Natural Dementia Cure and Treatment

Super Memory Formula

After the harsh reality that the doctor had to face his son ending his life, he suffered a major irreversible memory loss disease. This caused him to fall into depression and depend on the drugs from the pharma which was devasting for his mental and physical health and on so many other levels. After countless hours of research and experimentation, he realized that the root of all problems of memory loss was an enzyme that eats away the memory cells when the person gets older. This makes the person forget their loved ones, family and friends as if they have never met them. In some cases, they even forget about their past experiences, if they had children, how they came to the place they are in right now and who they are in the first place. This was exactly what the doctor had in his future if he did not make a decision. But he did and met with great people who helped him find the cure. This was a groundbreaking study that no one wanted to believe or endorse because it would go against the large pharma industry. However, the information is in there to protect yourself and your loved ones from such a devastating experience. You only need to follow the link and you will be guided to get the information downloaded to your device and follow the all-natural ways to get rid of memory loss. Continue reading...

Super Memory Formula Summary


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MMPs In Alzheimers Disease

AD, the most common cause of dementia in the elderly, is predominantly a degenerative disease of the CNS gray matter. The pathological and diagnostic hallmarks of the disease are the presence of extracellular deposits of p-amyloid protein and intracellular aggregation of neurofib-rillary tangles. Although the disease is degenerative in nature, recent evidence implicates inflammatory mechanisms. Activated microglial cells, which are capable of secreting pro-inflammatory cytokines, especially interleukin (IL)-1, have been demonstrated in the periphery of the p-amyloid plaques. Furthermore, elevated levels of IL-1 have been detected in brain tissue, CSF and serum from AD patients.3031 In addition, p-amyloid has been shown to stimulate the production of TNF-a in cultured astrocyte.31 The p-amyloid protein arises from the proteolytic cleavage of a larger membrane protein, p-amyloid precursor protein (APP). APP can be cleaved by the action of proteases, leading to the secretion of...

Global Proteomics Applied to Alzheimer Disease

A collaboration with Hyman Schipper, a neuropsychologist at the McGill University Memory Clinic, part of the Jewish General Hospital (JGH Montreal, Canada), was undertaken to investigate the effect of drug treatment on Alzheimer disease (AD) patients. Plasma was collected from patients after obtaining written informed consent and with approval of the research and ethics committee of the JGH. Included in the study were 33 age -matched healthy control, 19 untreated AD, and 25 donepezil-treated AD patients. Each patient was administered the Folstein Mini-Mental State Examination (MMSE), a qualitative test of disease severity 41 . In addition, clinical histories were obtained. Figure 4 Global proteomics analysis on Alzheimer disease and normal patients. Multidimensional scaling of proteomics data demonstrates the separation of healthy individuals (green spheres) from Alzheimer patients (red spheres). Caprion has defined a disease axis that is used to quantify relative disease state. The...

Overview and Pathogenesis of Alzheimers Disease

Alzheimer's disease is a devastating illness. It occurs mainly in the elderly population. Once afflicted, Alzheimer's disease produces progressive and unrelenting damage to the human brain. The average lifespan after being diagnosed with this illness is about 8-10 years 1 . Patients steadily lose cognitive functions including memory, executive functioning, and the ability to care for themselves. In addition, behavioral symptoms of agitation, depression, and psychosis are often co-morbid with Alzheimer's disease. This devastating illness affects not only the patients but also the families and anyone that provides care for them. In the United States, the staggering financial cost of the disease accounts for nearly 100 billion per year in medical and custodial expenses, with the average patient requiring about 27000 per year for medical and nursing care. Furthermore, 80 of caregivers of patients with Alzheimer's disease report stress, and about 50 report depression 2 . There are...

