parkinson’s plus disorders be distinguished clinically while the patient is alive?
We need to develop in-vivo diagnostic methods to distinguish diseases. Because, for example, if one day we develop α-synuclein therapeutics, it would be pointless against PSP or CBD.
Biomarkers:
- Biomarkers can be found in CSF
- In MSA, α-synuclein levels are particularly high, but we’re not sure how we can distinguish between this and PD, because it will slightly overlap with control patients.
- It is clear that no one protein stands out, so we may need to identify finger-print patterns of CSF proteins.
Imaging:
- Another approach is to use imaging
- There’s an increased resolution of imaging and metabolic imaging that may help us with the precise diagnosis
- PSP can be distinguished from CBD, MSA-P and PD by clinical and imaging differences at an early stage
Discuss the prion-like pathology of parkinsons plus disorders
- Many neurodegenerative disorders show prion-like spreading of the pathology - it was possible to passage human MSA into animal models, but only when actually injected α-synuclein into the brain (this doesn’t happen naturally).
- We can also cause α-synucleinopathy in culture
- This raises questions about the transmissibility of α-synucleinopathies
- Better understanding of the spread of disease may be helpful, but it is unlikely that infection is possible
- MSA in particular seems more spreadable in this way [the injecting method described above]
- But when you inject PD pathology into an animal model, pathology doesn’t develop
- What’s different between MSA and PD?
- Maybe it’s strain variation? – Subtle differences in protein that affect transmissibility?
What are the α-Synucleinopathies?
These are conditions that involve α-synuclein. They can be further broken down into:
- Lewy body diseases:
- Parkinson’s disease
- Dementia with Lewy bodies (Where lewy bodies affect frontal lobe before other regions)
- Lewy body dysphagia
- Pure autonomic failure
- Inherited Lewy body diseases
- Lewy body variant of AD
- Focal cortical syndromes
- Incidental Lewy body disease - very common 10-20% (normal accumulation of Lewy bodies but no Parkinsonian symptoms)
- Multiple System Atrophy:
- OPCA
- Striatonigral degeneration
- Shy-Drager Syndrome
These are in contrast to tauopathies which involve Alzheimer’s Disease, Fronto-temporal Dementia and PSP and CBD.
What are the risks for developing Parkinson’s Disease?
Age, family history, rural living, farming, gardening, pesticide use, well water, industrial/chemical exposure, diet, trauma, emotional stress, premorbid personality.
E.g. odds ratio of having lived in the country side as a Parkinson’s patient is higher than living in the city – possibly because of pesticides / industrial waste that seeps into the soil and water.
What are the categories of symptoms of Parkinson’s Disease, and what area of the brain cause which clinical features?
Degeneration of what area of the brain cause which clinical features:
- Motor symptoms caused by degeneration of the substantia nigra, PPN (Pedunculopontine Nucleus)
- Sleep dysfunctions caused by degeneration of the hypothalamus, PPN, thalamus, raphe, RAF
- Autonomic dysfunctions caused by degeneration of the hypothalamus, medullary nuclei, spinal cord, peripheral ganglia, cardiac sympathetic plexus and skin.
- Cognitive symptoms caused by degeneration of the substantia nigra, VTA, locus coeruleus, raphe, basal forebrain, limbic, hippocampus, cerebral cortex and thalamus
- Sensory symptoms caused by degeneration of the olfactory pathway, visual pathway & association cortex and retina.
- Neuropsychiatric symptoms
- Iatrogenic symptoms
- Other symptoms such as painful Dystonia (‘off’ or peak-dose), Pain in face/ limbs/ abdomen, Sweating/Flushing, Akathisia (restlessness), Breathlessness and Internal Tremor.
What are the motor symptoms in PD?
Tremor, Rigidity, Akinesia & Bradykinesia, Loss of postural reflexes
What are the neuropsychiatric symptoms of PD?
Hallucinations, Anxiety, Confusion, Depression, Cognitive decline, Dementia, Paranoia, Visuospatial dysfunction, Hypersexuality, Spending/ Gambling Mania
What are the cognitive symptoms of PD?
The cognitive symptoms of Parkinson’s Disease vary from individual to individual, probably reflecting the heterogeneity of the underlying neuropathology. The most common cognitive impairments are in attention, executive functioning and visuospatial processing.
What are the autonomic functions of PD?
Bladder, Bowel, Hypotension, Impotence, Dysarthria, Dysphagia, Drooling, Rash, Anosmia
What are the sleep symptoms of PD?
Restless Legs, REM Sleep disorder, PLMD, Nightmares, Nocturia, Immobility
What are the sensory symptoms of PD?
visual processing, anosmia, pain
What are the iatrogenic symptoms of PD?
dyskinesia, fluctuations, GI, falls, impulsivity (dopamine medication on hypersensitive ventral striatum and prefrontal cortex).
How does neurotransmitter levels affect PD pathology?
