Week 5- Introduction to Parkinson's disease + pathophysiology Flashcards
what is parkisons?
Parkinson’s disease is a chronic, progressive neurodegenerative
condition resulting from the loss of the dopamine- containing cells of
the substantia nigra.
The resulting dopamine deficiency within the basal ganglia leads to
movement disorders.
what is the prevalence of Parkinson?
PD is the 2nd most common neurodegenerative disease
• Around 137,000 people with Parkinson’s Disease in the UK
• Lifetime risk of being diagnosed with PD is 2.7% (1 in every 37 people)
• Increasing prevalence with age
• More common in men than women
• Early onset variant
• 1 in 20 patients diagnosed before 40 yrs
what are the motor symptoms of Parkinsonism?
- Bradykinesia
- Muscle Rigidity
- Tremor
what are the non-motor symptoms of parkinsons?
- Depression/anxiety
- Fatigue
- Cognitive impairment/dementia
- Sleep disturbance
- Constipation
- Hyposmia (reduced sense of smell)
- Sialorrhoea (drooling/excessive salivation)
- Excessive sweating
- Urinary/bladder problems
- Pain
- Hypotension
what is the dopaminergic pathways function?
• Functions of dopaminergic pathways divide
broadly into:
• Motor control (nigrostriatal system)
• Behavioural effects (mesolimbic and
mesocortical systems)
• Endocrine control (tuberohypophyseal system)
what does bradykinesia mean? hows it shown in Parkinson
• ‘Slowness of voluntary movement’
• This can be asymmetrical and unpredictable
• Mask-like face/limited expressions; limited blinking
• Hypophonia (soft voice) and/or monotonous voice
• Micrographia (small handwriting)
• Difficulty performing fine motor actions (e.g. fastening
buttons/shoelaces)
• Shuffling gait
what does rigidity mean? hows it shown in Parkinson
• Increased muscle tension
• Flexor muscles of trunk and limbs mainly
affected
• Characteristic stooping posture
• Rigidity affects balance increased risk of
falls
• Associated muscle pain common
what does tremor mean? hows it shown in Parkinson
• Not all Parkinson’s patients will have tremor. • It presents as: • Rest tremor – normally in one or both hands • ‘Pill-rolling’ • May affect chin, lips, face, and legs • May appear unilaterally
what type of tremor may a Parkinson patient have?
resting tremor
what should resting tremor not be confused with?
Not to be confused with ESSENTIAL TREMOR (ET):
• Unknown cause
• Associated with movement
• Mild and stable
• Both hands and arms
• May affect head and voice
- ET is the most common cause of postural & kinetic tremors.
-ET is normally treated with beta-blockers. This would normally be
propranolol, started at a low dose and titrated as required.
what are some other types of tremors?
- Postural tremor (occurs when the person maintains a position)
- Kinetic tremor (associated with voluntary movement)
what are some extrinsic causes for parkinsons?
environmental • Prescription drugs • Antipsychotics • Antiemetics • Reserpine & tetrabenazine • Recreational Drugs • Free radicals
physical • Cerebral ischaemia • Viral encephalitis • Brainstem injury • Dementia pugilistica
what are some intrinsic causes of Parkinsonism?
genetic • α - synuclein point mutations • Lewy body formation • Parkin gene mutation (early onset)
Age
-increases with age
whats the main cause of parkinsonism?
-unknown but increase in age
for enviornemntal what are specific drugs that can cause parkinsons?
-Antipsychotics
Typical antipsychotics
Extra-pyramidal side effects
Generally dose-related and reversible
-Antiemetics Metoclopramine, Prochlorperazine
Extra-pyramidal side effects
-Reserpine, tetrabenazine
Depletes monoamines from pre-synaptic storage, reducing
Dopamine release
-Recreational drugs
MPTP (contaminant found in MPPP ‘synthetic heroin’) –
metabolite kills dopaminergic neurones in substantia nigra
Sudden, irreversible Parkinsonism
for genetic what is the main cause of Parkinson?
- there is no known cause for most of parkinsons
- there is a genetic link for some patients
- can be change in α-Synuclein gene which can be hereditary
- they clump and accuimulate to form lewy bodies leading to brain cell death
mutation in the PARK2 GENE
• Important in flagging proteins for degradation
• Mutation – damaged / neurotoxic proteins not targeted
and degraded
• Neurotoxicity affects DA-ergic neurons of substantia
nigra
• Most common cause of early-onset PD (< 40 years old)
for physical what are specific drugs that can cause parkinsons?
