Terms in this set (46)
Where are neurons primarily lost within Parkinson's disease?
What aggregates are a major part of PD pathology?
What mutations can lead to PD?
Point mutations in the alpha-synuclein gene (polymeropoulus)
How is PD diagnosed?
Clinical Examination and history (cf neuroleptic use)
Unified Parkinson's Disease Rating Scale (UPDRS)
Good response to L-Dopa
What are some classical features of PD?
Resting Tremor, Rigidity Bradykinesia, Gait Disturbance Postural Instability
What are some additional features of PD?
Masked Facies, Decreased Blink Freezing, Micrographia, Flexion
What can PET 18F what can it detect and at what sensitivity?
Fluoro-DOPA Sens:85%+ -F-DOPA = analogue of L-DOPA - precursor for dopamine
What is can a SPECT scan detect in the PD brain and at what sensitivity?
123I‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)‐ N‐(3‐fluoropropyl) nortropane (DATScan) Sens: 95%+ Spec: 65%+
What scans can be done for the PD brain?
PET 18F - Fluoro-DOPA Sens:85%+ -F-DOPA = analogue of L-DOPA - precursor for dopamine
SPECT - 123I‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)‐ N‐(3‐fluoropropyl) nortropane (DATScan) Sens: 95%+ Spec: 65%+
99mTc-TRODAT-1 SPECT Sens: 80%+ Spec: 60%+
What controls the output nuclei of the PD circuitry?
Activity of the direct and indirect pathways
Which pathway becomes overactive within PD? What causes this and what is decreased in response?
In PD, dopamine deficiency causes overactivity of the indirect pathway leading to decreased direct pathway (GABA)
In PD, the activity of the direct pathway is decreased, what does this in turn cause?
Overactivity of the output nuclei (GABA) and excessive inhibition of the motor thalamus
How might PD be treated?
MAO-B inhibitors (selegiline, rasagiline)
"off" and "on" effects
Wearing off 2-5yrs, with delayed "on" periods
Side effects - Dyskinesia, Hedonia, Impulsivity, freezing
What advantage do non-ergot agonists, such as and Pramipexole, Ropinirole, have?
Oral monotherapy with reduced side effects
What side effects may occur with ergot dopamine agonists such as lisuride and cabergoline?
Pleuropulmonary and retroperitoneal fibrosis
What are some dopaminergic treatments?
Non-ergot Dopamine Agonists e.g. Pramipexole, Ropinirole (Oral monotherapy with reduced side effects)
Ergot Dopamine Agonists e.g. lisuride, cabergoline (Oral monotherapy - pleuropulmonary / retroperitoneal fibrosis)
Amantadine - DA reuptake inhibitor, dyskinesia
COMT inhibitors (tolcapone, entecapone)
MAO-B inhibitors (selegiline, rasagiline)
What surgical approaches may be used for PD treatment?
Subtalamic nuleus or GPi
Fetal nigral grafts
Autologous induced pluripotent stem cells
What are some non motor symptoms of PD?
Rapid eye movement sleep behaviour disorder
Excessive daytime sleepiness
Increased psychiatric problems
What can be a cause of non-motor symtoms in PD?
Pathology in brainstem laterodorsal/pedunculopontine
What percentage of patients experience non-motor symptoms?
What percentage of patients experience autonomic dysfunction?
What are some example of autonomic dysfunctional symtpoms?
Orthostatic hypotension, GI disturbances (constipation, gastroparesis, l-dopa uptake), Urinary Incontinence, erectile dysfunction
What causes urinary incontinence and what percentage of PD patients experience it?
Detrusor muscle overactivity, 20-60% of patients - can be treated with muscarinic antagonist
What are anticholinergics used to treat in PD?
Central striatal anti-parkinsonian effects. Autonomic effects such as sialorrhoea.
What are some side effects of anticholinergics?