But in Parkinson’s, it was demonstrated that only 10% of normal dopamine concentration was found in the basal ganglia. I.e. it’s necessary to lose 80-85% of dopaminergic neurons and deplete dopamine levels by 70% before symptoms appear. This shows there is a degree of compensation the brain can do in Parkinson’s disease. It also means that by the time a patient comes to the clinic, a lot of the damage has already been done.
How does the brain compensate for decreased dopamine from the midbrain?
- The remaining dopaminergic neurons increase the amount of dopamine released per nerve impulse
- The number of post synaptic receptors increases
- Usually, an extensive proportion of released dopamine is usually taken up by dopaminergic & neighbouring neurons, but not if dopaminergic neurons have degenerated. So there’s excess dopamine in the synapse
What is the general strategy in dopamine treatment?
Treatment focuses on using drugs to treat primary symptoms from low dopamine. These drugs include:
- L-DOPA
- Dopamine Agonists
- MAO Inhibitors
- COMT Inhibitors
- Anticholinergics
- Amantidine
There is also a need to treat the secondary symptoms of Parkinson’s disease:
- Autonomic features: low blood pressure, bladder, drooling, constipation, sweating
- Psychological: depression, anxiety/ panic, psychosis, hallucinations, delusions, dementia
- Pain,cramps
- Sleep: RBD, RLS, PLMS, nocturia
What are the dopmaine targetting drugs used in the treatment of PD?
These are to address the primary symptoms of Parkinson’s Disease. Types of dopamine targeting drugs include:
- Indirect Agonists:
- L-DOPA and Duodopa (precursors of dopamine)
- Amantadine (increases release of dopamine from presynaptic nerves)
- Direct Agonists:
- Apomorphine
- Pramipexole
- Ropinirole
- Rotigotine
- Enzyme Blockers:
- DDC (Sinemet (Carbidopa/Levodopa), Madopar)
- These are given with L-DOPA (levodopa) so that it is not converted to dopamine in the periphery. Carbidopa (the DCC antagonist) does not cross the BBB)
- MAO (Selegiline/ Rasagiline)
- COMT (Entacapone, Tolcapone, Opicapone)
- DDC (Sinemet (Carbidopa/Levodopa), Madopar)
- Other: Stalevo (L-DOPA + DDC + Entacapone)
Describe L-Dopa as a treatment for PD
L-DOPA is the gold-standard drug for PD. It is a large neutral amino acid, and the most effective drug for treating motor signs (especially rigidity and slow speed).
It is also converted to dopamine in the periphery (which would cause major side effects e.g. vomiting, arrhythmias) so usually given with a peripherally acting decarboxylase/COMT inhibitor such as co- carbidopa (Sinemet), co-beneldopa (Madopar).
It can be directly infused as “duodopa”
Is absorbed in the small bowel (because of dietary protein and stomach emptying) and also metabolised into dopamine in peripheral tissues. Only 5% goes to the brain.
Describe the different formulations of L-Dopa drugs
We can also produce sustained release formulations. These improve sleep and increase the amount of time the drug works (‘on’ time). However, the ‘on’ time comes on slowly and there can be accumulation in the evening leading to dyskinesia.
Or we can produce fast absorption drugs that are “dispersible”. This is effective in the “honeymoon period” to treat tremor, bradykinesia and rigidity. However, as the disease progresses, its efficacy declines and unwanted side effects start developing. This leads to early side-effects (nausea and vomiting), and late side-effects (“on/off effects”, peak-dose dyskinesias, yoyo-ing fluctuations and eventually permanent dyskinesias)
If a COMT inhibitor or other sustained release formulation is given at the same time, the fluctuations are decreased and there’s a more gradual response.
Name the direct dopamine agonists used to treat PD
These have a direct action on D2-like receptors. Examples:
- Bromocriptine (5 ergot ring structure = heart valve problems)
- Pergolide
- Ropinerol (non-ergot ring structure = addictive behaviours e.g. OCD-like or gambling)
Compare the dopamine agonsists to L-Dopa in the treatment of PD
They have a longer duration of action than L-DOPA (which is cleared away very quickly and has to be given 4 times daily) - hence has a smoother and more sustained response. Actions are also independent of presynaptic dopaminergic neurons. The incidence of dyskinesias is lower.
You can use them either early or late. Early to delay the introduction of L-DOPA. Late to reduce the dose of L-DOPA. It also may have neuroprotective action.
But there are side-effects as it’s less tolerated/effective that L-DOPA
What are the side-effects of direct dopamine agonists?
But there are side-effects as it’s less tolerated/effective that L-DOPA:
- Psychological impairment (hallucinations, delusions, paranoia, punding, impulsivity), because it targets mesolimbic dopamine pathways too.
- Nausea and vomiting
- Hypotension
- Oedema
- Fibrosis
- Somnolence
- Sleep attacks
How are the autonomic symptoms of PD treated?
