39. Parkinson's Disease Flashcards
Define
MPTP
a neurotoxin C12H15N that destroys dopamine-producing neurons of the substantia nigra and causes symptoms (as tremors and rigidity) similar to those of Parkinson’s disease
Define
Substantia nigra
a layer of deeply pigmented gray matter situated in the midbrain and containing the cell bodies of a tract of dopamine-producing nerve cells whose secretion tends to be deficient in Parkinson’s disease
Define
Akinesia
loss or impairment of voluntary activity (as of a muscle)
Define
Bradykinesia
extreme slowness of movements and reflexes (such as that caused by Parkinson’s disease or antipsychotic drugs)
Define
Prodromal
one that precedes and indicates the approach of another
Define
Lewy bodies
an eosinophilic inclusion body found in the cytoplasm of neurons of the cortex and brain stem in Parkinson’s disease, Lewy body disease, and other neurodegenerative disorders
Define
α-synuclein
a protein that is found primarily in neurons and accumulates to form Lewy bodies in people affected with Parkinson’s disease and some forms of dementia
Define
Levodopa
the levorotatory form of dopa that is obtained especially from fava beans or prepared synthetically, is converted to dopamine in the brain, and is used in treating Parkinson’s disease
Define
Pallidotomy
the surgical inactivation of a part of the basal ganglia in the treatment of involuntary movements (as in Parkinson’s disease)
Define
Globus pallidus
the median portion of the lentiform nucleus
Define
Parkinson’s disease (PD)
a chronic progressive neurological disease chiefly of later life that is linked to decreased dopamine production in the substantia nigra and is marked especially by tremor of resting muscles, rigidity, slowness of movement, impaired balance, and a shuffling gait
Definition
a neurotoxin C12H15N that destroys dopamine-producing neurons of the substantia nigra and causes symptoms (as tremors and rigidity) similar to those of Parkinson’s disease
MPTP
Definition
a layer of deeply pigmented gray matter situated in the midbrain and containing the cell bodies of a tract of dopamine-producing nerve cells whose secretion tends to be deficient in Parkinson’s disease
Substantia nigra
Definition
loss or impairment of voluntary activity (as of a muscle)
Akinesia
Definition
extreme slowness of movements and reflexes (such as that caused by Parkinson’s disease or antipsychotic drugs)
Bradykinesia
Definition
one that precedes and indicates the approach of another
Prodromal
Definition
an eosinophilic inclusion body found in the cytoplasm of neurons of the cortex and brain stem in Parkinson’s disease, Lewy body disease, and other neurodegenerative disorders
Lewy bodies
Definition
a protein that is found primarily in neurons and accumulates to form Lewy bodies in people affected with Parkinson’s disease and some forms of dementia
α-synuclein
Definition
the levorotatory form of dopa that is obtained especially from fava beans or prepared synthetically, is converted to dopamine in the brain, and is used in treating Parkinson’s disease
Levodopa
Definition
the surgical inactivation of a part of the basal ganglia in the treatment of involuntary movements (as in Parkinson’s disease)
Pallidotomy
Definition
the median portion of the lentiform nucleus
Globus pallidus
Definition
a chronic progressive neurological disease chiefly of later life that is linked to decreased dopamine production in the substantia nigra and is marked especially by tremor of resting muscles, rigidity, slowness of movement, impaired balance, and a shuffling gait
Parkinson’s disease (PD)
What is the average age of onset of PD?
Mean age of onset is 55 with incidence increasing with age
What is the difference in gender prevalence in PD?
Gender is a risk factor – male to female ratio is 3:2
What percentage of PD cases are not genetically linked?
95% of cases are sporadic PD with no genetic linkage
Which molecule is implicated in the environmental toxin hypothesis of PD?
Environmental toxin hypothesis – N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinsonism. Its active metabolite, MPP+ is neurotoxic.
What is the cause of the symptoms of PD?
Results from death of dopaminergic neurones in the substantia nigra
What are the clinical features of PD?
T – tremor at rest (4-6 Hz)
R – muscular rigidity
A - akinesia
P – postural/gait instability
How do we confirm PD?
