Dementia: Pathology and Symptoms

Question 1

Dementia

Answer 1

• Dementia: loss of cognitive functioning that affects daily life and activities
• Worldwide, approx. 50 million people with dementia. Set to increase as populations age
• Different types:
  
  • Alzheimer’s Disease (AD) (most common: 50-70% of cases)
  • Vascular (multi-infarct) dementia
  • and others…

Question 2

Vascular (multi-infarct) dementia

Answer 2

• Second most common cause of dementia
• Loss of cognitive functioning due to a series of small ‘silent’ strokes
• Symptoms: progressive cognitive impairment, that occurs step-wise, after each stroke
• Some improvement between each stroke possible
• Risk factors: age, high blood pressure, high cholesterol, diabetes, smoking
• Early detection essential: treatment involves targeting these risk factors,
• Diagnosis can be difficult since features overlap with other dementias

Question 3

Alzheimer’s disease

Answer 3

• Age biggest risk factor
• 0.5% prevalence at 55 years
• Risk then doubles every five years (60yrs: 1%, 70 yrs: 4%, 80 yrs ~15 to 20%)
• About 7.7 million new cases of AD each year. Globally, someone is diagnosed every 4 seconds (Source: WHO)
• Early-onset familial Alzheimer’s disease (EOFAD) shows a clear inheritance pattern
• Minority of cases (1%), but studies have identified specific genes responsible
• Symptoms and progression:
• AD progresses from Mild to Moderate to Severe
• Initial symptoms are in memory domain
• These worsen over time and progress to other domains
• In later stages: mood and behavioural disturbances, loss of independence

Question 4

Mild Cognitive Impairment (MCI)

Answer 4

• Mild Cognitive Impairment (MCI) is a clinical diagnosis that indicates a high risk of transition to AD
• Criteria for the Diagnosis of Mild Cognitive Impairment (MCI)
• Evidence of impairment (from cognitive testing) in one or more cognitive domains
• Daily function not impaired

Question 5

AD treatment options

Answer 5

• The available pharmacological therapies only treat symptoms, with temporary clinical benefits. These cholinesterase inhibitors were discovered 25 years ago
• They increase the levels of the neurotransmitter acetylcholine; Acetylcholine (Ach) has an established role in learning and memory
• In the synapse, ACh is broken down by acetylcholinesterase (=enzyme)
• By blocking that enzyme, acetylcholinesterase inhibitors (AChEIs) increase ACh.
• No new drug has been marketed for nearly 20 years. Main obstacle is a lack of understanding as to exactly what causes AD
• 3 major theories (Cholinergic, Amyloid, Tau) that have guided drug development

Question 6

Cholinergic hypothesis

Answer 6

• Post-mortem studies in the mid-1970s found reduced levels of the enzyme responsible for the synthesis of acetylcholine (ACh), in the cortex of AD patients
• In AD, severe and selective loss of cholinergic neurons in basal forebrain (Whitehouse et al., 1982)
• Detectable at preclinical stages and advances as the disease progresses (Arendt et al., 2015)
• Cholinesterase inhibitors (AChEIs) improve symptoms in about 50% of cases
• Improvements in cognition are sustained for ~2 years on average but then become ineffective (Doody et al., 2001) e.g. Donepezil
  • They are not disease modifying i.e. course and progression of disease are not treated
  • Not all patients respond to the drug
• This hypothesis is no longer favoured because ACh is not the only neurotransmitter system affected by AD and other disorders affect ACh → loss of cholinergic neurons is probably a knock-on effect of some other pathology

Question 7

Major hallmarks of AD

Answer 7

1. Amyloid-beta plaques
2. Neurofibrillary tangles

Question 8

Amyloid plaques

Answer 8

• Amyloid Beta (Aβ) is a fragment of a larger protein called APP found in healthy neurons but something goes wrong in AD → it gets broken up in a dysfunctional way in AD
• In AD, abnormal cleavage of APP leads to higher levels of Amyloid Beta (40 and 42)
• Amyloid Beta 40 is soluble and toxic
• Amyloid Beta 42 is insoluble and ‘clumps’ into toxic plaques
• Familial AD implicates genes involved in the production of Amyloid Beta

Question 9

Neurofibrillary tangles

Answer 9

• Tau protein = stabilises the microtubules that transport nutrients and molecules from the cell body to the axon and dendrites.
• In AD abnormal chemical changes affect tau
• It becomes ‘hyperphosphorylated’ and forms neurofibrillary tangles (NFT)
• These impair microtubule function (it gets blocked and dies)

Question 10

Measuring amyloid

Answer 10

• Positron emission tomography (PET) uses a radioactive ‘tracer’, which is injected into a vein
• More expensive and less safe than MRI
• 11C-PIB is a tracer that binds to Aβ plaques
• Higher binding in AD patients
• Amyloid levels predicts conversion from MCI to AD → shows good evidence that amyloid is important in the development for AD

Question 11

Progression of amyloid plaques in AD

Answer 11

• Post-mortem and PET imaging studies have shown that plaques follows a characteristic pattern as AD progresses
• Begins in hippocampal regions, then spreads into temporal lobe, frontal; eventually affecting entire cortex
• Spread of Tau pathology similar to that seen with amyloid, but seems to occur later than amyloid

Question 12

Amyloid cascade hypothesis

Answer 12

• Plaques detectable very early in the disease process
• The ‘amyloid cascade hypothesis’ states that build-up of amyloid is the initiating event in AD, which then triggers symptoms and other pathology
• Limitations:
  
  • All drug treatment strategies based on Amyloid hypothesis have so far failed
  • Up to 30% of cognitively normal controls show high levels of amyloid, measured by PET scans
  • Amyloid load doesn’t correlate with symptoms in AD (Tau correlates better)

Question 13

Anti-amyloid drugs

Answer 13

Strategies include:

1. Block/inhibit the overproduction or aggregation of Aβ - inhibit the enzymes which break down APP into Aβ

• Gamma secretase inhibitors
• Beta secretase inhibitors

2. Promote clearance

• Active immunisation
• Passive immunisation

⇒ However all drug treatment strategies based on Amyloid hypothesis have so far failed - most drugs don’t make it to the clinical trial stage and even if they do, they have all completely failed in treating the disease

Question 14

Summary and future direction of AD research

Answer 14

• Despite decades of research, no effective treatment for AD
• Drugs to reduce Tau pathology are in development
• Perhaps preventative strategies are better..
• Amyloid removal in middle age?
• Target risk factors (obesity, diabetes, high blood pressure, physical inactivity, smoking?)