Parkinson's

Question 1

Types of movement disorders

Answer 1

Upper motor neurone diseases: stroke, MS, amyotrophic lateral sclerosis (ALS)

Lower motor neuron disorders: peripheral neuropathy, myasthenia graves, immune disease against NMJ nAChRs.

Involuntary movement disorders: Parkinson’s, Huntington’s, tremor

Cerebellar disorders: various tumours

Question 2

Symtpoms

Answer 2

Neurodegeneration of the extrapyramidal system, including the basal ganglia: loss of DA

unable to perform normal motor function: poor and slow movement (bradykinesia), postural abnormalities, rigid movement, tremor, mask-like expression

later stages:
depression, dementia, endocrine dysfunction

Question 3

Basal ganglia role, and effect in parkinsons

Answer 3

they programme how, when and where to move. they put motor plans into action

in parkinsons, the individual is unable to specify the programmes accurately

Question 4

neurobiology and other brain regions affected.

Answer 4

Nigrostriatal pathway affected in parkinson’s

there is loss of pigmented neurones in the substantial nigra pars compacta in Parkinson’s

60-70% loss of dopamine in the striatum. Mood changes from loss of DA in mesolimbic pathway (but less so). Decrease in hypothalamic amines (causing endocrine dysfunction). Loss of cortical NA and ACh (cognitive impairments). loss of substance P and enkephalins, compounding motor impairments.

There is loss of DA nerve terminals, but not loss of the post-synaptic D2 receptors.

Question 5

Imaging of Parkinson’s/diagnosis

Answer 5

PET scans can visualise DA with use of radioligands which bind to DAT.

SPECT with DAT ligand

Question 6

Pharmacological treatment

Answer 6

L-DOPA is administered with a peripherally acting DOPA decarboxylase inhibitor (Carbidopa), in order to increase CNS dopamine, without increasing peripheral DA. Not entirely effective, choreic movements develop after 2 years, rapid fluctuations in clinical states, nausea/anorexia, and psychotic effects from increase in mesocortical signalling.

D2 agonists are also used, as D2 is present in high concs in the basal ganglia (Gai-coupled).

Ropinirole is a full agonist at D2-like receptors (D2/3/4), which all decrease adenylyl cyclase activity, thus decreasing cAMP, open K+ currents, and decrease Ca influx through VGCCs.

MAOIs (MAO-B inhibitor - selegiline) and COMT inhibitors may also be used (sometimes in conjunction with L-DOPA)

Amantidine may also be used, as it increases DA release.

Adenosine A2A antagonists has been approved as an add on for L-DOPA treatment.

mAChR antagonists may be used to control tremor.

Question 7

Genetic causes

Answer 7

15% of patients have a first-degree relative with PD. Familial early onset PD is rare, with only 5% of cases.

PARK1 encodes the protein alpha-synuclein, which in PD is seen to aggregate. Early onset PD with Lewy Bodies and marked rigidity is associated with autosomal dominant mutations in PARK1.

an autosomal recessive early onset form of PD with restricted SN cell loss, but no Lewy bodies is associated with mutation in PARK2 (encodes parkin, a ligase)

PARK6 mutation results in autosomal recessive form of PD

LRPK2 and PARK1 mutations are present in sporadic cases of parkinsonism, likely high risk factor