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Neurodegenerative Disease Alzheimer’s Disease


temporoparietal glucose utilization, or very high beta-amyloid levels revealed using exogenous ligands.


In the second, ‘minimal cognitive impairment’ (MCI) phase, mild behavioral problems are observed, particularly involving memory and cognition. However, patients are not demented and can still perform most quotidian activities. This stage is associated, at autopsy, with abundant accumulation of amyloid and loss of synapses in the hippocampus, cerebral cortex, and elsewhere in the brain.


In the third phase, the patient is overtly demented and brain size is diminished, reflecting the loss of neurons and synapses, and damage to white matter and blood vessels.


Each of these phases is usually associated with characteristic abnormalities in the metabolism of the brain protein amyloid precursor protein (APP) and its A-beta subunits. During the first phase of AD, CSF levels of A-beta 1–42, the most amyloidogenic APP subunit, are, perhaps paradoxically, depressed; during the second and third phases, large amounts of highly insoluble beta-amyloid, formed by the aggregation of A-beta subunits, are deposited, particularly in ‘senile plaques.’ Soluble oligomers of A-beta subunits are thought to be neurotoxic and to cause the degeneration of dendritic spines, the anatomic precursor of glutamatergic synapses;7–9


then degeneration of the synapses themselves;


and, ultimately, the loss of hippocampal and cortical neurons. The insoluble amyloid formed by the aggregation of A-beta subunits had, until recently, been conceived as neurotoxic; however, more recent observations suggest that amyloid formation may provide neuroprotection by removing toxic A-beta oligomers from solution.10


Attempts to slow the course of AD by


administering agents which suppress A-beta formation or remove it from the bloodstream have, to date, been largely unsuccessful.


An intervention based on nutrients which act pharmacologically to enhance synaptogenesis might be expected to slow the course of AD, or even to partially restore memory functions if it also enhances neurotransmission in affected brain areas. Providing this intervention very early in the disease, while abundant neurons are still available to form new dendritic spines and synapses might, theoretically, be optimally effective. Such an intervention might require many years of administration, hence the use for this purpose of nutrients—compounds which are normally present in, and readily metabolized by, the body—might confer particular benefit.


Do Nutrient Deficiencies Contribute to the Pathogenesis of Alzheimer’s Disease? Does adequate epidemiological or experimental evidence exist that deficiencies in individual nutrients can constitute risk factors for developing AD, or that supplementation of each such compound can prevent AD or slow its course?


Blood levels of several nutrients in AD patients, particularly the omega-3 fatty acid DHA and the vitamins required for methyl group synthesis (folic acid, B12, B6) have been described as subnormal by some investigators but not by others, and there is at present no consensus as to whether these deficiencies actually exist. Similarly, some studies have demonstrated significant correlations between the amounts of these nutrients present


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The possibility remains that deficiencies in folic acid, vitamin B12, or vitamin B6 manifested as elevated plasma homocysteine levels may be contributory to AD, e.g., in subsets of patients with relatively minor deficiencies in folate levels; however, such subsets have yet to be described.


in plasma (e.g., the DHA content of plasma phosphatidylcholine [PC]),11 or provided by the diet, and an individual’s cognitive scores or his/her risk of developing AD,12 do so.13,14


Apparently, there is agreement that AD brains contain lower levels of free and esterified DHA than brains from control subjects.15–18


Circulating


DHA in humans can derive from the pre-existing DHA present in some foods and from the conversion of dietary alpha-linolenic acid to DHA in the liver.19,20


conversion is reportedly deficient in AD,19 of circulating DHA is compromised.


The gene for one of the enzymes that mediates this hence this endogenous source


Possible Utility of Nutrient Mixtures that Promote Synaptogenesis in the Management of Alzheimer’s Disease


The loss of cortical and hippocampal synapses,3–5 probably reflecting


both impaired synaptogenesis (perhaps consequent to a deficiency in dendritic spines)7–9


An animal model of AD


which overproduces A-beta peptides exhibits a similar early decrease in brain synapses,21


and accelerated synaptic degeneration, is an early neuropathologic correlate of AD and is probably the finding that best correlates with early memory impairment.4,5


and oligomers representing aggregates of such


peptides can, when applied locally to the brain, damage synapses, distort neurites, and decrease the formation of the dendritic spines needed to form glutamatergic synapses.10


These observations support


the widely held view that a treatment that blocked A-beta synthesis, or removed the peptide from the circulation, might slow the loss of synapses in AD and thereby sustain cognitive functions in patients. A generation of efforts by diligent researchers has provided abundant information about A-beta’s synthesis, fates, and toxic effects, and this information is now being used to generate drug candidates for slowing A-beta production or removing it from the circulation. Some of these agents have been shown to lower A-beta levels in body fluids. However, none to date has been able to improve or even sustain memory or other cognitive functions. Perhaps a future drug candidate that reduces brain A-beta might succeed in slowing the course of AD; however, in the interim, an alternative therapeutic strategy might provide patients with more benefit than that presently obtained from the acetylcholinesterase inhibitors or metabotropic glutamate receptor (mGluR) antagonists currently in use—or might amplify the benefits produced by those drugs.


There are various loci at which such a treatment might work. For example, it could increase the flux of free calcium into stimulated dendrites, activate receptors that control the formation of dendritic spines, increase the synthesis of pre- or post-synaptic proteins, or generate new synaptic membrane, the main constituent of synapses. One such treatment, which has been shown to improve cognition in studies on experimental animals24 in patients,25


One such therapeutic strategy might entail finding a treatment that accelerates synaptogenesis, thus diminishing the net loss of synapses caused by AD.22,23


and is being tested is based on administering nutrients which promote US NEUROLOGY


while other studies have failed to


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