Overview of Cholinesterase Inhibitors in the Treatment of Alzheimers Disease

The use of cholinesterase inhibitors may preserve activities of daily living, slow progression of memory loss and improve behavioral and cognitive symptoms associated with Alzheimer's and related dementias. Treating Alzheimer's disease often takes great patience on the part of physicians as well as patients and caregivers. Response to drug may take weeks, sometimes months before caregivers may notice a difference in symptoms, if at all. The efficacy produced by cholinesterase inhibitors is not always clear-cut. For example, there is some evidence that donepezil may benefit moderate to severe Alzheimer's dementia in outpatients, however, the results have been conflicting in the nursing home population 17 . In addition, both donepezil and galantamine have not yet shown consistent results in improving behavioral and psychotic symptoms in patients with Alzheimer's disease. Improvement in psychosis is seen with rivastigmine which has shown improvements in behavioral symptoms in mild to...

Use of Donepezil in the Treatment of Alzheimers Disease

The efficacy of donepezil in Alzheimer's dementia has been demonstrated in several trials. In a study by Rogers and colleagues, the efficacy of donepezil in treating patients with mild to moderate Alzheimer's disease was investigated in a randomized, double-blind, placebo-controlled, fashion. Patients were followed for 24 weeks followed by a 6-week placebo washout period. The primary efficacy was measured by the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog) and the Clinician's Interview Based Assessment of Change-Plus (CIBIC plus). There was statistically significant improvement in cognition in patients who were on donepezil versus placebo at the end of 24 weeks. After the 6-week washout period with placebo, there was no difference in the scores from both groups. This suggests that donepezil improved cognition in patients while they were taking the medication, but if stopped, the improvement in cognition might be reduced to minimal. Patients in this study...

Use of Rivastigmine in the Treatment of Alzheimers Disease

Rivastigmine's approval by the FDA in 2000 was supported by several trials. One such trial was by Corey-Bloom and colleagues 38 . In this randomized, placebo-controlled trial, 699 patients with mild to moderately severe AD were enrolled. Patients were randomized to either high dose rivastig-mine (6-12 mg day), low dose rivastigmine(1 -4 mg day), or placebo. Subjects were then followed over a 52-week period. At the end of the study, subjects originally treated with high dose rivastigmine of 6-12 mg day had significantly better cognitive function than patients originally treated with placebo 38 . This study however was limited by the fact that from week 26-52, the study became an open-label study. In a different study, Birks and colleagues compiled data of randomized, double-blind, placebo-controlled trials from the Cochrane database. In all, there were seven trials, which included 3370 subjects. The researchers found that after 26 weeks, high dose of rivastigmine in the range of 6-12...

Use of Cholinesterase Inhibitors in Other Dementia Related Illnesses

Besides their use in Alzheimer's disease, cholinesterase inhibitors have been extended to treat other dementias and related illnesses, which may include vascular dementia, dementia with Lewy Bodies, dementia associated with Parkinson's, mild cognitive impairment, and mixed dementia. Research is particularly important in this area since it is not uncommon for Alzheimer's disease to be co-morbid with other types of dementia. Therefore, it is important to devote a section briefly discussing recent findings and the use of cholinesterase inhibitors in the treatment of dementias other than Alzheimer's disease. With the prevalence of cardiovascular diseases such as hyperlipidemia, diabetes, hypertension, which may over time lead to cerebrovacular disease, there is a direct correlate between the presence of vascular disease and dementia. Studies have shown that there is also a cholinergic deficit in vascular dementia due to ischemia to neurons in the basal forebrain and the cholinergic...

Behavioral Problems in Nursing Home Residents Safe Ways To Manage Dementia

Pharmacological, that can help control these behaviors. Non-pharmacological treatment options include environmental changes, bright-light treatment, and restraints and behavior modification. Pharmacological options involve the use of neuroleptics, benzodiazepines, and other agents such as beta-blocker therapy, carbamazepine, lithium, trazodone hydrochloride, and buspirone hydrochloride. According to the authors, patients should be assessed to differentiate delirium from dementia, and possible precipitants of disturbed behavior should be investigated. The authors suggest that ultimately, long-term success with patients with dementia may depend in part on realistic expectations. 21 references.