- Low BP (orthostatic hypotension; dizziness, falls): fluids, salt, NSAIDs, Fludrocortisone, Midodrine, DHE, Flurbiprofen, Indomethacin, L-DOPS
- Bladder (frequency, urgency, incontinence, nocturia): Oxybutinin, Tolteradine, Desmopressin
- Bowel (constipation): diet & fluids, oral meds, enemas, suppositories
- Drooling: Anticholinergic druhs: ophth. gtt., Atropine, Glycopyrrolate, patches, BTX
- Seborrhoea: tar shampoo, topical steroids
- Impotence: drugs, surgery
How are the sleep symptoms of PD treated?
- Avoid Rasagiline, Amantadine (caffeine!) late in day
- Use: Sustained release L-DOPA,D2 agonists (e.g. cabergoline) and short-acting hypnotic: Zolpidem, Temazepam
- Nocturia: anticholinergic, Desmopressin
- Treat depression and joint problems.
How are delusions/hallucinations in PD treated?
- Do not treat ‘benign hallucinations’
- Remove/reduce inciting medication (anticholinergics, dopamine agonists, Amantadine), identify triggers (infection, trauma, surgery)
- Avoid conventional dopamine-blocking drugs
- Clozapine, Quetiapine, Olanzapine, Risperidone, Sulpiride, Aripiprazole
- (NB- benefit of Donepezil, Rivastigmine, Memantine in Lewy Body Type Dementias = PDD & DLB)
How is depression in PD treated?
- Optimise Dopaminergic therapy
- Tricyclics (now second line). Side-effects: constipation, delay L-DOPA absorption, worse dyskinesia, sedation & confusion, cardiac dysrythmia
- SSRI/ SNRI/ NSSA/ MAO-A(B)
- Counselling / Carer Input / Group Activities
- Exercise
- Electroconvulsive therapy
What is the impact of Parkinson’s disease on Carers
Parkinson’s disease can have a huge impact of carers for patients, as many of them have reduced physical and mental health and this includes symptoms of depression, irritability and emotional & physical exhaustion, especially due to ageing population
Carer Fatigue: symptoms
- Withdrawal from friends, family, loved ones
- Loss of interest in activities
- Feeling low, hopeless or helpless
- Changes in appetite, weight, sleep
- Frequently falling ill
- Feelings of wanting to hurt self or person cared for
- Emotional & physical exhaustion, irritability
What are the corrleates/causes of carer fatigue?
Carer Fatigue: factors that correlate with stress, poor well being in carers
- Disturbed behaviour in care-recipient
- Withdrawal in the care recipient or poor relationship
- Being a wife rather than a husband
- Being a daughter rather than a spouse
- Conflicting roles and responsibilities
- No support from a partner / No social support
- Limited coping strategies/lack of active problem-solving
- No satisfaction from caring
Carer Fatigue: causes
- Role Confusion: establishing separate carer role as spouse, child or friend
- Unrealistic expectations: caring may not have a positive effect on health/happiness of person cared for
- Lack of control: frustration over lack of money, resources, skills to manage & organise care
- Unreasonable demands: placing demands on oneself, seeing caring as individual’s sole responsibility
- Recognising illness: carers do not recognise fatigue, depression, losing control
What are the four dopaminergic pathways?
- Nigrostriatal pathway - from Substantia Nigra pars compacta (SNpc) to striatum (caudate and putamen)
- Mesolimbic pathway (reward pathway) - from Ventral Tegmental Area (VTA) to Nucleus Accumbens (NA)
- Mesocortical pathway - from Ventral Tegmental Area (VTA) to the cortex
- These pathways perform several functions in the reward system, control of emotion, motivation, cognition and motor behaviour and are connected to several psychiatric and movement disorders including schizophrenia, drug addiction and Parkinson’s disease
- Tuberoinfindibular pathway - from arcuate nucleus to pituitary gland (control of hormone secretion)
What is the gross pathophysiology of PD symptoms?
Degeneration of midbrain dopaminergic neurones. In the nigrostriatal pathway, this causes motor symptoms such as tremor, regidity, akinesia, postural instability. In the mesocorticolimbic pathway this causes cognitive and emotional changes, impulsivity, addiction.
What causes dopaminergic neurones in the SNpc to degenerate?
- a-synculein - Neuritic Dystrophy Hypothesis of Lewy Neurodegeneration?
- The ubiquitin–proteasome pathway: a mechanism for protein homeostasis
- Evidence for ROS involvement
- Microglia activation in neuroinflammation
- Mitochondrial dysfunction
Describe the involvement of the ubiquitin–proteasome pathway PD pathology
The ubiquitin-proteosome pathway is dysfunctional in the parkinsonian brain. Normally, Ubiquitin C-terminal hydrolase (UCH) processes ubiquitin (Ub). Ub (polyubiquitin chain) is conjugated to a substrate, which is then ready to be fed into a proteasome.
The main evidence that this is involved in PD is that parkin, a gene implicated in Parkinson’s, known to be an E3 ligase, required for normal recycling of proteins.
What is the evidence for ROS involvement in PD pathology?
