Dementia & Alzheimer's Disease

Dementia- is a state of cognitive impairment resulting from the progressive lose of previously acquired mental abilities

• Cognitive impairment - which prevents the normal accomplishment of tasks of daily living such as cooking, cleaning etc.
  
• A deline in memory- makes independant living impossible
  
• A deline in thinking, planning and organising daily activities
  
• Gradual loss of orietation in space and time
  
• A deline in emotional control or motivation or a change in social behaviour
  

Condition causing Dementia

• Alzheimer's disease (AD)
  
• parkinson's disease (PD)
  

Alzheimer's Disease (AD)

Aetiology

• AD is characterised by both cell structure and biochemical changes

- it is associated with the presence of amyloid plaques and neurofilbrillary tangles in the brain. These cause neuronal death in cortical and subcortical regions.

- Amyloid plaques are formed by the accumulation of beta-amyloid of tau proteins. The reasons why these occur are not understood.

1st explaination
- Amyloid precursor protein (APP) abundantly expressed in the membranes of many nerve & gila cells and they are used as function for cell structure and cell-cell recognition.
- In normal life APP is produced and then secretase enzymes sever the chain and release A-beta peptide into the extrecellular space.
* In AD, too much A-beta is produced or it is not being removed properly - so formed the beta-amyloid plaques.
- as the plagues increase in size, they appear to stimulate an autoimmune inflammatory response.
- they inferfere with synaptic function and the regulation of transmitter reuptake.
- excess extracellular transmitter due to impaired reuptake may generate excitoxicity; so eventually cells adjacent to the plaques die.


2nd explaination

• it is also thought that declining memory and cognitive function results from a lack of acetylcholine and an excess of excitatory amine acids, especially glutamate
• Acetlycholine is normally broken down by 2 cholinesterase enzymes, actylcholinesterase and butyrylcholinesterase. In AD, the deline in activity of acetylcholine in accompanied by a decrease in the production of acetylcholinesterase, further contributing to the deline of acetylcholine levels.
  
• Glutamate is a major excitatory neurotransmitter. Its action on the NMDA ( N-methyl-D-aspartate) receptor can lead to overstimulation of neurones, causing permanant damage.

Hypothese on causes of AD

• Genetic factors : Faulty genes
  
• Environmental Factors : Health and degeneration
  

Risk Factors

• Female ( Because females tend to live longer than males)
  
• Head injury
  
• Parkinson's disease
  
• hypothyroidism
  
• chronic exposure to aluminium
  
• cardiovascular disease
  
• smoking
  
• chronic high alcohol intake
  

* Average survial time from diagnosis is 10 years, although patients and their familiesand carers often experience a significant decrease in quality of life for a large part of this time.

Sign and symptoms

AD is characterised by a gradual decline in cognitive and memory function. Therefore, it can present in many ways. Physical signs are:

1. unable to perform daily activities, such as dressing, washing, feeding
   
2. behaviour problems
   
3. reduced muscular function
   
4. sleeplessness
   
5. aggression
   
6. apathy - the feeling of not being interested in or enthusiastic about anything
   
7. delusion and hallucinations
   
8. loss of autonomic control

Symptoms

1. Amnesia - memory impairment ( impaired ability to learn new information or recall info)
   
2. Aphasia - Language disturbance
   
3. Apraxia - impaired ability to carry out motor activities despite intact motor function
   
4. Agnosia - failure to recognise or identify objects despite intact sensory function
   
5. Disturbance in executive function ( planning, organising, sequencing and abstracting)
   

Faulty Genes

• Chromosome 21: APP gene
  
• Chromosome 19: APO E4, a form of apolipoprotein
  
• Chromonsome 1 & 14: Protein called prosenilin-2 & presenillin-1
  

Role of Apolipoprotein E (APO E)

• it is a plasma lipoprotein that is one of the principal constituents of chylomicrons and a very low density lipoprotein (VLDL)
  
• it plays a vital role in cholesterol transport in the blood.
  
• 3 known isoforms of APO E, coded by APO E2, APO E3 and APO E4 genes.
  
