Understanding Dementia

Dementia

• Dementia is a cluster of conditions which is characterized by a widespread progressive decline in intellectual functions.
• Symptoms of dementia include memory loss in addition to emotional, personality, and motor changes.
• Social decline and failure to live independently are also characterisitc of dementia
• Dementia develops in middle/later life, disrupting one's normal lifestyle.
• Dementia associates with neuropathological changes like atrophy due to neuronal cell loss, especially in the frontal and temporal cortex.
• Some forms of dementia reflect a genetic disorder such as Huntington’s disease or Creutzfeldt-Jacobs disease.
• Mild dementia may be extremely common, affecting 5-20% of people over 65.
• The proportion of elderly individuals in the population is increasing, especially in developed countries.
• This increase puts a strain on healthcare services.
• Normal ageing is noticeably different from dementia.

Prevalence of Dementia

• Prevalence rises with age increasing from 6% for individuals over 65 to 40% for those 95 years of age and older.
• The incidence rate is estimated between 0.5-2% of the population per annum.
• Most cases of dementia are diagnosed as Alzheimer's disease although there is no definitive way to diagnose until post-mortem.
• Multiple-infarcts are noted as the second most common cause of dementia.
• 50-70% of all demented patients manifest symptoms of Alzheimer's disease.
• Multi-infarct dementia involves multiple small foci of ischaemic brain destruction.

Symptoms of Dementia

• Symptoms of dementia: disorientation (space & time), memory disturbances especially with respect to new information, concrete thinking, and difficulty in reasoning.
• As dementia progresses, more functions are disturbed.
• Dementia patients often become moody, delusional, tearful, apathetic, withdrawn, and depressed.
• Some patients develop motor problems, speech difficulties aggression, personality change.
• Working memory deficits are apparent in Alzheimer's, in both verbal and non-verbal tests.

Diagnosing Alzheimer's Disease

• Diagnosing Alzheimer’s is not straightforward with no ‘definitive sign’ before death.
• Plaques & tangles along with brain shrinkage and enlarged ventricles are definitive at post-mortem.
• A tentative diagnosis can be given if other causes of dementia seem unlikely.
• Dementia due to thyroid hormone lack, vitamin B12 deficiency or alcoholism must be ruled out.
• EEG is usually abnormal in AD.
• CT or MRI scans show enlarged ventricles and sulci on the brain.

Alzheimer's Disease

• Alzheimer autopsied a woman in her 50s in 1907.
• The woman suffered from progressive dementia; autopsy revealed unusual pathology in her brain tissue.
• Microscopic neuritic plaques and neurofibrillary tangles are associated with Alzheimer's pathology.
• Alzheimer's disease generally refers to pre-senile cases of dementia, although similar changes are seen in senior cases (older than 65).
• Neurofibrillary tangles are seen in brains of AD patients post mortem.
• Tangles are made of tau protein: microtubules, protein aggregation, and tau protein within neurone.
• Neurofibrillary tangles are formed by hyperphosphorylation of a microtubule associated protein resulting in aggregations and insoluble forms.
• Hyperphosphorylation of tau is unable to bind, resulting in unstable disintegrating tubules.
• Amyloid-plaque formation involves degenerating nerve terminals and astrocytes, with centre of amyloid protein.
• Senile (amyloid) plaques, neurofibrillary tangles, Tau protein, Loss of cortical cholinergic neurons, Neurotransmitter losses such as Acetylcholine, Norepinephrine, serotonin, glutamate, GABAs occur within Alzheimer's pathology
• ß-amyloid is generated by two enzymes which cut APP (Amyloid precursor protein) at two different positions, producing Aẞ and APPsẞ:

What Happens in the Brain?