- Dopamine and its metabolites have an intrinsic tendency to form ROS
- Substantia nigra is rich in iron and copper, cofactors in biosynthetic enzymes involved in catecholamine metabolism such as tyrosine hydroxylase and dopamine β-hydroxylase
- The oxidation-reduction cycle of iron can generate free radicals and toxic metabolites (e.g., hydrogen peroxide)
- Mitochondrial abnormalities (e.g., deficiency in the mitochondrial respiratory chain complex 1), which lead to uncoupling of redox reactions and generation of reactive oxygen species, have also been implicated in Parkinson’s disease.
- Substantia nigra in Parkinson’s disease may be deficient in antioxidant molecules such as glutathione
Discuss the role of microglia in the pathophysiology of PD
(Liu et al. 2003) “It remains to be determined, however, whether microglial activation plays a role in the initiation stage of disease progression or occurs merely as a response to neuronal death.” Indirect neurotoxins can cause activation of microglia. Direct neurotoxins can cause death of the neurones, which leads to microglia activation –> feedback loop leading to more neuronal death.
Describe the role of mitochondrial dysfunction in the pathopshyiology of PD
Mitochondrial dysfunction lead to cytochrome c release, which in turn leads to apoptosis. Researchers have found that mitochondria are indeed dysfunctional in Parkinson’s disease. E.g., deficiency in the mitochondrial respiratory chain complex 1. Some Parkinson’s genes are known to affect mitochondrial membrane integrity. Other genes are known to be localised by mitochondria.
Mitochondria also aid in metabolism of substrates, which allow the cell to grow, regenerate and become metabolically efficient. Affecting the electron transport chain, you make the mitochondria in the cell inefficient.
Why are the Dopaminergic Neurones in the SNpc Susceptible to Degeneration?
- Sensitivity to toxins
- The development of midbrain dopaminergic neurons is likely to be the cause of vulnerability in SNpc neurons
- Epigenetics
- Genetics involved in mitochondiral dysfunction
How could mechanisms of toxicity contribute to the vulnerability of midbrain dopaminergic neurons?
It is believed that environmental toxins produce degeneration of SNpc neurons specifically. People though that understanding the molecular mechanisms of toxicity will provide cues into the mechanisms of neurodegeneration. This can be evident in toxin-based animal models:
- In 1984, scientists found that MPTP (used by some heroin addicts) induced Parkinsonism in human and non-human primates - in terms of clinical and experimental aspects of the disease.
- MPTP is injected and metabolised into MPP+, and taken up into dopaminergic neurons by a transporter
- This is then concentrated as MPP+ in mitochondria
- It is hence suggested that mitochondrial dysfunction is a key aspect of the disease, which is demonstrated by various immunohistochemical changes
Other environmental factors that produce PD also affect mitochondrial function:
- Such as post-encephalitic PD and post-traumatic PD
- And toxins such as Rotenone, paraquat, 6-hydroxydopamine
How could neurodevelopmental processes contribute to the vulnerability of midbrain dopaminergic neurons?
The transcriptional profile of the neurons are ultimately a result of a cascade of developmental events. The transcription factors are essential for development, survival and maintenance (vulnerability) of mesDA neurons and may be the molecular key to vulnerability of neurons during PD.
Loss of neurons in the developmental models is mediated by mitochondrial dysfunction
What neurodevelopmental transcriptional factors may have an imact on the vulnerability of midbrain dopmainergic neurones?
As shown in the diagram, numerous transcription factors are important to confirm regional identity (including SHH, engrailed, Wnt1, etc.) After this, SHH, LMX1a and Fgf8 are important in starting the specification of cell types.
- Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurones
- Nurr1-deficient mice fail to develop dopaminergic neurons and also cannot maintain the survival of dopaminergic precursor cells after development.
- FoxA2 (and FoxA1) has been found to regulate multiple phases of midbrain dopaminergic neuron development (in a dose dependent manner).
- The FoxA2 gene also controls the birth and spontaneous degeneration of dopamine neurons in old age
- This is demonstrated by greater FoxA2 expression in the adult
What neurodevelopmental genetic factors may have an imact on the vulnerability of midbrain dopmainergic neurones?
Engrailed genes are also important in controlling the fate of midbrain dopaminergic neurones - Engrailed genes are required for preventing apoptosis in mesencephalic dopaminergic neurons; this can be seen because there’s a slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice.
- Again, there’s a dose-dependent survival effect: as more Engrailed alleles (En1 or En2) are knocked out, there’s more cell loss and inability to survive
- How does Engrailed help the neurons survive? This is done through the apoptosis pathway; Engrailed genes induce the expression of pErk1/2 and p75, which shift the balance to pro-survival / anti-apoptosis (via Bcl-2)
How may epigenetics confer vulnerability of SNpc neurones?
VTA neurons are more resilient than SNpc Neurons. They only degenerate later in the disease than the SNpc neurones. Therefore the expression profile of the two neuronal subtypes must be different.
- The expression of VTA-specific genes may result in protection against cytotoxins in SNpc
- Differential expression
Summary of approach 3:
- Several pro-survival genes (expressed in VTA) are missing/ downregulated in the SNpc
- Overexpression of the pro-survival genes is protective against toxin-induced neurodegeneration
- Overall: the SNpc cells are inherently vulnerable to degeneration/cell death
How may genetics confer vulnerability of SNpc neurones?
