2 - Neurodegeneration in the Basal Ganglia Flashcards
Pathology of Parkinsons
Loss of dopaminergic cells (black) in substantia nigra pars compacta
Presence in neurons of Lewy bodies
Lewy bodies
Intracellular formations enriched in the protein α-synuclein
Also found in dementia
Striatum
Caudate and Putamen
Inhibitory to thalamus
Direct Pathway
Gpi –> Thalamus –> Cortex
Indirect Pathway
Gpe –> STN –> Gpi
What happens in the pathways in parkinsons
Indirect pathway much more active and direct pathway less active
Thalamus inhibited so Less excitatory drive to the motor cortex
Imaging
Dopaminergic cell loss via Dopamine transporter imaging (DaT0
What can you use to label the projections of DaT scan
SPECT ligands
Motor features of parkinsons
o Resting tremor, bradykinesia (akinesia), rigidity
o Frozen facial expression
o Flexed posture
o Altered gait and postural changes
o Difficulty in initiating and stopping movement
Non-motor features
olfactory dysfunction depression psychotic symptoms cognitive dysfunction dementia (late phase)
How many years do non motor symptoms precede parkinsonian motor symptoms
12-15 years
How do you score parkinsosn
Schwab and England Activities of Daily living
Most common genes associated with parkinsosn
LRRK2
Which gene codes for protein alpha-synuclein
SNCA
MPTP
A drug which is metabolised into MPP+ which is neurotoxic to do dopaminergic neurons
What no. complex of the mitochondrial respiratory chain when dysfunctioned can lead to oxidative stress
Complex I
What are the precursors of dopamine
Ltyrosine -> L-Dopa -> dopamine
What is dopamine oxidised to
Dopamine -> DOPAC -> Homovannilic acid
What are the 3 dopaminergic pathways in the CNS
Mesocortical
Mesolimbic
Nigrostriatal
Dopamine receptors
GPCR
D1 receptor subtypes
D1
D5
D2 receptor subtypes
D2
D3
D4
L-DOPA
Levodopa
What is LDOPA combined with
DOPA decarboxylase inhibitor
DOPA decarboxylase inhibitor
Carbidopa
Benserazide
Adverse effects of L-DOPA
Nausea, impulse control disorders, postural HT
On off effect, wearing off
dyskinesia, dystonia
Dopaminergic Agonists
ropinirole, pramipexole, rotigotine, pergolide, bromocriptine, cabergoline
Rotigotine
Transdermal Patch
Apomorphine
Infusions
MAOB inhibitors
• Rasagiline, selegiline
Anticholinergic (antimuscarinic) compounds
Orphenadrine, procyclidine, trihexyphenidyl
COMT inhibitors
• entacapone, tolcapon
Which drugs can induce cardiac fibrosis
pergolide, cabergoline, bromocriptine
Which chromosome is protein huntingin on
4
What codon are the abnormal repeats (in huntingtons)
CAG
Glutamine
What is the pathology of huntingtons
degeneration of striatal neurons
cortical atrophy
Loss of medium size spiny neurons (striato-pallidal and striato-nigral pathways)
Intranuclear inclusions of huntingtin
Cause of neurodegeneration in huntingtons
Excitotoxicity
Aggregates of huntingtin
Increased oxidative stress
Why is there increased drive to the motor cortex in huntingtons
Destruction of striatum so both direct and indirect pathways are lost
Increased thalamic drive so Increased drive to motor cortex
Symptoms of huntingotns
Choreic movements
gait abnormalities
lack of coordination
cognitive impairment
Vesicular amine transporter inhibitor
HUNTINGTONS
tetrabenazine
haloperidol, olanzapine
Anti-dopaminergic drugs to treat huntingotns
Antidepressants for huntingtons
imipramine, amitriptyline