The Future of Treating Alzheimers Disease

The mechanisms underlying the progression of Alzheimer's disease are complicated. With the current therapy of cholinesterase inhibitors, we have just scratched the surface in treating this complicated illness. In addition to enhancing cholinergic neurotransmission, the latest medications used to treat Alzheimer's disease involve blocking neurotransmission by glutamate thus protecting the brain from neurotoxicity. Knowing the pathogenesis of this complicated disease is essential to developing new therapies. Researchers have already begun researching other ways to slow or prevent the progression of this disease process. Future medications may have mechanism of actions that prevent or reduce the amyloid plaques by inhibiting enzymes that produce the plaques, interfering with formation of the amyloid sheets, or helping to speed the clearance of the amyloid plaques once they have developed 93 . With an expanding population of ever-increasing longevity, new medications that can modify the...

Practical Considerations in Managing Alzheimers Disease

Summary This article presents a panel discussion on the role of the physician in the treatment of Alzheimer's, including handling the patient's response to the diagnosis, managing behavioral aspects of the illness, treatment of depression and other emotional symptoms, treatment of other medical conditions, and helping patients live with cognitive impairment. The panelists also considered such drug therapy as THA, Hydergine neuroleptics for agitation, and benzodiazepines for sleep disorders.

Use of Psychotropic Medication in the Management of Problem Behaviors in the Patient With Alzheimers Disease

Summary This article reviews the literature on alternatives to neuroleptics in the treatment of the agitated patient with progressive dementia. Specific neuroleptics discussed are the following serotoninergic agents (trazodone), azapirones (buspirone), benzodiazepines, beta-blockers, anticonvulsants, and lithium. The authors state that, although a variety of potential alternatives to the neuroleptics in the management of agitated behavior in Alzheimer's disease exist, more large, well-controlled studies are needed. At present, neuroleptics remain the standard treatment for this problem. 2 tables, 59 references.

The Treatment Of Neurodegenerative Diseases 431 Alzheimers Disease

Alzheimer's disease is a degenerative neurological disease in which the patients increasingly lose their memory and become confused. It is the most common cause of dementia in the elderly. Nerve cells in the brain particularly in the hippocampus and the cerebral cortex, die and the levels of several neurotransmitters including acetylcholine 4.6, fall.

Pharmacologic Approach to Management of Agitation Associated With Dementia

Summary This article reviews the phenomenology of agitation and its pharmacologic treatment in patients with dementia, including the use of benzodiazepines, neuroleptics, beta-adrenergic-blocking agents, serotonergic agents, carbamazepine, and lithium. Persistent and acute agitation may be treated through sedation with neuroleptics or benzodiazepines. However, care should be taken to not maintain patients on these medications for protracted period of time, i.e., beyond 4 to 6 weeks. For chronic agitation, the severe side effects and limited efficacy of neuroleptics and benzodiazepines diminish their usefulness. The authors recommend a trial of the serotonergic agents, including buspirone, trazodone, and serotonin selective reuptake inhibitor antidepressants, as first-line treatment for chronic agitation in patients with dementia. Second-line treatment includes beta-blockers, carbamazepine and lithium when agitation is associated with manic affects. The authors suggests the usage of...

Pharmacologic Treatment of Behavioral Symptoms of Alzheimers Dementia A Review and a Possible Strategy

Summary This article reviews the use of both neuroleptics and nonneuroleptics in the treatment of behavioral symptoms of Alzheimer's disease. The author suggests that using current knowledge about the possible neurobiological basis of behavioral symptoms in Alzheimer's disease and the actions of medications may make possible a pharmacologic strategy for the treatment of aggression and agitation in Alzheimer's disease. This strategy may need to consider the specific neural network dysfunction as