About 10% of PD cases are familial. There are 28 confirmed and unconfirmed chromosomal regions associated with PD. Mutations have been found on 12 genes. A comparison of the functions of the mutated vs. wild type PD genes will provide cues into the causes of the disease.
Genetic mutations have been implicated in:
- α-synuclein
- Parkin
- PINK1
- DJ1
Summary of approach 4:
- Several PD genes are found in mitochondria
- Loss of function mutations cause mitochondrial dysfunction
- Mitochondrial dysfunction leads to loss of cellular/synaptic energy, imbalance in calcium homeostasis and to apoptosis
- A crosstalk exists between proteasome degradation pathway and mitochondria, and this is modulated by PD genes 268
What is the epidemiology and demographics of Familial Parkinson’s Disease?
- Only around 10% of Parkinson’s patients carry these familial gene mutations.
- Some of them are also very rare like DJ1, while PARK2 is much more common
- Many mutations are autosomal dominant, while others are recessive (which means you would have to inherit both copies to get familial AD of this type)
- 10% of people are diagnosed under the age of 45
What main genes are implicated in Parkinson’s Disease?
- α-Synuclein
- Parkin
- PINK-1
- DJ-1
- LRRK2
What are the clinicopathological correlates of dementia?
In general, cortical Lewy body and neuritic pathology is more extensive in Parkinson’s Disease Dementia than PD without dementia, implicating α-synuclein pathology as the strongest correlate of dementia. Evidence of this is:
- PDD cases almost exclusively are of the limbic-predominant stage or neocortical-predominant stage of α-synuclein pathology.
- Global cortical and limbic α-synuclein pathology can be used to discriminate between PD and PDD.
- Diminishing performance on several cognitive measures correlates with advancing α-synuclein stage.
- Multivariate regression analyses found that the burden of cortical and limbic Lewy bodies and neurites was the strongest correlate of dementia in a large, well-annotated cohort of patients with PD or PDD.
Some patients with PDD may also have significant AD pathology (PDD + AD).
- Amyloid-B and NFTs may work synnergistically to worsen dementia alongside a-synuclein.
How is α-Synuclein (SNCA gene) implicated in PD pathology?
In addition to Lewy body formation and propagation, misfolded α-synuclein aggregates can also:
- Lead to oxygen free radicals leakage from mitochondria
- Interfere with mitochondria fission process – leading to build-up of malfunctioning mitochondria and decreased mitochondria formation
- Affect autophagy processes
- Proteasome inhibition
As you can see, misfolded α-Synuclein is toxic. The cell knows this, and tries to expel the protein from the cell. This is how you get transmission from one cell to another.
What is the physiological function of α-Synuclein?
α-Synuclein is found in brain, heart, muscle and blood. In CNS, it is involved in synaptic vesicular trafficking - by promoting membrane curvature, SNARE complex assembly (which provides the mechanical tethering and force for vesicle fusion), and neurotransmitter release.
Describe the evidence for the role of α-Synuclein in PD pathophysiology
Evidence for role of α-Synuclein in PD pathophysiology:
- Pathogenic mutations in the SNCA gene cause familial PD.
- Several experimental models support a role of α-Synuclein aggregation in neurodegeneration:
- Overexpression A53T mutant of α-Synuclein leads to Lewy-body like and neuritic pathology in animals. As well as cognitive and motor clinical phenotype and reduced survival time.
- Examination of a large number of PD and control cases by Braak et al reveal stereotypical caudal-to-rostral ascending progression of α-Synuclein pathology.
- However, not all studies demonstrate a similar topography of disease spread.
- Furthermore, up to 30% of elderly patients with α-Synuclein pathology at autopsy show no clinical signs of dementia or movement disorder prompting such areas to be termed incidental Lewy body disease (ILBD).
What are the physiological functions of LRRK2?
LRRK 2 (used to be called PARK8) is a mixed linage-like kinase found in cytoplasm and outer membrane of mitochondria. Interacts with Parkin.
LRRK2 has many cellular functions:
- Synaptic vesicle endocytosis
- Synaptogenesis
- Lysosomal positioning & autophagy
- Golgi sorting & retromer function
- Cytoskeleton & Neurite outgrowth
- Protein synthesis
What is the role of LRRK2 in PD pathophysiology?
Because this protein has a lot of physiological function within the cell, this explains why there is so much variety of phenotype and pathology between patients (pleomorphic type pathology)
- E.g. some have deposits in glial cells too; some have multiple Lewy body-like structures, etc.
- (Whereas α-synuclein has limited function, so patients have very similar clinical pathology)
A lot of possible mutations – but not all of them form pathological mutations (most just nonsense mutations. Different mutations lead to mixed and strange pathology -E.g. some have Lewy bodies, some do not – some only have it in some areas and not others Some have fibrillary tangles – like FTLD.
