Overview of Dementia Diseases

Overview of Dementia Diseases    Brain has billions of neurons, each with an axons and many dendrites. To stay healthy, neurons must: o Communicate with each other. o Carry out metabolites. o And repair themselves. AD disrupts all three of these essential jobs. Anatomical changes in AD  Cortex shrivels up, damaging areas involved in thinking, planning and remembering.  Shrinkage is especially severe in the hippocampus, an area of the cortex that plays a key role in formation of new memories.  Ventricles (fluid-filled spaces within the brain) grow larger. Histology  Many fewer nerve cells and synapses than a healthy brain.  Senile plaques: o Abnormal clusters of protein fragments build up between nerve cells. o Large deposits of beta-amyloid peptide and cellular material.  Neurofibrillary tangles: o Twisted fibres composed of the protein Tau. o Accumulates inside dead and dying neurons. Senile plaques  Amyloid precursor protein (APP) is the precursor protein of betaamyloid. o It is a neuronal transmembrane protein.  Enzyme complexes (called β- and γ- secretases that contain presenilin) cleave APP into protein fragments, including betaamyloid.  Beta-amyloid fragments aggregate to first form small oligomers, and then amyloid plaques.  The most damaging form of beta-amyloid may be amyloid oligomers.  These block cell-to-cell signalling at synapses and inhibit long-term potentiation (LTP). They may also activate immune systems cells that trigger inflammation and devour disabled cells. Neurofibrillary tangles  Neurons have an internal support structure partly made up of microtubules.  A protein called Tau helps stabilise the microtubules.  In AD, Tau becomes hyperphosphorylated, causing microtubules to collapse, and Tau proteins aggregate to form neurofibrillary tangles. Progression  Plaques and tangles tend to spread through the cortex in a predictable pattern.    Early stage: changes may begin 20 years or more before diagnosis. Mild to moderate stage: generally last from 2 – 10 years. Severe state: may last from 1 – 5 years. Cholinergic system  Two major cholinergic cell groups.  Cholinergic neurons located in: o The basal forebrain constellation, including the basal nucleus of Meynert. o Dorsolateral tegmentum of the pons. Other factors   Inflammation and oxidative stress (release of free radicals) occur around amyloid plaques. Glucose hypometabolism in AD. Potential drug targets  Cholinergic deficit.  Amyloid (soluble oligomers or plaques).  Neurofibrillary tangles.  Inflammation and oxidative stress.  Glucose hypometabolism. Problem  Unsure on what the cause of AD is.  Unable to design an appropriate therapy. Cholinergic neuron  Changes in cholinergic neurons in the aged and early AD: o Alterations in high-affinity choline uptake. o Impaired ACh release. o Deficits in the expression of nicotinic and muscarinic receptors. o Dysfunctional nneurotrophin support (i.e. NGF receptors). o Deficits in axonal transport.  ACh-esterase inhibitors.  ACh receptor agonists (alpha-7 nicotinic). o Co-agonist in combination with ACh. o Sensitises the alpha-7 receptor; makes it possible for smaller amounts of naturally occurring ACh to be effective in activating the A7 receptor. o Potentially alleviate the undesirable side effects caused by other systemic compounds (ACh-esterase inhibitors), which are dose-limited by toxic side effects. Amyloid  Observations: o Plaques are deposited in AD and in close proximity to degeneration neurons. o Early onset in patients with mutations in APP/PSEN 1 and 2 (proteins linked to amyloid production).  Conclusions: o Amyloid is probably the cause of AD. o Removing amyloid or stopping its production will cure or arrest AD progression.  Semegacestat (gamma secretase): o Results from two ongoing long-term phase III studies showed it was associated with worsening of clinical signs and patient’s ability to perform activities of daily living. o Treated patients also has an increased risk of skin cancer. o The drug is being halted.  Unfortunately, recent studies have shown that amyloid may not be the cause of AD. o Labelling with Pittsburgh component B followed by PET. o Although formation of beta-amyloid plaques is seen in some patients at the initiation of the study, resultant dementia and progression of Alzheimer’s is not positively correlated with increased deposition of beta-amyloid plaques. Correlations with other factors  Risk factors: o Increasing age. o Fewer years of education. o APOE4. o High-fat dairy, red meat, organ meat and butter.  Protective factors: o Non-steroidal anti-inflammatory drugs. o Wine consumption. o Coffee consumption. o Regular physical activity. o Drinking juice (one study showed a reduction by 76%). o Salad dressing, nuts, fish, tomatoes, poultry, fruits and vegetables (because of their anti-inflammatory effect).  No association with: o Family history of dementia. o Gender. o History of depression. o Oestrogen replacement therapy. o Head trauma. o Smoking, high BP, heart disease, stroke. Summary  No cure and no disease-modifying treatment; only symptomatic treatment with ACh-esterase inhibitors.  AD prevention by anti-inflammatory drugs and “neutraceuticals”. o Fruits and vegetables. o Fish oil.