Molecular and Cellular Aspects of Oxidative Damage in Alzheimers Disease

Evidence for free radical damage in Alzheimer's disease includes damage to lipids, proteins, and nucleic acids and is likely a consequence of redox-active metal accumulations, mitochondrial damage, and the formation of advanced gly-cation end-products. Furthermore, free radical-mediated events are linked to all of the genetic modulators of the disease since P-protein precursor, amyloid-P, presenilins, and apolipoprotein E are associated with reactive oxygen species production or processes intimately associated with oxidative stress such as apoptosis. An involvement of free radicals accounts for the two most striking features of Alzheimer's disease, namely, the multitude of abnormalities affecting essentially every system and the strict age dependence. Furthermore, in therapeutics, the commonality between a number of efficacious agents appears to be oxi-dative stress reduction. In this chapter, we present evidence that oxidative stress is the element that links the multitude of changes...

Pharmacologic Management of Alzheimers Disease

Summary This journal article discusses pharmacologic approaches to the management of Alzheimer's disease (AD) and some of its symptoms. The first section discusses treatment strategies using various types of cholinergic drugs, including acetylcholine (ACh) precursors, cholinesterase inhibitors, a combination of ACh precursors and cholinesterase inhibitors, cholinergic agonists, and indirect enhancement of cholinergic activity in the brain. The next three sections address the use of antiinflammatory agents, antiamyloidogenic and antioxidant therapy, and estrogen replacement therapy to prevent or delay the onset of AD. The fifth section examines the management of psychosis and agitation in AD with such medications as antipsychotics, benzodiazepines, trazodone, buspirone, anticonvulsants, beta-adrenergic blockers, lithium, and selective serotonin reuptake inhibitors. Finally, the article discusses the use of selected antidepressant medications for the management of depressive symptoms in...

The Pathology Of Alzheimers Disease

The other classical lesion observed by Alois Alzheimer in his original patient is the neuro-fibrillary tangle (NFT). Tangles are generally intraneuronal cytoplasmic bundles of paired, helically wound 10-nm filaments, sometimes interspersed with straight filaments.19 NFTs usually occur in large numbers in the AD brain, particularly in entorhinal cortex, hippocampus, amygdala, associated cortices of the frontal, temporal and parietal lobes, and certain subcortical nuclei that project to these regions. The subunit protein of the NFT is the micro-tubule-associated protein, tau. NFTs are not limited to the tangles found in the cell bodies of neurons, but also occur in many of the dystrophic neurites present within and outside the amyloid plaques. Biochemical studies reveal that the tau present in NFTs comprises hyperphosphorylated, insoluble forms of this normally highly soluble cytosolic protein.20 Tangles composed of tau aggregates that are similar

Nongenetic Risk Factors For Alzheimers Disease

Age is clearly the most important risk factor for AD. Alois Alzheimer originally described this disorder as a form of premature aging.58 Many studies have implicated low education as a risk factor for cognitive impairment in elderly people.59,60 Although Filley et al61 and Beard et al62 did not find that education provides protection against dementia, it must be recalled that their subjects had relatively high schooling levels. Education may enhance brain reserve by increasing synaptic density in the neo-cortical association cortex.63 Individuals with higher levels of education may have greater brain capacity (i.e. more cortical synapses) than individuals with lower levels of education, and thus have more resistance to the deterioration caused by the progressive synaptic and neuronal loss associated with aging than do less educated individuals.24 Our study in Wadi Ara confirmed an association between education and dementia. However, these factors could only partly explain the very...

Vascular Components In Alzheimers Disease

Autopsy, with or without myocardial infarction, was found to be associated with a six-fold increase in the proportion of older patients with significant Alzheimer amyloid deposits in the brain.79 Brun and Englund80 reported that 60 of patients with autopsy-proven DAT also had white matter changes, which are usually attributed to compromised circulation. Thus, vascular disease may contribute to DAT pathogenesis or may accelerate the clinical presentation of DAT. A significant interaction might exist between aging and vascular risk factors such as hypertension. For example, one study found that midlife blood pressure is the strongest predictor of later-life brain volume and the extent of white matter hyperintensities81'82 Hypertension in later life may have less influence on brain structure and function than does midlife hypertension.82 Further evidence shows that abnormalities of cerebral white matter share stroke risk factors83,84 and that these abnormalities significantly predict...