"turn off all the taps"
Dry mouth, constipation
Cognitive effects in older patients
Cardiovascular disease, hypertension, glaucoma,
Name some muscarinic antagonist used to treat PD (anticholinergic)
trihexyphenidyl, orphenadrine, procyclidine
How many patients present with memory problems at first diagnosis?
How many patients will experience memory problems over 5 years?
What other cognitive problems, beside memory, may occur in PD patients?
Halluncinations, fluctuating attention
What happens to the reward circuit when dopamine levels are lowered?
Lowering dopamine levels means the rewarding 'buzz' received from stimulus is less so than it would be usually.
How may biochemical markers be used to test for PD?
The plasma level of phosphorylated α-synuclein has potential value as a diagnostic tool, whereas the level of total α-synuclein could act as a surrogate marker for the progression of PD.
How could you image alpha-synuclien?
PET or SPECT but suitable marker needed
What is the prion hypothesis of PD?
The discovery of alpha-synuclein's prion-like behaviors in mammals, as well as a non-Mendelian type of inheritance, has led to a new concept in biology, the "prion hypothesis" of Parkinson's disease. The misfolding and aggregation of alpha-synuclein (α-syn) within the nervous system occur in many neurodegenerative diseases including Parkinson's disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA). The molecular basis of synucleinopathies appears to be tightly coupled to α-syn's conformational conversion and fibril formation. The pathological form of α-syn consists of oligomers and fibrils with rich in β-sheets. The conversion of its α-helical structure to the β-sheet rich fibril is a defining pathologic feature of α-syn. These kinds of disorders have been classified as protein misfolding diseases or proteopathies which share key biophysical and biochemical characteristics with prion diseases.
What is the name of the potential antibody vaccine which may be able to target the protein misfolding of alpha-synuclien?
What are the three types of Atypical Parkinsonism?
Progressive supranuclear palsy, Cortico-basal-ganglionic Degeneration, Multiple system atrophy
What are is the main sign for atypical parkinsonism?
Poor response to L-dopa
What are the main symtoms of multiple systems atrophy?
Subtypes MSA-P with parkinsonism, MSA-C with cerebellar signs
Marked autonomic dysfunction (>95%)
L-dopa poor response
What are the pathological hallmarks of MSA?
Cerebellum, pons, and basal ganglia affected
Widespread alpha-synuclein pathology in brain in neurones, oligodendrocytes and astrocytes
CSF testing in MSA - shows higher volume of alpha-synuclein compared to PD, AD and PSP
What are the main symtoms of PSP?
Impaired eye movement (downward gaze - damage to oculomotor nucleus)
Slowed vertical saccades
Falls, often backwards
Hummingbird Sign in MRI due to atrophy of the midbrain tegmentum, with a relatively preserved pons.
What is the prevalence of PSP?
PSP prevalence 1-6.5:100,000
~4,000 in UK
What are some of the hallmarks of PSP and CBD
Tau pathology in neurones and astrocytes
"tufted astrocyte" key pathological feature
H1c tau haplotype strongly associated
What are some of the symptoms of CBD?
Similar to PSP clinically
Prominent cognitive/memory problems
Isolated limb problems, "phantom limb", paraesthesia, myoclonus, dystonia
Lateralisation of symptoms including cognitive
What are some symptoms of post encephalitic parkionson's disease - von Economo's Encephalitis Lethargica
Prominent during 1918-30 flu pandemic
Post flu syndrome with rash and movement disorder
Deep sleep and eye movement symptoms
Rigidity, coarse tremor
Straight tangles in SN
Short lasting response to l-dopa
What parts of the brain degenerates within PD?
Subtantia Nigra, caudate nucleus and putamen.
What percentage of SN neurons are lost before PD symptoms arise?
What does the loss of dopamine's modulatory influence on neuronal activity result in?
Increased inhibitory drive of the excessively active GABAergic medical pallidum/nigra reticulata neurons. Thus the end result of striatal dopamine loss is inhibition of cortically initiated movement (hypokinesia).
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