Viral illness • Encephalitis lethargica epidemic • Sufferers gradually ‘seized up’ • Eventually catatonic – state of permanent rigidity • Some short term relief from L-DOPA
• Brainstem injury • Muhammed Ali’s Parkinson’s? • Dementia pugilistica • Late onset syndrome of dementia and Parkinsonism • Occurrence associated with professional fighters • Other trauma affecting the DAergic system • Head injury or stroke
how is parkinsons diagnosed? test?
• PD patients will normally present in primary care
• Symptoms tend to develop gradually, so it may be months or years before a patient seeks advice
• All people with suspected Parkinson’s disease will be referred urgently, and untreated, to a
specialist (neurologist/geriatrician), for confirmation of the diagnosis and exclusion of alternative
diagnoses.
• No tests can conclusively diagnose Parkinson’s disease. Diagnosis will be decided on symptoms,
medical history and a detailed neurological examination.
• Brain scans e.g. MRI – may be used to exclude differential diagnoses
• SPECT or DaTSCAN – measures the density of nigrostriatial dopamine transporter sites
• An improvement in symptoms upon staring Parkinson’s medications will support a diagnosis of PD.
what is the pathophysiology of parkinsons?
-Loss of dopaminergic neurons in the nigrostriatal pathway
• 60-80% are lost before symptoms occur
-Lewy bodies, aggragation
-Mitochondrial dysfunction
what is occurring when there is a Loss of dopaminergic neurons in the nigrostriatal pathway?
-losing cell bodies in the substantia nigra and loss of dopamine in the synapses in the Striatum
what are the 2 pathways that are involved in the basal ganglia in control of movement?
- The direct pathway (enables movement)
* The indirect pathway (inhibits movement)
how do dopaminergic neurons work to have both excitorary and inhibition effects?
Dopaminergic neurons from the SN to the striatum (the nigrostriatal pathway) provide excitatory input via D1 receptors (to the direct pathway) and inhibitory input via D2 receptors (to the indirect pathway)
how do dopaminergic neurons work to have both excitorary and inhibition effects?
Dopaminergic neurons from the SN to the
striatum (the nigrostriatal pathway)
provide excitatory input via D1 receptors
(to the direct pathway) and inhibitory input
via D2 receptors (to the indirect pathway)
DA control of direct and indirect pathways
both lead to release of inhibition of
excitatory relay neurons from thalamus to
motor cortex, thus providing stimulatory
input to the motor cortex – DA input
promotes movement via both pathways
what does stimulation of the direct pathway do in The Nigrostriatal Pathways?
-result in the promotion of movement via the motor cortex
what dopaminergic neurons are lost in parkinsons?
Dopaminergic neurons between the SN
and the striatum are lost in Parkinson’s
disease.
what is the cholinergic pathways? effect for parkinsons?
Cholinergic interneurons are abundant in the striatum Dopamine usually inhibits ACh release in the striatum Lack of dopamine in PD leaves ACh unopposed • Hyperactivity of cholinergic synapses Contributes to tremor
what are lewy bodies? how they form? link to dopaminergic neurons
-Intracellular aggregations of α-synuclein found in
neuronal cells
-α-synuclein is a highly abundant neuronal protein
involved in exocytosis of synaptic vesicles and
vesicle recycling
-Misfolding leads to aggregation and plaque
formation
-Removal via proteosomal pathways is reduced in
PD
-Link with death of dopaminergic neurons
• Mutation of α-synuclein causes early onset PD
and there is an increased number of Lewy
bodies
what is mitochondrial damage? affect in parkinsons?
Dopaminergic neurons require a lot of energy for their function
Damage to the mitochondria is believed to play an important
role in the pathophysiology of the disease
• Chemicals that induce PD (eg. rotenone, MPTP) cause
mitochondrial stress and dysfunction
• Parkin and PINK1 (genes that when mutated lead to PD)
involved in mitochondrial turnover – mutation means that
damaged mitochondria are not recycled
• Mitochondrial damage leads to death of the dopaminergic
neurons
• Generation of oxidative stress (reactive oxygen species)
• Secondary to this – excitotoxicity, neuroinflammation
