Parkinson's Plus Disorders Flashcards
Define the term parkinsonism and list the CNS disorders which may present in this way Identify the key neuropathological features of progressive supranuclear palsy (PSP) Identify the key neuropathological features of multiple system atrophy (MSA) Identify the key neuropathological features of corticobasal degeneration (CBD) Research how Parkinson's plus disorders can be distinguished clinically while the patient is alive
How many patients diagnosed with PD are found to have a different parkinsonian disorder post-mortem?
10-15%
Name the 2 PD subtypes
Tremor dominant and akinetic-rigid dominant
Which PD subtype has a better prognosis?
Tremor dominant
Give at least 5 non-PD causes of parkinsonism
Drug-induced (e.g. MPTP), multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, vascular pseudo-parkinsonism, frontotemporal neurodegeneration
Name the 3 disorders covered by the term multiple system atrophy
Olivopontocerebellar atrophy (OPCA), Shy-Drager syndrome, and striatonigral degeneration
Which disorder within multiple system atrophy most closely resembles PD?
Striatonigral degeneration
Which disorder within multiple system atrophy is largely autonomic?
Shy-Drager syndrome
Give the 2 classifications of multiple system atrophy
Predominant parkinsonism (MSA-P) and predominant cerebellar (MSA-C)
Give at least 3 major signs of multiple system atorphy
Tremor, squeaky hypophonia, dysrhythmia of rapid alternating movements, hypermetria
Describe the macroscopic pathology caused by multiple system atrophy
Motor and premotor cortical atrophy, marked cerebellar atrophy, shrinkage of the middle cerebellar peduncle, pons, and inferior olivary nucleus, pallor of the substantia nigra and locus coeruleus
Name the classic sign of multiple system atrophy seen on MRI
Hot cross bun sign
How is the microscopic pathology of multiple system atrophy different to that of PD?
It is both neuronal and glial, whereas PD pathology is just neuronal
Describe the microscopic pathology seen in multiple system atrophy
Alpha-synuclein immunoreactive cytoplasmic and nuclear inclusions in glia and neurons, Papp-Lantos bodies, neutrophil threads
In which cells are the cytoplasmic inclusions of multiple system atrophy most obvious?
Oligodendrocytes
Define corticobasal degeneration (CBD)
A progressive neurodegenerative disorder causing rigidity, clumsiness, and stiffness and jerking of one limb (alien limb syndrome)
Which limb is most commonly affected by alien limb syndrome in corticobasal degeneration?
Arm
Which protein is involved in CBD pathogenesis?
Tau
Name the three brain areas primarily affected by corticobasal degeneration
Cerebral cortex (specifically frontal and parietal cortices), deep cerebellar nuclei, substantia nigra
Describe the microscopic pathology of corticobasal degeneration
Glial and neuronal inclusions, prominent neutrophil threads, balloon neurons
Which part of astrocytes is tau predominantly deposited in?
Proximal processes
What is the most common form of atypical parkinsonism?
Progressive supranuclear palsy
Does progressive supranuclear palsy respond to L-DOPA?
No
Give at least 4 signs of progressive supranuclear palsy
Mild slowing of horizontal saccades, major slowing of vertical saccades, ophthalmoplegia, gradual uphaze and downgaze with no fast corrective saccades, bradykinesia worse on one side, dystonia, tremor
Describe the macroscopic pathology of progressive supranuclear palsy
Atrophy of the basal ganglia, subthalamus, and brainstem
Describe the microscopic pathology of progressive supranuclear palsy
Neuronal loss and gliosis, neuronal and glial tau-positive inclusions (including ‘tufted’ astrocytes and ‘coiled bodies’ in oligodendrocytes)
Describe the difference between microscopic coiled bodies in MSA and PSP
In MSA they have a coiled profile, whereas in PSP they have a circular profile
Which chromosome codes the gene for tau?
17q21
How many exons code for tau?
16
How many isoforms of tau can be produced?
6
What makes tau 3 repeat or 4 repeat?
The number of microtubule binding domains
What is the foetal form of tau?
3R/0N
What is the function of tau?
It is a microtubule associated protein (MAP) which binds to and stabilises microtubules and promotes their polymerisation
Which type of tau is more efficient - 3R or 4R?
4R
Describe the phenotype of the tau knockout mouse
No overt phenotype, as other microtubule associated proteins compensate for its loss
How many potential phosphorylation sites are there on tau, and where are they?
79 - with serine or threonine residues, clustered around microtubule binding sites
How does over-phosphorylation impair the function of tau?
As phosphorylation sites are clustered around microtubule binding sites, it reduces microtubule binding, hence impairing function
Name 2 kinases which phosphorylate tau
GSK-3beta and CDK5
Which types of tau are involved in AD?
All of them
Which types of tau are involved in PSP and CBD?
4R taus
Which types of tau are involved in Pick’s disease?
3R taus
Can patients have both PD and a tauopathy?
Yes