• Structurally, changes occur in areas associated with learning and memory first.
• Plaques and tangles appear in the hippocampus and associated cortex.
• Cell degeneration occurs in these areas.
• Neurochemically, a decrease in ACh transmission occurs from the basal forebrain.
• There is also a decrease in pyramidal cells which leads to reduced glutamate.
• Over time, many neurotransmitters are reduced with Ach & glut changing earliest.
• There is a major finding of a significant decrease in choline acetlytransferase, indicating a decline in cholinergic function.
• There is also loss of cells with major cholinergic projections in the Nucleus basalis of Meynert from the cortex and hippocampus.
• Cholinergic system degeneration in the forebrain provides a key hypothesis for Alzheimer’s disease.
• Cholinergic degeneration underlies the memory impairments associated with dementia.
• Other neurotransmitter changes are noted in dementia/Alzheimer's.

Current & Potential Treatments

• Current treatment replaces decreased Ach levels due to AD destroying cholinergic neurones.
• Cholinesterase inhibitors are used to block the breakdown of Ach in the synapse, thus prolonging duration.
• Transmission is increased.
• Current therapy alleviates cognitive decline to some extent in some AD patients; side effects can be unpleasant.
• Example drugs include Aricept and tacrine.
• Some researchers are investigating abnormal processing of the β-amyloid plaques from families.
• Drugs that stop amyloid plaques from depositing in the brain may eventually slow/stop AD.
• Other researchers are investigating ApoE identified as a product of the mutation in the genetic familial cases of AD.
• Cholinergic drugs have been developed in an attempt to replace declining cholinergic function
• Agents with a direct agonist effect on the muscarinic receptor (e.g. arecoline) or compounds inhibiting acetylcholinesterase (e.g. eserine) have all been tried

Novel Symptomatic Therapy

• Cholinergic enhancement is used, given ACh depletion in the AD brain
• Glutamate is depleted; no therapy targeting this problem has been designed.
• Glutamatergic drugs are potentially dangerous (excitotoxic), but work on neurotransmitters that modulate glutamate transmission may be possible.
• It is hypothesised that 5-HT1A antagonists may provide an alternative.

Pharmacological Models

• Attempts have been made to reproduce some of the symptoms of dementia in animals by disrupting the cholinergic system with lesions of the NBM or administering scopolamine to block cholinergic function.
• Animal models also disrupt the brain vascular system.
• Animal performance before and after testing is evaluated using T-maze, radial maze, passive avoidance and other behavioural tasks so potential anti-dementia drugs can be evaluated.
• Currently, there are no clinically useful drugs for dementia with research ongoing.
• Knowledge of neurone death and how to prevent such is required.

Cholinergic Drugs

• Tacrine, a cholinesterase inhibitor, was the first drug approved for treating AD.
• Tacrine shows modest improvements in tests of memory and cognition in about 40% of Alzheimer's patients, but did not have benefits for quality of life
• Tacrine is given four times daily producing cholinergic side effects such as nausea, abdominal cramps, and hepatotoxicity
• Donepezil, Galantamine are reversible inhibitors of acetylcholinesterase and treat mild to moderate disease
• Rivastigmine is a reversible non-competitive inhibitor of acetylcholinesterase that treats mild to moderate disease.
• Memantine is a NMDA-receptor antagonist that affects glutamate transmission that is used to treat moderate to severe Alzheimer's disease
• Providing abundant amounts of precursor substances lecithin and choline has proven to have modest success.

Additional Therapies

• Cerebral vasodilators showed little, if any, cognitive improvement.
• Piracetam, oxiracetam, aniracetam and similar drugs improve memory in animal tests by enhancing glutamate release, but are probably ineffective in AD.
• Vasopressin has demonstrated some effects in animal models for memory consolidation, but inconsistent effects have been obtained in man.
• Vasopressin may improve attention.
• Ondansetron and other 5-HT3 receptor antagonists have been shown in animal models at Bradford to increase cognitive performance.
• "Smart drugs are now being used by healthy people

5-HT1A Antagonist Studies

• Primates underwent training using a learning task.
• A drug that blocks glutamate transmission (MK-801) was administered.
• Learning was impaired.
• A 5-HT1A antagonist was administered restoring learning to normal levels with WAY.

