Dementia

Question 1

Give four main types of Dementia disorders

Answer 1

• Alzheimer’s disease
• Dementia with Lewy bodies
• Frontotemporal dementia
• Vascular dementia

Question 2

What are the two ways to look at the Neuropathlogically presentations of dementia

Answer 2

• Microscopically
  
  • Intra neuronal inclusion bodies
  • Extra neuronal changes (plaques)
• Macroscopically
  
  • Generalised brain atrophy
  • Region specific atrophy depending on dementia disorder
  • Enlarged ventricles

Question 3

Give some microscopic causes of Dementia

Answer 3

• Misfolding of proteins
• Abnormal accumulation
• Neuroinflammatory environment
  
  • Damaged neurons
    
    • Cell death
• Proteins involved:
  
  • Amyloid
  • Tau
  • Synuclein

Question 4

What dementia disease is caused by Tau abnormalities?

Answer 4

• Alzheimer’s disease
  
  • can also be caused by Amyloid abnormalities
• Frontotemporal dementia

Question 5

What is Tau?

Answer 5

• a highly soluble protein found mostly in the brain
• it is mostly present in axons
• it has 6 isoforms and disease process lead to hyperphosphorylated forms of the protein

Functions

• modulate the stability of axonal microtubules
• transport

Question 6

Abnormalities in Tau

Answer 6

Hyperphosphorylated forms of Tau

• Paired helical filaments (PHF)
• Neurofibrillary tangles (NFTs)
• PHFs –> NFTs –> Neurodegeneration
  ​
• Phosphorylation of tau is regulated by activated kinases
  
  • Hyperphosphorylation of tau can result in the self-assembly of tangles of paired helical filaments (PHF).

Question 7

Explain Neurofibrillary tangles

Answer 7

Described by Alois Alzheimer: consist of paired 10-nanometer diameter filaments twisted around each other in a helical manner (paired helical filaments HF)

• Seen in neurons after staining
  
  • Hematoxylin
  • Eosin
  • Bielschowsky
  • Bodian
  • Congo red
• Most commonly found in temporal lobe structures
  
  • Hippocampus
  • Amygdala

Question 8

Amyloid Precursor Protein (APP) in normal and diseased brains

Answer 8

• APP is a transmembrane glycoprotein which is broken down and eliminated in normal brain
• APP is split by enzymes ß-secretase then y-secretase.
• ß-amyloid is a peptide of 39–43 amino acids
  
  • Most common isoforms are Aβ40 and Aβ42
• Aβ40 is more common of the two, but Aβ42 is the more fibrillogenic and is thus associated with disease states.
• Fragments accumulate to form plaques, the build-up of ß-amyloid plaques cause neuronal damage

Question 9

Frontotemporal Dementia (FTD)

Answer 9

• Tau pathology, Pick’s disease described by Arnold Pick 1892
• Pick bodies
  
  • rounded, microscopic structures found within neurons
  • Aggregates of tau
• Hirano bodies
• Neurons swell, taking on a “ballooned” appearance. Hence, called balloon cells.
• Plaques and tangles are not found in Pick’s disease.
• FTD is present in frontal and anterior temporal lobes.

Question 10

What are Synuclein abnormalities?

Answer 10

• Parkinson disease
• Dementia with Lewy bodies
• Fibrillary aggregates of alpha-synuclein protein

Question 11

What are Synuclein?

Answer 11

• Small, presynaptic neuronal proteins comprised of α-, β-, γ-synucleins of which only α-synuclein aggregates
• Proteins of 140 amino acids, that is expressed predominantly in neurons
• Found in neurons and glial cells
• Function as lipid vesicle binding, inhibition of phospholipase D2 and protein kinase C, dopamine uptake and as a chaperone have been ascribed to α-synuclein.
• Predominantly expressed in neocortex, hippocampus, substantia nigra and cerebellum.
• Can aggregate to form intracytoplasmic inclusions in neurons (Lewy bodies).

Question 12

What are Lewy bodies?