The clinical diagnosis of families with LRRK 2 mutations is usually Parkinson’s Disease, a few have Dementia with Lewy Bodies, other with PSP and others with PD + FTLD. In the UK, some patients had a very early age of onset, and some had a later age of onset (33-86). However in pathology, it was found that the patients wither had PD, DLB, PSP, FTLD, MSA, no lewy bodies, or no lewy neurites!
What are the phsyiological functions of Parkin?
Parkin is a ubiquitin E3 ligase which participates in addition of ubiquitin molecules to target proteins, marking them for degradation by the proteasome. It is also linked to both the regulation of apoptosis and the turnover of damaged mitochondria.
How do mutations in Parkin contribute to PD?
Mutations in gene for Parkin cause autosomal recessive form of PD. It is the most common genetic cause. Loss of Parkin function therefore leads to an inability to break down aging/damaged proteins and organelles.
What is the physiological function of PINK-1?
PINK1 is a mitochondrial serine/threonine-protein kinase
- Protect cells from stress-induced mitochondrial dysfunction
- PINK1 activity causes Parkin to bind to depolarised mitochondria to induce mitochondrial autophagy.
How do mutations in PINK-1 lead to PD?
Mutations in this gene encoding PTEN-induced putative kinase 1 (PINK- 1) cause autosomal recessive PD.
PINK-1 is unable to protect cells from stress-induced mitochondrial dysfunction.
What is the phsyiological function of DJ-1?
This is a redox-sensitive chaperone, as a sensor for oxidative stress, stabilises mitochondrial membrane potential.
It is targeted to mitochondria:
- Under oxidative conditions, DJ-1 inhibits the aggregation of α- synuclein via its chaperone activity
- Protects cells from oxidative stress
- Modulates mitochondrial membrane potential
How do mutations in DJ-1 cause PD?
Loss of function mutations cause autosomal recessive early onset PD
What doe GWAS studies in PD show?
Molecular processes involved in PD pathogenesis as highlighted by genetic findings. Using genes recently nominated as risk factors for idiopathic PD along with those responsible for familial PD, it is possible to extrapolate a number of cellular processes that may underlie disease development.
Some genes like SNCA and LRRK2 are associated with multiple processes. While the majority of cellular pathways contribute to both familial and sporadic forms of the disease
Neuro-inflammation likely plays a more prominent role the latter.
Conversely, mitochondrial dysfunction shows a greater association with familial PD.
Describe the main epigenetic mechanisms
DNA methylation
- Gene repression occurs through both physical blocking of DNA to transcription factors and via recruitment of methyl binding proteins, such as methyl-CpG binding protein 2 (MeCP2), which further exacerbates this blockade.
- DNA methylation causes long-term gene repression
Histone modification
- Chromatin packaging determines how accessible the genome is to transcriptional factors
- Condensed means transcriptionally inactive (heterochromatin)
- Relaxed means transcriptionally active (euchromatin)
- HDACs (histone deacetylase) – take acetyl groups off histones – takes away electrostatic repulsion between histones and histones come closer – decreases gene expression
- HATs (histone acetyltransferases) - pushes histones apart, easier gene expression
- Histone modification is for short-term genetic repression
What are the epigenetic changes seen in Parksinson’s Disease?
- DNA methyltransferases (e.g. DNMT1) are translocated out of the nucleus in PD, resulting in hypomethylation. (Basically activation of genes)
- Methylation changes in α-synuclein and PD risk genes (PARK16/1q32, GPNMB and STX1B) occur as well. (I’m guessing this means greater transcription of these PD risk genes).
- Histone modification occurs in PD striatal neurons
- α-synuclein accumulation itself promotes histone H3 hypoacetylation using HDACs, which means histone H3 is masked. (so a-syn causes then causes mass genetic repression?)
Describe the drug used to combat epigenetic changes in PD
Valproate:
Inhibiting HDACs – decreases hypoacetylation – so increased gene expression – and neuroprotective/
We can use valproic acid (valproate), which is used clinically as an anticonvulsant and mood stabilising drug primarily in the treatment of epilepsy and bipolar disorders. It blocks a broad range of class I and IIa HDACs.
Describe the evidence supporting valproate use in PD
Lactacystin injection is a new model of Parkinson’s disease, which recreates the damage to proteasomes of the dopaminergic neurons of the substantia nigra region of the brain observed in Parkinson’s disease patients.
Lactacystin doesn’t cross the blood-brain barrier, so you have to inject it into the substantia nigra to develop a slow and progressive model of Parkinson’s disease
In this model, you can see that H3 acetylation is decreased after lactacystin (hypoacetylation), meaning that it is transcriptionally repressed, but if you start valproate treatment to block HDACs and increase H3 acetylation again, then forelimb movement increases
In lesioned animals, there is a decrease in use on one (lesioned) paw, and increase in healthy paw – but when valproate added, this non- function was restored back to normal [yellow line in graph below].
ALSO In MRI studies, you can see that high dose valproate also ameliorates the damage in PD brains.