Risk Factors

• Down syndrome is caused by the presence of an extra copy of chromosome 21.
• APP is located in chromosome 21; Down syndrome patients will have an extra copy of APP.

Potential Treatment Strategies

• Acetylcholinesterase inhibitors can be used such as Donepezil, Rivastigmine, Galantamine AD patients have lower levels of Acetylcholine.

• Ach is necessary to send messages between nerve cells.

• Cholinestererase inhibitors prevent acetylcholineserase, increasing Ach in communication between nerve cells, alleviating symptoms of AD

• Adverse effects of cholinestererase inhibitors include nausea, vomiting, diarrhoea, anorexia, tremors, bradycardia, Myalgia

• NMDA-glutamate receptor antagonists block NMDA receptor-associated ion channels, limiting Ca2+ influx into the neuron, inhibiting overstimulation by glutamate

• Such NMDA-glutamate receptor antagonists can lead to confusion, agitation, and/or restlessness.

• Memantine is also used.

• Antipsychotics are used in reducing aggression, psychosis and can be used such as Risperidone

• Cognition enhancing drugs are prescribed and though they do provide benefits

CJD

• It can be obtained from mad cows and cannibals,
• CJD along with BSE are spongiform encephalopathies.
• Brain tissue resembles sponge in range of species/diseases such as cows dying from BSE, sheep dying from scrapie, cannibalistic tribes people from Papua New Guinea, and victims of 'new variant' CJD

Scrapie

• “Dementing illness of middle-aged sheep” from 17th century.
• Causes behavioural/motor impairment, starting with an 'awkward' gait and ending in death.

CJD/GSS/FFI

• Creutzfeldt-Jakob disease (CJD) affects 1 in a million people,
• Specific mutations in some families can cause CJD in offspring with a 50% inheritance.
• CJD is contracted through iatrogenic routes due to operative procedures (or possibly due to BSE-infected material).
• Gerstmann-Straubler-Scheinker (GSS) is similar to CJD and occurs in specific families with particular mutations

Additional Prion Disease

• Fatal Familial Insomnia (FFI) is an unusual inherited spongiform encephalopathy.
• Symptoms are slightly different to motor symptoms as observed in CJD &GSS with effects on sleep patterns.
• These disorders are invariably fatal.
• None of these disorders are 'new' (except for the iatrogenic forms).
• In the 1950s, Australian doctors working in Papua New Guinea described Kuru in the Foré tribes.
• CJD was an obscure disorder that the disease resembled.
• The people of the Foré tribe were developing motor impairments that led onto dementia and death primarily affecting women and children.
• An endo-cannibalism funerary ritual included preparation, cooking and eating of the body for family members.

Women, Children, and Kuru

• Women and children were most affected since men tended to get the 'choice' muscle, and women/children ate the internal organs which had infective material.
• Legislation made cannibalism illegal and ended the practice in the 1950s.
• Kuru has almost totally died out in Papua New Guinea, but some individuals may be affected based on the incubation time.

BSE

• Bovine Spongiform Encephalopathy is related to intensive farming methods involving the use of rendered meat from sheep carcasses as a foodstuff used for cattle
• A subtle change to the rendering process in the 1980s led to a new disease, BSE in which sheep scrapie crossed the species barrier into cattle.

BSE and new variant CJD

• CJD is now well known by the general public.
• Usual pattern for CJD involves onset in the patients' late 40s and the disease progression to death takes an average of 6-8 years.
• Shortly after the BSE crisis, unusual cases of CJD were seen.
• These cases have normal CJD pathology, younger onset, diagnosis to death time of only 12-24 months, and are notably 'atypical'.
• A relationship to BSE is likely, however does not accurately project the course of new variant cases.
• Incubation periods are hard to estimate due to historical cases such as Kuru.