Neuropathology of Parkinson's Disease Flashcards
Identify the key neuropathological features of PD List the stages of pathology progression seen in the brain in PD Discuss how well the post-mortem staging of pathology correlates with motor and non-motor symptoms seem during life Evaluate the 'dual-hit hypothesis' of an environmental trigger for PD
Is PD more common in males or females?
Males
What is the prevalence of PD in males and females?
19 per 100,000 men, 9.9 per 100,000 women
Give 4 cardinal features of PD
Bradykinesia, postural instability, tremor, and (cogwheel) rigidity
How much must dopamine levels be depleted by before symptoms appear?
70%
What causes the impaired mobility in PD?
When dopaminergic neurons in the substantia nigra die, the reduction in dopamine release in the striatum causes cholinergic neurons there to overstimulate their targets, impairing mobility
What is the difference between PD with dementia, and dementia with Lewy bodies?
In PD with dementia, the dementia onset is more than a year after the onset of PD. In dementia with Lewy bodies, the dementia is evident before or within a year of akinetic-rigid syndrome (PD)
Where is the main site of Lewy bodies in PD?
Substantia nigra
Name an alpha-synucleionpathy than causes parkinsonism other than PD
Multiple system atrophy (MSA)
Name at least two tauopathies which cause parkinsonism
Progresisve supranuclear palsy (PSP), corticobasal degeneration (CBD), Guam Parkinson dementia complex
Name a TDP-43 disorder which causes parkinsonism
Perry syndrone, frontotemporal lobar degeneration
Name a toxic cause of non-degenerative parkinsonism
MPTP, manganese poisoning
Which virus typically causes post-encephalitic parkinsonism?
Influenza
Which class of drugs typically cause drug-induced parkinsonism?
Anti-psychotics
In which area of the substantia nigra is neuronal loss typically the most pronounced in PD?
Ventrolateral
Which pathways are most affected by PD?
Nigrostriatal
Does PD typically affect mesocortical pathways?
No
How do adult substantia nigra pars compacta neurons have a distinct physiological phenotype?
They have pacemaker-like properties leading to frequent intracellular calcium transients, in order to maintain a basal dopaminergic tone in target structures and permit movement
Why are ventral tegmental area dopaminergic neurons less susceptible to PD?
Unlike substantia nigra pars compacta neurons, they have no calcium transients and lower calcium channel density. They also express high levels of the calcium ion buffering protein calbindin. This is believed to make them less suceptible
Describe the appearance of the substantia nigra post-mortem in PD patients
Paler than normal due to loss of melanin (dopaminergic neurons are melanin pigmented)
What causes alpha-synuclein to change conformation to an alpha-helix in normal physiology?
Exposure to negatively charged lipids
Where is alpha-synuclein located in healthy individuals?
Pre-synaptically
What are Lewy bodies?
Tightly packed inclusions of alpha-synuclein
How are type B alpha-synuclein oligomers toxic to cells?
They intercalate themselves into the membrane and form a pore, resulting in toxicity
Describe the neuritic body hypothesis of Lewy neurodegeneration
Lewy bodies form in the synaptic terminal, where alpha-synuclein is most concentrated, and then are retrogradely transported into the axon towards the cell body, where they cause the largest burden of pathology
According to the Braak hypothesis, where does Lewy body pathology start in the brain?
Dorsal motor nucleus of vagus and the anterior olfactory nucleus
Where are Lewy bodies found in Braak stage 3?
Central subnucleus of the amygdala, substantia nigra, nucleus basalis of Mynert
Where are Lewy bodies found in Braak stage 4?
Transition zone between allocortex and neocortex, anterior cingulate
Where are Lewy bodies found in Braak stage 5?
Insular and cingulate cortices
Describe the difference in frontal-executive deficits between PD dementias and AD
In PD, frontal-executive deficits develop early and are prominent. In AD, these develop later and are less severe
Describe the difference in memory deficits between PD dementias and AD
In PD, retrieval memory is impaired but encoding memory less affected. In AD, early memory complaints are common with both retrieval and encoding memory affected
Describe the difference in visuospatial deficits between PD dementias and AD
In PD, impairments are often found. In AD, they are present but much less pronounced
Describe the difference in behavioural deficits between PD dementias and AD
In PD, visual hallucinations are common. In AD, hallucinations are uncommon, with suspiciousness and disinhibition more common
Where are Lewy bodies found in Braak stage 1?
Dorsal motor nucleus of vagus in the medulla
Where are Lewy bodies found in Braak stage 2?
Locus coeruleus in the pons
