Dementia

Dementia is a progressive loss of cerebral function which may result in a generalized disturbance in function. It is common in the developed world and its prevalence is increasing as the age of population is increasing. It involves more than one area of cerebral function, for example, memory, language, and judgment, and may result in severe dysfunction of daily life.

The prevalence of dementia is approximately 6 percent in those over 65 years and 30 percent of people aged over 90 years. Dementia is rare before the age of 60. Symptoms of dementia include loss of memory, personality changes, and loss of executive function such as the ability to make decisions.

There are several diseases that cause dementia. The most common cause is Alzheimer's disease (AD); it accounts for 30 to 50 percent of dementia. AD is characterized early on by neuropathological changes, primarily in the hippocampus. It is stated that AD pathology is more likely to be clinically expressed as dementia in women than in men. AD is a neurodegenerative disease with histopathological features such as loss of synapses and cells and presence of amyloid plaques and neurofibrillary tangles (NFTs). NFTs are pathological protein aggregates in neurons; they are associated with the microtubule associated protein tau in the cerebral cortex particularly in the temporal lobe. The presence of NFTs may contribute to the cognitive decline such as impairment in language (aphasia), skilled movements (apraxia), and recognition (agnosia). Other symptoms of AD include loss of memory and deterioration of musculature and mobility leading to unsteady gait. AD patients generally have reduced acetylcholine activity, high concentrations of homocysteine, and folate deficiency leading to increased risk of dementia and cognitive decline. Higher plasma vitamin B-12 may reduce the risk of homocysteine-associated dementia.

Factors known to increase risk of the AD include mutations in the amyloid precursor gene and the apolipoprotein E (apoE) genotype. The apoE gene has three alleles called ∊2, ∊3, and ∊4. The ∊4 allele (chromosome 19) accelerates the age of onset of familial AD and increases the risk of developing late-onset “sporadic” AD. Its presence has been associated with an increase in β-amyloid protein (Aβ) senile plaques and neuritic plaques. ApoE in the normal brain is involved in the transport of cholesterol, redistributing lipids among CNS cells for normal lipid homeostasis, repairing injured neurons, maintaining synapto-dendritic connections, and scavenging toxins. ∊4 binds to Aβ; this interaction prevents toxic aggregation of Aβ. This property is lost in AD, thus leading to Aβ accumulation and resulting plaque formation. ∊4 is also associated with small vessel arteriolosclerosis and microinfarcts of the deep nuclei perhaps as a result of the plaque accumulation. Aβ protein is produced from proteolytic cleavages (using β and γ secretases) of amyloid precursor protein (APP). Aβ accumulates in the brain cortex and hippocampus of patients with AD and self-aggregates to form toxic oligomers causing neurodegeneration

Another risk factor for AD is mutations in the presenilin gene. Presenilin mutations are the main cause of familial disease. These mutations seem to result in a gain of toxic function, and a partial loss of function in the gamma-secretase complex, which affects several downstream signaling pathways. The loss of function of presenilin causes incomplete digestion of the Aβ and might contribute to an increased vulnerability of the brain, thereby explaining the early onset of the inherited form of AD. Other risk factors of AD include head injury, Down syndrome, lower premorbid intellect, and proneness to psychological distress; chronic stress is associated with hippocampal damage and impaired memory in humans.

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