Therapy Of Alzheimers Disease

Based on the hypothesis of a cortical cholinergic deficit in AD that correlates with dementia, the main classes of drugs evaluated to date in AD are cholinomimetic agents, including cholinesterase inhibitors,93-103 as well as nicotinic and muscarinic104 agonists. The expected outcome of cholinergic enhancement is palliation (improved symptoms) rather than an effect on the underlying biology of AD. Cholinesterase inhibitors may provide benefit in AD beyond cognitive performance. Behavioral symptoms such as apathy and loss of initiative, agitation, delusions, hallucinations and irritability appear to develop less often in treated patients.105-107 Evidence for increased oxidative stress and free

Treatment of Alzheimers disease patients with CQ

This study was followed by a larger double-blind placebo-controlled trial involving 36 patients also with mild to moderate AD treated over 36 weeks 180 . CQ doses were 125 mg twice daily (first 12 weeks), 250 mg twice daily (weeks 13-24) and 375 mg twice daily (weeks 25-36). Subsequent analysis of patients revealed that CQ significantly arrested the rate of cognitive decline (on ADAS-cog) at week 24 (and a tendency to significance at week 36) in the patients suffering moderate dementia 180 . The patients with mild dementia did not deteriorate in ADAS-cog scores during the study period, making it impossible to appreciate a change in deterioration rate over the study in this subgroup. CQ significantly lowered plasma AP1-42 levels, while plasma Zn levels were elevated and there was no change in plasma Cu 180 .

Psychiatric Symptoms and Behavioral Disturbances in Dementia A Review of Therapy

Summary This journal article reviews selected drug treatments for psychiatric symptoms and behavioral disturbances in dementia. Several different classes of drugs have been used in the treatment of behavioral disorders in dementia neuroleptics, anticonvulsants, antidepressants, beta-blockers, and benzodiazepines. Neuroleptics are the drugs of first choice for treating behavioral disorders, and they generally are considered to be moderately effective. These drugs are known to improve anxiety and mood and reduce aggression, agitation, hostility, and uncooperativeness. Anticonvulsants such as carbamazepine and sodium valproate also may be effective in some patients with dementia. Antidepressants have been used not only for the treatment of depression but also to reduce agitation, aggression, and shouting in patients without a definable additional affective disorder. Beta-blockers generally have been found to be effective in younger patients with evidence of brain damage, and several...

Alzheimers Disease

Alzheimer's disease is a neurodegenerative disorder characterized by a progressive loss of memory, intellectual function, and cognitive abilities (Wisniewski et al., 1994). In the normal population, AD usually arises during the fifth or later decades of life and affects approximately 10 of individuals aged 65 and above (Keefover, 1996). In DS, however, almost 100 of patients develop Alzheimer's-type neuronal pathology by the third to fourth decade of life (Dalton and Wisniewski, 1990). There is now considerable evidence that both amyloid -peptide (A 3) and oxidative stress are implicated in the pathogenesis of AD (Friedlich and Butcher, 1994 Mattson, 1997a). It has been shown that A 3, which is a normal product of cell metabolism derived from the 3-amyloid precursor protein (APP), is overproduced in the brain of individuals with AD and forms insoluble fibrillar aggregates, called senile or neuritic plaques, that promote neuronal degeneration (Mattson, 1997b). This neurotoxic effect of...

