neurodegenerative disorders Flashcards
Examples and brief overview
AD: loss of cholinergic and adrenergic neurones in brainstem. starts in hippocampus, but spreads.
PD: loss of DA neurones in substantial nigra, causing motor control and coordination defects
ALS: selective loss of motor neurones in CNS, leading to progressive loss of muscle control until death from respiratory failure.
also Huntington’s and MS
Protein misfolding examples, implications, and mechanism of forming/spreading
Tau (AD and more), B-amyloid (AD), a-synuclein (PD) and Huntingtin (huntington’s)
While misfiles are often seen in these diseases, other disease can also contain them.
Often result in neuroinflammation.
The proteins go from monomers to oligomers to protofibrils, to fibrils. This fibrils are aggregates that can spread from cell to cell, or fragment and then also spread.
Huntington’s mechanism, symptoms and treatments
The amount of CAG repeats in huntingtin gene determines the risk of the disease. High number of repeats will lead to the aggregation of huntingtin
Causes memory lapses, involuntary movements, loss of motor control, and mental health conditions.
No treatments, only symptomatic alleviation, e.g., SSRIs, or lifestyle adjucstments, e.g. diet, physio, exercise
AD mechanism, and treatment
Form senile plaques (B-amyloid) and neurofibrilary tangles (tau aggregates) also sees reduced ACh transmission and glutamatergic excitotoxicity.
AChE inhibitors to increase tonic [ACh]
memantine, an uncompetitive NMDA inhibitor to prevent the glutamatergic excitotoxicity. Preventative treatment.
antidepressants and antipsychotics for managing symtpoms of more severe dementia
Monoclonal antibodies for B-amyloid being tested, with modest results (32% decrease in decline)
PD mechanism + aggregate, symptoms, and treatment
Lewy bodies form (a-synuclein aggregates). Loss of the nigrostriatal neurones, and compromised DA transmission in the striatum. Degrades the DA mediated control over the extrapyramidal motor system - vulnerable to excitotoxicity.
Tremors, bradykinesia (slow movements), rigidity, urinary tract problems, constipation, depression/anxiety, and dementia
L-DOPA first line treatment (DA precursor), often used with carbidopa, which is a peripherally acting L-DOPA decarboxylase inhibitor (to prevent increased DA in periphery).
D2 agonists may also be used, e.g., ropinirole, pramipexole, which have bad side effect profile: hallucinations, compulsivity, impulsivity, and activation of other DA pathways.
MAOIs may also be used as an add on therapy.