ALSO In microarray analysis, you can see that there’s increased gene expression of protective + anti-apoptotic factors with high doses of valproate, i.e. the upper end of the range should be used to treat humans.
What is the problem of using valproate in PD?
Neuroprotective mechanism of valproate leads to overexpression of protective genes. The problem with valproate however is that you need a high dose, such a high dose that you start getting side effects (so can’t start using it for Parkinson’s - only for epilepsy like it is currently used for). So now looking for more selective HDAC inhibitors.
Why are animal models of PD difficult, or a ‘big ask’?
It is very difficult to generate true animal models of Parkinson’s Disease because the human brain’s dopaminergic neurones have hundreds of thousands of more synaptic connections; the human dopaminergic neurones experience more stresses and strains in terms of increased protein turnover, distance etc, that is not seen in the rodent.
- Animals do not naturally develop PD (PD is a human disease), so we need to design a model ourselves
- Human PD is a slow neurodegenerative disease developing over many years. However for animal models, we need it to be a quick disease progression because we need to test drugs quickly and cheaply
No ideal animal model of PD exists. Only mirrors some aspects of the disease.
What are the types of animal models for PD?
- Toxin-treated mice, rats and moneys. Models include 6-OHDA, MPTP and lactacystin.
- Genetically-altered mice, rats and flies. E.g. those with altered PARK genes. Note though: putting gene mutations identical to human ones doesn’t always work.
- Stem cells from people carrying PD mutations. Induced pluripotent stem cells, “disease in a dish”.
What pathophysiological factors are trying to be emulated by toxin-based models of PD?
- Mitochondrial inhibition
- Iron accumulation and oxidative stress
- Selective neuronal loss
- Altered protein protein formation/deposition
How do toxin-based rodent models of PD work?
Toxins are injected into the nigrostriatal system or systemically to kill dopaminergic neurons. The route of delivery differs, depending on whether the toxin is lipophilic enough to penetrate the blood-brain barrier.
Models include:
- 6-OHDA
- MPTP - does cross the BBB
- Lactacystin
All 3 models are very short acting, lactacystin is the longest with 5 weeks.
Normally, when generating a lesion with the toxins, you leave one side of the brain in-tact as you don’t want to impair their ability to eat etc. Furthermore, the contralateral side is usually the control.
Each different toxin produces different pathogenic mechanisms, none produce all of them (apart from MPTP in select dosages) for generating a Parkinson’s model.
Describe the principle neurodegenerative mechanisms which underpin the 5-OHDA model of Parkinson’s disease
6-OHDA is an oxidative product of dopamine itself. In the body when produced, it is very quickly removed. 6-OHDA when injected in the brain induces:
- Oxidative stress caused by free radicals and iron accumulation
- Mitochondria respiration inhibition
- Inflammation
It does not cause neuronal inclusions nor altered protein formation.
How is the 5-OHDA model of PD generated?
5-OHDA can be injected at different sites, depending how quickly you want the cells to die.:
- SNpc – rapid loss of cells (3-4 days)
- Medial forebrain bundle (bundle of axons from SN to striatum) – moderately rapid loss of cells (7-9 days), some progression
- Striatum – Slow progressive loss (over 2 weeks)– but only regional loss of DA neurons
6-OHDA shows a dose-responsive loss of nigrostriatal dopaminergic neurons. Assessed by quantifying the loss of tyrosine hydroxylase immunopositive neurons. With this you can titrate the level of cell loss, allowing you to model different levels of progression of the disease.
Administered by stereotactic injection of 6-hydroxydopamine into the medial fore-brain bundle or SNc.
How does MPTP generate a model of PD?
MPTP was forming a very pure form of Parkinson’s. It is lipophilic, so it penetrates the blood brain barrier and be given systemically. It only affects man, monkeys and C57Black mice (an humans when it was accidentally found in heroin). Mice, rats, cats and dogs are relatively resistant to MPTP. MPTP can:
- Induces mitochondrial inhibition and oxidative stress
- Selective neuronal loss
- MPTP gets into mitochondria – inhibits complex 1
- Doesn’t form protein inclusions (unless given with probenicid)
In non-human primates, three doses of MPTP produces a persistent behavioural syndrome, which includes akinesia, flexed posture, increased limb rigidity, tremor, clumsiness and freezing episodes. This is very similar to PD seen in man.
- In the primate brain, MPTP is rapidly converted into MPP+, which hangs around for several days
- In other species, both MPTP and MPP+ are rapidly removed from the brain
- Loss of dopaminergic cells in the substantia nigra occurs, though dopaminergic cells in the adjacent VTA are intact.
- Behavioural changes are reversed by L-DOPA + carbidopa or dopamine agonists.
While this seems like an excellent model, it is very difficult to get approval for experiments on non-human primates from the home office.
Discuss how Lactacystin produces a model of PD
Lactacystin is a PSI (Proteosome Inhibitor) model. Proteasomes are the cellular machines that degrade altered proteins, which would otherwise build up and lead to oxidative stress and programmed cell death. PSI are peripherally administered to inhibit proteasomes using 2 injections per week for 5 weeks.
