huntingtons disease, alzheimers

draw the map of early motor symptoms in huntingtons

On the figure below, draw the four main dopamine pathways in the human brain. Label the pathways and the key structures within them (4 marks)

0.5 marks for name of pathway, 0.5 marks for correct origin and target

overview of huntingtons

• autosomal dominant

• progressive brain degeneration

• symptoms start in middle life

symptoms of huntingtons

• cognitive problems eg dementia

• severe motor dysfunction

• psychiatric problems

  • depression, anxiety, aggression, compulsive behaviour

aeitology of huntingtons

• trinucleotide repeat disorder

  • depends on number of CAG (Q) repeats in huntingtin protein

  • the more repeats, the more severe disease

how many repeats for 50% risk of child to get huntingtons

>36

huntingtin protein

• ubiquitous

• function is unclear

• mutant huntington seems to be toxic - mitochondrial dysfunction?

• whole brain is affected

  • basal ganglia cells are more sensitive to the damage

  • indirect pathway MSNs lost first

early motor symptoms in hungtintons are caused by what

• less inhibition of the thalamus by the indirect pathway

• resulting in increased unwanted movement

  • gives rise to chorea symptoms of huntingtons

why does dopamine have reduced effect via indirect pathway?

loss of indirect pathway striatal GABAergic neurons

draw the map of late motor symptoms in huntington’s disease

explain the late motor symptoms of huntingtons

• MSN neurons are lost from direct and indirect pathway

• inc inhibition of thalamus and paucity of movement

pharmacological treatments for huntingtons

• tetrabenzanine (VMATi)

• chloropromazine (dopamine antagonist)

• haloperidol, olanapine, risperidone, quietapine (dopamine antagonists)

tetrabenazine

• inhibitor of VMAT (vesicular monoamine uptake)

• decreases dopamine levels

• used in huntingtons

chloropromazine

• dopamine antagonist

• usually used as antipsychotic

haloperidol, olanzapine, risperidone and quietiapine

• dopamine antagonists

• antipsychotics

symptoms of alzheimers

• loss of declarative memory

• leads to cognitive functions - reasoning, language, calculation

• psychosis with hallucinations and delusions

• final stage sufferers of alzheimers characteristics

  • mute

  • incontinent

  • bed-ridden

epidemiology of alzheimers

• prevalence increases with age

• mean life expectancy is only 7 years

  • due to pneumonia, cardiovascular disease, wasting, dehydration

increase risk factors for alzheimers

• female

• older

• obesity

• poor cardiovascular health

• smoking

• genetic factors

• head trauma

• down syndrome

• poor sleep pattern

what dec the risk of alzheimers

• male

• physical activity

• social engagement

• mediterranean diet

• NSAID usage

early onset genetic risk factors for alzheimers

• Amyloid precursor protein (> 30 different mutations)

• Presenilin (γ secretase)

late onset of alzheimers genetic risk factors

• Mostly sporadic (no identifiable cause)

• Apolipoprotein E mutations increase risk

  • Heterozygotes 3-fold

  • Homozygotes 15 to 20-fold

down syndrome risk factor for alzheimers

• Early onset Alzheimer’s (age 40)

• Amyloid precursor protein gene is on chromosome 21

progression of disease and areas of brain affected

• preclinical areas of brain affected

  • basal forebrain and hippocampus

• mild to moderate areas affected

  • large area of basal forebrain

  • some areas of cortex

• severe disease areas of brain affected

  • most of the brain

donzepil

• AChE inhibitor in CNS

• used for mild to moderate AD

Give 2 examples of AChE inhibitors which are used for mild to moderate alzheimer’s disease. [2 marks]

• donzepil

• rivastigmine

rivastigmine

• CNS selective

• reversible AChE inhibitor

• mild to moderate AD

Give example of a drug for mild to moderate alzheimer’s disease which allosterically enhances nAChR?

• galantamine

galantamine

• CNS selective

• allosterically enhances nAChR

• mild to moderate AD

memantine

• nmda antagonist

• moderate to severe AD when AChEI are not tolerated

• side effects : constipation, hypertension, headache, dizziness, drowsiness

What drug is considered for alzheimer’s disease when acetylcholinesterase inhibitors are not tolerated? Side effects may include constipation, hypertension and headache.

Memantine

Mechanism of memantine in AD

• used in moderate and severe AD

• NMDA antagonist

  • neuroprotective effect perhaps

• improvements short term

antipsychotics used in AD

• can cause premature death, used to control the difficult behaviour such as danger to self or others

• target specifics behaviours such as danger to self or others

• risperidone, haloperidol

which antipsychotics are licensed for Alzheimers Disease

• risperidone

• haloperidol

amyloid formation

• amyloid precursor protein mutations inc beta secretase cleavage

• presenilin mutations increase the rate of gamma secretase cleavage

• this leads to alpha beta peptide which forms amyloid plaque

mutations for formations of amyloid plaques

• Amyloid precursor protein mutations

• presenilin mutations

drug targets for amyloid plaque formation

• block cleavage - secretase inhibitors

• MAb vs monomers

• MAb vs oligomers

• MAb vs plaques

• Oligomerization inhibitors

biologics in trial against amyloid plaques

• adacanumab

• lecanemab

adacanumab

• monoclonal antibody vs amyloid beta plaques

• appeared to slow rate of decline

• only in memory and thinking engage and only at higher doses

• high cost

lecanemab trial

• Ab vs soluble oligomer

• phase iii

• slows decline

• some serious side effects

How is AD progression monitored on a biological level?

• Aβ accumulation is an early event

• glial activation follows Aβ

• tau accumulation is best correlate of clinical decline and neuronal dysfunction.

tau as a target

• initial studies on aggregation, kinases → failed

• immunotherapies may have promise

neurofibrillary tangles

hyperphosphorylation leads to neurofibrillary tangles and mitochondrial damage, denoted by bursting mitochondrion

are tau and amyloid beta prion like?

yes

alternative targets for AD

• Tau

  • initial studies on aggregation, kinases → failed

  • immunotherapies may have promise

• Type 2 diabetes

  • insulin resistant may compromise brains repair function

  • GLP-1 agonist liraglutide works in animal models

  • may work in non diabetics too

• neuroinflammation

  • epidemiological studies - NSAID

    • clinical trials show more harm than good, little effect