Criterion Validity Do the Symptoms Respond to Treatment Pharmacologic or Nonpharmacologic Antipsychotic Treatment in

Summary This journal article reviews the Literature on antipsychotic treatment in patients with behavioral disturbances of dementia. First, it reviews results from the four randomized, double-blind, placebo-controlled trials of neuroleptics in dementia which were published in the past 20 years. Then it summarizes findings concerning the efficacy and safety of clozapine, risperidone, and benzodiazepines. Next, the article discusses the optimal dose of haloperidol, the optimal duration of antipsychotic treatment, and antipsychotic side effects. In 1 study of the course of psychopathology, conducted by the author and colleagues, 235 patients with early, probable Alzheimer's disease (AD) were followed at 6-month intervals for up to 5 years. Agitation was found to be the most persistent symptom, which suggests that prolonged treatment may be needed. Finally, the article suggests an approach to initiating and monitoring antipsychotic treatment in older patients with dementia. In the...

Treatment Strategies for Agitation and Psychosis in Dementia

Summary This journal article reviews treatment strategies for agitation and psychosis in patients with dementia, specifically Alzheimer's disease. It describes types of behavioral disturbances that are associated with dementia and a systematic approach used in evaluating and managing these behavioral complications. It discusses the treatment of psychosis in dementia using traditional antipsychotic agents (haloperidol and thioridazine), newer antipsychotic agents (clozapine and risperidone), and other drugs. It also discusses the benefits and side effects of treatment of agitation in dementia using antipsychotic agents anticonvulsant agents (carbamazepine and valproic acid) anxiolytic agents (benzodiazepines and buspirone) antidepressants (trazodone and selegiline) serotonin selective reuptake inhibitors (alaproclate, citalopram, fluvoxamine, fluoxetine, and sertraline) cholinergic therapy and other therapies such as electroconvulsive therapy, hormonal therapy, and phototherapy. 4...

Cellular and Molecular Pathophysiology of Alzheimers Disease

Alzheimer's disease (AD) is the most prevalent form of dementia in the world today, afflicting approximately 4 million people, or 60-80 percent of the cases of dementia in the United States.2-4 The disease has both familial and sporadic forms, both of which cause dysfunction in behavioral regulation, higher cognitive function and, most strikingly, short-term memory. AD presents unique challenges from a social and medical view. Because it is insidious and progressive, society's costs, both direct and indirect, are high. Additionally, AD presents a problem in that most patients do not come to medical care until significant impairment has occurred. Thus, patients do not always benefit from early diagnosis and treatment. Finally, at this point, AD cannot be definitively diagnosed until autopsy. As clinicians expand the therapeutic arsenal for AD, a definite pathway for diagnosis pre-autopsy is of the utmost importance.

GSK3 in Alzheimers Disease Brain

The levels of active GSK-3 are increased in the frontal cortex in Alzheimer's disease patients. Studies of the cellular distribution of active GSK-3 shows that GSK-3 co-localises with several phospho-tau epitopes in the somatoden-dritic compartment, an early event preceding the formation of NFTs 18 . Active GSK-3, measured as Tyr216 phosphorylation, co-localises with pre-tangle and tangle bearing hippocampal and cortical neurons in Alzheimer's disease brain 4 . It should be noted, however, that phosphorylation and de-phosphorylation are often very rapid dynamic events and as a consequence, the post-mortem stability of phosphorylated GSK-3 in these samples is likely to be very short 19 . Elevated levels of GSK-3 protein in Alzheimer's disease brains are observed in some studies, whereas others fail to show similar results. A recent study on a limited number of subjects shows that total GSK-3 levels were not increased in Alzheimer's disease patients 4 . However, the limited number of...

Neuropathology of Alzheimers Disease

The original definition of AD was based upon characteristic morphology associated with the AD brain. To this day, the histological features of the AD brain remain as hallmarks of this form of dementia. Histologically, AD is characterized by the presence of neurofibrillary tangles within neurons and senile plaques located outside neurons (Alzheimer,

Alzheimers disease and cognition

At GalR1, galanin inhibits the release of hormones or neurotransmitters, affecting memory (Bartfai et al. 1993). Galanin acts as a postsynaptic hyperpolarizing substance to reduce LTP (Mazarati et al. 1992, 1998, 2000, 2001). One of the most intriguing features of galanin neurobiology is the overexpression of galaninergic fibres around the few surviving cholinergic cell bodies in autopsy material from patients with Alzheimer's disease, primarily in cholinergic basal forebrain neurones (Chan-Palay 1988 Kohler et al. 1989 Mufson et al. 1998, 2000). One explanation for this phenomenon may be that galanin acts as a trophic factor in this area, promoting growth and survival of some ACh-containing neurones. Since there is a very large loss of cholinergic cells in the Alzheimer's disease brain, factors like galanin, which may influence the survival and function of those cells that project to the hippocampus and play a major role in cognitive function, is of great importance.