Post mortem Pathological Examination
- Degeneration of the substantia nigra pars compacta
- Lewy bodies and Lewy neurites
What are the motor symptoms of PD?
- Bradykinesia – slowness of movement
- Akinesia – progressive decreased amplitude or speed
- Tremor in fully resting limb which is suppressed during movement initiation
- Rigidity – velocity independent resistance to passive movements not solely reflecting failure to relax
When do non-motor symptoms of PD appear?
Precedes the motor symptoms by at least a decade (prodromal)
What are the non-motor symptoms of PD?
- Sleep dysfunction – sleep maintenance insomnia and excessive daytime somnolence
- Autonomic nervous system dysfunction – constipation, daytime urinary urgency
- Olfactory dysfunction – hyposmia
- Psychiatric symptoms – delusions, paranoia, hallucinations (most commonly visual)
- Cognitive impairment – dementia
- Pain
What is the pathological hallmark of PD?
Lewy bodies (with aggregated a-synuclein in the core) and Lewy neurites with a-synuclein stained processes
Why is loss of smell a prodromal symptom of PD?
Lewy bodies initially found in olfactory bulb, enteric and autonomic nervous systems and brain stem prior to appearance in substantia nigra pars compacta (SNc)
Which protein is misfolded in PD?
α-synuclein
What are the autosomal dominant causes of PD?
- Mutations in a-synuclein – first gene linked to familial PD, major constituent of Lewy bodies and neurites
- Leucine Rich Repeat Kinase 2 (LRRK2) – mutations are the most frequent genetic cause of familial PD, also account for 4% of sporadic PD
- Vacoular protein sorting associated protein 35 (Vps35) – causal mutation with late onset PD, subunit of the retromer complex involved in endosomal-lysosomal trafficking
What are the autosomal recessive causes of PD?
- Parkin – autosomal recessive juvenile Parkinsonism, major mutations for early onset PD (up to 50%), more than 100 mutations identified, deletions, insertions, duplications, point mutations
- DJ-1 – 1-2% of early onset PD, positive regulator of PINK1 to modulate cell metabolism and proliferation
- Phosphatase and tensin homolog-induced novel kinase 1 (PINK1) – 2-4% of early onset PD with slow progression and often atypical features e.g. dystonia, sleep benefit, psychiatric co-morbidities such as anxiety and depression
- ATP13a2 – lysosomal ATPase – mutations cause juvenile onset PD
What environmental factors increase the risk for PD?
Pesticide exposure
Prior head injury
Rural living
Beta-blocker use
Agricultural occupation
Well water drinking
What environmental factors decrease the risk for PD?
Tobacco smoking
Coffee drinking
NSAID use
Calcium channel blocker use
Alcohol consumption
What drugs are used to treat the motor symptoms of PD?
- Drugs designed to enhance central dopamine content or stimulate dopamine receptors
- Levodopa
- Dopamine agonists – e.g. apomorphine, rotigotine, bromocriptine
- Monoamine oxidase B inhibitors – rasagiline, selegiline
- Anticholinergics – e.g. trihexyphenidyl, for treatment of tremors
- Anti-psychotic Clozapine – for treatment of tremors
What drugs are used to treat the non-motor symptoms of PD?
- Dementia – Cholinesterase inhibitors
- Psychosis – Atypical antipsychotic
- Sleep disorders – benzodiazepines, melatonin
- Autonomic dysfunction – peripheral dopamine antagonist
What should disease modifying treatments of PD target?
- a-synuclein accumulation and aggregation
- Cell death - neurotrophins
- Neuroinflammation
- Mitochondrial dysfunction
- Oxidative stress
- Calcium channel activity
What are the pathways involved in PD?
Direct and indirect dopaminergic pathways
How does the substantia nigra cause the symptoms of PD?
Substantia nigra dysfunction causes over activity of the indirect and underactivity of the direct pathways result in more inhibitory output from the basal ganglia output structures (GPi) to the thalamus and the pedunculopontine nucleus (PPN), and ultimately reduced amplitude of movements, including gait
Targeting which brain structures using DBS can relieve symptoms of PD?
subthalamic nucleus
globus pallidus
thalamus