- However, not reproducible around the world because PSI is very unstable – need to inject within 5 minutes.
- So researchers now use lactacystin because it is more stable, however can’t cross BBB, so need sterotaxic surgery
Unilateral MFB lactacystin is a more stable model, as it induces nigral cell loss, protein inclusions & chronic progression. It is a lot better than 6-OHDA or MPTP as it induces neuronal death over a longer period of time, allowing the study of how treatments affect neuronal cell loss.
- Microglial activation occurs before cell loss or protein inclusion formation
- Protein inclusions can be found in the remaining dopaminergic neurons
What are the behavioural testing methods of Rodent models?
- Vertical Cylinder Test is a test of asymmetry of forelimb usage. The rats push off using their paws, use their forepaw for exploration, and landing.
- You will see an asymmetry of paw usage, which is a good marker for disease progression.
- Amphetamine Induced Rotation. Giving amphetamine to any animal will cause them to keep running in a straight line. In the PD model, because of limb asymmetry they will rotate. The number of rotations counted over 30 minutes indicates the amount of dopaminergic cell loss.
What are the genetic models of PD?
The genetic models of PD are:
- α-synuclein
- LRRK2
- MitoPark mouse
Describe the α-Synuclein transgenic models in mice, and how it is generated.
Mice that overexpress wild type human α-synuclein show neuronal inclusions, but these are not fibrillar in composition like Lewy bodies are. Instead, they develop these mostly in the spinal cord
- They’re not associated with neuronal loss in the SNc and do not reproduce the neuropathological features of PD
- May lack tipping factors to promote abnormal α-synuclein formation
- Maybe this is because mice expressing single gene mutations don’t show pathological features?
But if they have overexpression of 2 mutations e.g. A30P/A53T (double mutant) form of α-synuclein, then they show an age-dependent decline in SNc TH cell number and reduction in motor function, but no inclusion formation. However, no PD patients have this double mutation.
It’s expensive to produce and must be maintained for a long time to check for age-associated neurodegeneration.
Because the transgenic animals are very poor in producing a good PD model, people now use viral vectors.
rAAV-a-synuclein model of Parkinson’s (adeno-associated virus):
- rAAV viral vectors are used to transfect neurons to overproduce human wild type α-synuclein or PD-associated mutant A53T. It is able to drive expression at a much higher rate than in transgenic mice.
- Led to formation of a-syn immunoreactive deposits that resembled Lewy bodies.
- Causes loss of dopaminergic striatal terminals and cell bodies - leading to deficits in motor behaviour (but require >40-50% loss of DA neurones).
- Progressive with time.
Describe the LRRK2 transgenic models in mice, and how it is generated.
Expression of mutant LRRK2 induces apoptotic cell death in neuroblastoma cells and in mouse cortical neurons. Expression of the mutant LRRK2 in the mouse fails to replicate neuronal loss on the SNc, but dysfunction in synaptic dopamine levels is observed, and that precipitates as some movement dysfunction.
If you stress the system by causing mitochondrial dysfunction you can trigger neurodegeneration. This also leads to abnormal aggregation and accumulation of protein including a-synuclein but this does not cause neurodegeneration on its own. However, is this really PD if extra stress is being induced?
Describe the MitoPark transgenic model in mice, and how it is generated.
mtDNA (mitochondrial DNA) encodes 13 key subunits of the respiratory chain and therefore is critical for mitochondrial biogenesis. mtDNA mutations increase with age and a higher degree of mutations in DA neurons is seen in PD patients.
Mitochondrial transcription factor A (Tfam) directly regulates mtDNA transcription. Tfam knockout mice have reduced mtDNA expression and mitochondrial respiratory chain deficiency in DA neurons. This model shows:
- Adult onset disease
- Progressive impairment of motor function
- Loss of dopamine neurons
- Loss of striatal dopamine
- Loss of intraneuronal inclusions
Unfortunately, the α-synuclein and LRRK2 transgenic models are not very good. But the MitoPark mouse (Tfam knockout) one is good, as it demonstrates motor deficits due to the SNc neuronal loss, selective neuron loss, and protein deposition similar to that seen in PD. However, the MitoPark transgenic animals are not widely available.
What are the current obstacles in developing neuroprotective drugs for PD?
- Incomplete understanding of the Pathogenesis of Parkinson’s
- Lack of accurate models
- Challenges in clinical trials:
- Limitations in trial design – current design insufficiently sensitive to identify disease modifying effects.
- Separating symptomatic from disease modifying effects sufficient washout periods
- Delayed start trial design – initial phase must be long enough to observe neuroprotection, drug-naïve patients remaining on placebo for long periods…
- Suboptimal patient selection – early stage patients but 10% wont have Parkinson’s
- Need validated biomarkers – sensitive biomarkers for diagnosis and monitoring of treatment responses
- Insensitive end point and outcome measures – no reliable CSF, blood or imaging biomarkers – rely on clinical endpoints