• APO E4 genotype : implicated as a risk factor for AD
  
• Recent studies : APO E4 may influence the CNS 's response to injury

Investigations

• As the condition predominately affects cognitive and memory functions, the investigations focus on these areas rather than physical examinations.
  
• it is also possibke to make a presumed diagnosis of AD, as a definiti diagnosis in only possible through autopsy
  
• A number of assessment methods can be utilised that define both cognitive and memory function. This includes:
  

1. Mini Mental State Examination (MMSE) - 5 x cognitive Domain Tested
   
   • Orientation: ( what day of the week is it? / what building are we in? )
     
   • Memory (1) : Immediate word recall
     
   • Attention & calculation: Counting & spelling backwards
     
   • Memory (2) : Delayed recall
   • Language Writing & drawing: Shown 2 daily item & name them. Following simple instructions, sentence writing & intersecting shape drawing.
     
   Maximum score of 30: AD patients will score <26
2. Alzheimer's disease Assessment Scale
3. The blessed test of information
   

Neuroimaging- using techniques such as :

• MRI ( Magnetic Resonance Imagining) - AD's patients shown enlarged ventricles and sulci
  
• CT
• PET (Position emission Tomography) scans- show the differences in brain activity between a norma brain and a brain affected by AD.
  

Management - the aim of treatment is to relieve symptoms and prevent the progression of the disease.

• Four drugs are currently available in the UK

1. Cholinesterase inhibitors- donepezil
   
2. Galantamine
3. Rivastigmine
   
4. NMDA-receptor antagonist - Memantine

Cholinesterase inhibitors ( e.g. Donepezil) CI

- Approximately 30-50% of patients show a definable decrease in their rate of cognitive decline after 3 months of treatment.
- the same degree of modest improvement in approx. 30-40% of patients with mild to moderate AD.

- The major effect of CI lies in their potential to reduce severity of symptoms & slow the rate of symptom progression , but it does not cure it.
- they do not stop the essential pathological process.

Mode of action:

• they reversibly bind with and inactivate the enzyme cholinesterase which breaks down acetylcholine.
• they potentiate the duration of action of ACh in the cholinergic synapse.
  

Side effect/ Adverse effect:

• The main adverse effects are from their cholinergic activity, such as nausea, vomiting, diarrhoea, anorexia, urinary frequency and depression.
  
• This can be a problemas those with AD often losing weight through the disease

(To decrease the potential side effects, the drugs are introduced gradually with a steady dose tituation )

Dose

• One 5mg tablet daily ( can be increase up to 10mg over 4 weeks)
  

Galanthamine

Mode of action

• it is a reversible non competitive inhibitor of acetylcholinesterase + direct nicotinic agonist. They bind to inactivate the enzymes to breakdown acetylcholine and act as an agonist to acetylochine nicotinic receptors.

Side effect/ AE:

• N/V
• Dizziness
• agitation ( an state of excitment, disturbance or worry)
  

Dose

• one 4 mg tablet twice daily for 4 weeks. ( can be increased up to 8mg twice daily for 4 weeks then maintain 8-12 mg twice daily)
  

Rivastigmine

Mode of action:

• same as Donepezil
  

Side effect/ AE:

• N/V
• confustion
• angina
  
• agitation

Dose

• one 1.5mg table twice daily, increased by 1.5mg gradually.

Memantine

Mode of action

• Glutamate transmits its signal via the NMDA receptor.
  
• NMDA receptor activation and Ga2+ influx are important for learning processes
  
• Glutamate is recycled in glial cells
  
• Beta Amyloid inhibits glutamate recycling
  
• excessive glutamate masks the neuronal singal transmission.
  
• so... Memantine blocks effects of excess glutamate and restoration of physiological transmission occurs.
  
• in result to improvement of the symptoms of AD.
  

Side effect/ AE:

• Dizziness
• confusion
• anxiety
• cystitis
  

( so do not use in cases of renal impairment)

Dose

• One 5mg tablet daily ( can be increased up to 10mg twice daily gradually)
  

* Atypical antipsychotic drugs such as SSRI or Lithium and Haloperidol are sometimes used to manage the behavioural problems that can occur in AD.