Human Brain in Health and Disease
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Topics from the Human Brain
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Alzheimer's dementia is now endemic and on the increase, afflicting at least 2 in 10 people over the age of 70 in the USA. From a US perspective, Boyles wrote: “The number of Americans with Alzheimer's disease will triple over the next 50 years unless new ways to prevent or treat the degenerative condition are found, according to newly revised national figures. Thirteen million elderly people in the U.S. are projected to have the disease in the year 2050, compared to about 4.5 million today. The larger-than-expected increase could easily overwhelm the nation's health-care system within the next few decades. Alzheimer's Association president Sheldon Goldberg suggested that the approaching epidemic represents the health-care crisis of the century… If left unchecked, Alzheimer’s disease will destroy the health-care system and bankrupt Medicare and Medicaid. The US federal government will spend roughly $640 million in 2003 to study the disease, but the Alzheimer's Association is calling for a funding increase to $1 billion annually.”
According to neurologist, Dennis Selkoe: "The loss of memory, judgment and emotional stability that Alzheimer's disease inflicts on its victims occurs gradually and inexorably, usually leading to death in a severely debilitated, immobile state between four and twelve years after the apparent onset. The cost to American society for diagnosing and managing Alzheimer's disease, primarily for custodial care is currently estimated at more than $80 billion annually." About 40 percent of the population who are at risk for Alzheimer disease (AD) have genetic factors. Genes that confer susceptibility influence the handling of amyloid precursor protein (APP) PS1, PS2, and APP mutations cause overproduction and accumulation of the neurotoxic derivative, amyloid-peptide, the main event in AD. APP accumulation triggers the accumulation of tau protein in neurofibrillary tangles.
Memory loss in Alzheimer’s disease has become a focus of research activity. In Alzheimer's patients, an old region of the temporal lobe, the hippocampus, is progressively damaged. The hippocampus and related medial temporal processors are essential to the processing of memory. A severely impaired Alzheimer's patient will continue to live, however, and function as a real-time processor enjoying eating and other routine activities but there is no remaining sentient being capable of skillful tasks, meaningful connections, proper sequencing and appropriate decisions. Alzheimer's disease probably progresses over several years to one or two decades and the diagnosis is usually made late in the disease.
Early cognitive problems, for example, are:
Short-term memory loss as revealed by the: inability to repeat three short words within a minute of hearing them.
Problems doing simple arithmetic showing up as difficulty with calculations, balancing checkbooks and making change.
Repetition and perseveration: repeating the same stories and asking the same questions.
Difficulty driving, especially getting lost on familiar routes.
Poor judgment and inappropriate behavior.
Interrupted sequencing and disorganization shows up as the inability to complete familiar tasks without direction.
Forgetting names of relatives, friends and neighbors.
Inability to learn new information.
Withdrawal from social and recreational events.
As dementia advances, patients lose the ability to self-manage and eventually require custodial and nursing care. The disability is less obvious if the aging person lives in an extended family since other family members contribute the missing cognitive functions, supply custodial care and will often minimize or deny the cognitive disability. In family groups, emotional changes are more disruptive than cognitive decline. A couple or solitary person living alone will become more disorganized, disoriented and will eventually fail to sustain self-care. Episodes of confusion, sometimes with hallucinations will draw attention to deteriorating brain function.
Often dementia is linked to dysphoria and angry outbursts are common. I recall a retired English teacher in a group home who would dress in a suit with his tie in disarray. Looking quite eccentric, he played solitaire everyday in the dining area, arranging chaotic columns of cards in random order; he hissed and hit the ladies if they dared to assist him.
The brains of Alzheimer's sufferers develop deposits of the protein, beta amyloid. Amyloid precursor protein breaks down into A 1–42 peptides, which aggregate. Researchers proposed that injecting beta amyloid into the blood would trigger an immune response that might remove the protein. Tests in mice showed benefits of the amyloid “vaccination” Trials in human Alzheimer's patients were halted in January 2002, when patients developed meningitis and encephalitis – immune-mediated inflammatory responses that suggested that the vaccinations excited a general attack on brain tissues. Jucker et al injected elderly mice with antibodies against amyloid. Five months later, the mice had smaller deposits of the amyloid in their brains, but they developed small hemorrhages in cerebral blood vessels. The future prospects for an Alzheimer’s vaccine are not obvious. You might argue that the deposits of amyloid proteins and peptides are late artifacts of a disease process that damages and kills neurons and that removing the proteins will not incur any benefit.
Dementia with Lewy bodies (DLB) is diagnosed by the presence of Lewy bodies in neurons of the brainstem, diencephalon, basal ganglia and neocortex. Lewy pathology results from protein misfolding and the accumulation of alpha-synuclein in the cell cytoplasm. There are similarities with Alzheimer's disease and Parkinson’s disease and there may be a common underlying disease process. In both DLB and AD, reductions in acetylcholine and abnormalities in acetylcholine receptors are found. Drugs to improve acetylcholine activity have been disappointing, but patients with DLB may receive greater benefits from cholinergic therapy. Patients with DLB who display parkinsonian signs have dopamine deficiencies similar to patients with PD, although DLB patients may have no benefit from levodopa treatment. They do have severe adverse reactions to dopamine-blocking psychotropic drugs.