Answer 12

• Spherical, intranuclear, cytoplasmic eosinophilic inclusions
• Abnormally truncated and phosphorylated neurofilament proteins
• Contain:
  
  • Alpha-synuclein
  • Ubiquitin
  • Associated enzymes.

Question 13

Vascular dementia

Answer 13

• Can result from ischemic or hemorrhagic brain damage.
• The three most common mechanisms causing disease
  
  • Single, strategically placed infarcts
  • multiple cortical infarcts
  • subcortical small-vessel disease.
• Clinical deficits are determined by the size, location, and type of cerebral damage.
• Because of the variety of pathogenic mechanisms involved in vascular dementia, clinical manifestations can vary.

Question 14

What steps need to be taking to reach a diagnostic conclusion of a Dementia disease?

Answer 14

• History
• Examination
• Bloods/ECG
• Neuropsychological
• Behavioural/Activities of Daily Living
• Neuroimaging

Question 15

What examinations are done when Dementia is a differential diagnosis?

Answer 15

• General examination
• Neurological examination
• Mental State Examination

Question 16

What bloods/ ECG would be taken for a neurological consultation?

Answer 16

• FBC
• ESR
• U/Es
• LFT
• TFT
• B12/folate
• Syphilis serology
• ECG

Question 17

What Imaging can be done during a neurologic consultation?

Answer 17

• CT
• MRI
• SPECT
• PET

Question 18

What treatment can be given for Alzheimer’s dementia?

Answer 18

• Donepezil,
• Rivastigmine,
• Galantamine,
• Memantine

Question 19

What treatment can be given for Vascular Dementia

Answer 19

• Identify & Treat vascular risk factors
  
  • Hypertension
  • Diabetes
  • Hyperlipidaemia
  • AF
  • Carotid disease
• put patients on anticoagulants

Question 20

Treatment for Frontotemporal dementia

Answer 20

• SSRI antidepressants

Question 21

Treatment for Dementia with Lewy Bodies

Answer 21

• Donepezil
• Rivastigmine

Question 22

What are future management strategies for dementia?

Answer 22

• Prevention
• Slow down progression
• Introduce disease-modifying treatment
• Cure

Overall support patients to live well with dementia

Question 23

What are the fixed risk factors for dementia?

Answer 23

• Age
• Genetics
• Brain injury
• Education level
• Alcoholism

Question 24

What are changeable risk factors fro dementia?

Answer 24

• Diabetes
• Hypertension
• Brain injury
• Sleep disorders
• Depression
• Obesity
• Physical Health

Question 25

What methods can be used to slow down the progression of dementia?

Answer 25

* Use available drugs: Donepezil, Rivastigmine, Galantamine, Memantine, Huperzine A * Psychological support * Lifestyle changes: Vitamins B12 and D, diet, exercise, cognitive stimulation * Timely diagnosis and treatment of physical and mental health conditions

Question 26

The use of Vitamin E in dementia treatment

Question 27

The use of NSAIDs in Dementia treatment

Answer 27

* many side effects *

Question 28

The use of Ginkgo Biloba in Dementia treatment

Answer 28

* Extract EGb 761 * 17 active metabolites; 3 antioxidants * Dose: 120-240 mg * Side Effects * Allergy * Bleeding * Skin reactions * GIT * Drug interaction

Question 29

What other variables cause an acceleration in decline?

Answer 29

* Psychosis * Anti-psychotic treatment * Depression * Delirium * Infections * Anaesthesia * Decreased cognitive reserve * Physical Inactivity * Genetic status * Age * Polypharmacy * Hypothyroidism/vitamins deficiency?

Question 30

What methods can be used to modify the disease?

Answer 30

Targeting the **Tau** and **Amyloid** proteins that misfold and accumulate in the brains of patients with AD * Anti-amyloid treatment: * destroys existing amyloid plaques: *Bapineuzumab, Solanezumab, Crenezumab & Gantenerumab* * *​CNS clearance hypothesis* * *peripheral sink hypothesis* * stops aggregation: through agents blocking or modulating beta and gamma secretases * Anti-Tau treatment * reformulated methylene blue * reduces levels of aggregated or misfolded Tau proteins