Vascular disease is the second commonest cause of dementia after Alzheimer's disease. There are difficulties in classifying patients with cognitive impairment since there are so many variables with arterial disease. The neuropathology of Alzheimer's and vascular dementia overlap. Increasing evidence suggests that many of the risk factors that lead to cerebrovascular disease also increase the incidence of Alzheimer’s disease. For example, the generation and clearance of beta amyloid in the brain are regulated by cholesterol. Elevated cholesterol levels increase amyloid beta in cellular and most animal models of AD. Drugs that inhibit cholesterol synthesis lower amyloid in these animal models. A variant of the apolipoprotein E (APOE) gene is a genetic risk factor for Alzheimer’s disease. One gene abnormality that is linked to vascular disease is also found in AD patients, the ApoE epsilon 4 gene that leads to deficiency of a protective protein, ApoE. Patients with a history of severe head injury involving coma have a high risk of developing AD if they have the ApoE epsilon 4 gene presumably because they lack the protection of ApoE.
Another theory is that immune-mediated inflammation plays a role in this brain deterioration. McGeer at the University of British Columbia found evidence of chronic inflammation in the brains of patients dying with Alzheimer's disease. Infiltration of brain tissues by lymphocytes suggests an immune-mediated or allergic disease. I can connect the inflammation theory to delayed pattern food allergy. Of the staple foods, milk, egg and gluten proteins are the most common cause of symptoms such as fatigue, concentration difficulties, memory impairment and sleep disturbances. Gluten allergy is known to damage the brain and peripheral nerves.
If you had to choose just one risk factor to eliminate early in the process, it might be low folic acid in the diet. High blood levels of the amino acid, homocysteine, increase the risk of Alzheimer’s dementia. Increased homocysteine is likely with typical high fat and high protein American diets and can be lowered by eating foods featured in the Alpha Nutrition Program. Additional evidence links high fat diets and increased serum cholesterol levels with Alzheimer’s disease. Morris et al reported that a high intake of a mixture of vitamin E tocopherols from food sources rather than from supplements is associated with a reduced risk of Alzheimer's Disease. A slower rate of cognitive decline was associated with intakes of vitamin E, α-tocopherol equivalents, and α- and γ-tocopherols. Fotuhi and associates followed 5000 elderly residents for 8 years, noting their consumption of vitamins C and E, ibuprofen, or a combination of the three. They found reduced cognitive decline with the combination; patients who had the APOE-epsilon-4 gene experienced the greatest benefit from the triple-combination. Scarmeas followed cognitively normal elderly patients with an average age of 77 years, and found that those who ate more fruit, vegetables, olive oil, some fish and alcohol, but little dairy and meat had a 39-40% lower risk of developing Alzheimer's disease.
Several drugs have been marketed for the treatment of AD. Drugs were designed to increase acetylcholine, a neurotransmitter that is critical in learning and memory functions. These drugs have modest to negligible short term effects. Aricept (donepezil) has been the most popular Alzheimer's drug since it was introduced in 1999. In Canada up to 800,000 prescriptions were filled in one year. An English study of 565 community-resident patients asked whether donepezil produces worthwhile improvements in disability, dependency, behavior and/or delayed institutionalization. The study authors concluded that: “Donepezil is not cost effective, with benefits below minimally relevant thresholds. More effective treatments than cholinesterase inhibitors are needed for Alzheimer's disease.”
Many leads have been followed with the hope of finding an effective treatment. For example, in a review of Mematine, Areosa and Sheriff stated: “Alzheimer's disease, vascular and mixed dementia are the commonest forms of dementia in older people. There is evidence that the excitatory activity of L-glutamate plays a role in the pathogenesis of Alzheimer's disease and in the damage from an ischaemic stroke. A low affinity antagonist to N-Methyl-D-aspartate (NMDA) type receptors, such as memantine, may prevent excitatory amino acid neurotoxicity without interfering with the physiological actions of glutamate required for memory and learning... Memantine is a safe drug and may be useful for treating Alzheimer's, vascular and mixed dementias of all severities. Most of the trials so far reported have been small and short duration – not long enough to detect important benefits.”
Bennet et al stated: “The high incidence of dementia in the aging population provides strong impetus to search for new compounds with the potential to reverse the deficits in short-term memory. The neuropathological changes underlying age-related cognitive decline and AD are complex and poorly understood. However, the loss of forebrain cholinergic neurons that project to the cerebral cortex and hippocampus is a hallmark of this disease. In addition, the deposition of A in both the brain parenchyma and cerebral blood vessels, and the formation of intracellular neurofibrillary tangles containing tau-protein are also observed. Studies in Alzheimer's patients have revealed that the extent of cholinergic depletion correlates with the severity of memory deficits. Thus, animal models of cortical and hippocampal cholinergic depletion have been widely used to induce relevant cognitive deficits for the purpose of identifying potential new therapeutic compounds for the treatment of AD.” The researchers have pursued the idea that enhancing nitric oxide mediated signalling may be a better strategy than trying to boost the activity of damaged or missing cholinergic neurons.
Maazza et al described finding 19 of the 25 anthocyanins present in blueberries in human serum after subjects ate freeze-dried blueberry powder. The appearance of anthocyanins in the serum was correlated with an increase in serum antioxidant capacity. Denisova et al first showed that blueberry supplementation reversed the deleterious effects of aging on motor behavior and neuronal signaling in senescent rodents. They then fed blueberries to young transgenic mice who were predisposed to develop Alzheimers’ disease. The mice were protected against this tendency and showed no increase in brain amyloid beta burden. They suggested that the protective mechanisms are derived from blueberry-induced enhancement of memory-associated neuronal signaling and alterations in phospholipase C activity. They concluded that it may be possible to overcome genetic predispositions to Alzheimer disease through diet revision.
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