Neurodegenerative Disorders Alzheimers and Parkinsons Disease

In the elderly, age-related brain dysfunction and progressive occurrence of dementia are common causes of disability. Moreover, an increasing number of individuals are affected by Alzheimer's (AD) and Parkinson's Disease (PD). In both diseases, the underlying processes are a progressive pathologic degeneration of neurons, apoptotic cell death, and a substantial neuronal loss. This leads to dementia with cognitive and functional impairments and ultimately early death (108,109). Progressive formation of protein aggregates such as senile plaques (amyloid p-peptide protein) and neurofibrillary tangles (t protein) in AD patients and Lewy bodies (a-synuclein protein) in PD patients is concomitant with severe oxidative stress associated with altered metabolic pathways, inflammatory processes, and neurodegeneration (110,111). A unique role of vitamin E in brain function is evident because inadequate tissue concentrations lead to brain dysfunction and peripheral neuropathy in humans (129-131)....

Other Forms of Dementia

Dementia as a consequence of cerebrovascular disease, ischemia-reperfusion, and stroke is another important disorder in elderly persons. Results from observational studies showed that a low dietary intake of vitamin E was associated with an increased risk of dementia (152-154), whereas other investigations found no association (155,156). Vitamin E was strongly related to cognitive performance in the Euronut-SENECA study of elderly Europeans from different countries (157). Moreover, in a sample of 4809 elderly subjects participating in the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994), serum levels of vitamin E were inversely correlated with memory function, whereas other antioxidant nutrients including vitamin C, p-carotene, and selenium did not show such an association (153). It may be suggested that prevention of vascular dementia by vitamin E via protecting neurons against oxidative damage as well as via inhibition of platelet aggregation or...

Donepezil Improves Symptoms of Delirium in Dementia Implications for Future Research

Summary This journal article discusses a case study of delirium, complicated by preexisting dementia, that was resolved rapidly following initiation of the cholinesterase inhibitor donepezil. The authors suggest that cholinergic dysfunction may have played a role in the etiology of the patient's delirium. Delirium is a common complication of dementia that may produce agitation, which may be refractory to conventional medications such as antipsychotics and benzodiazepines. Delirium may also produce considerable morbidity. Delirium is not always reversible and there is no specific treatment for persistent delirium the main treatment approach is to treat the underlying medical problem. The authors state that future research needs to be directed at the issue of cholinergic activity in delirium through monitoring serum anticholinergic activity and its response to procholinergic therapy. 17 references. (AA-M).

Imaging for Pathophysiological Evaluation and Early Diagnosis of Alzheimers Disease AD

In recent years, the number of patients with dementia has been increasing. The deposition of senile plaques (SPs) in the brain has been demonstrated to represent the neuropathological characteristics of AD 13 . The progressive accumulation of SPs has been considered to be fundamental to the initial development of AD. The deposition of SPs in the brain is present even in very mild AD and precedes the initiation of cognitive impairment at the clinical level 43, 44 . That is why noninvasive imaging of SP deposition would be useful for the early detection of AD. In addition, several anti-amyloid drugs are already under development for the treatment and prevention of AD 45 . This could be another good motivation for the promotion of the noninvasive imaging of SP deposition. Though several imaging techniques have been developed for this purpose, PET has been the most advanced and practical method for the in vivo evaluation of SP deposition. At present, 2-(4'methylaminophenyl)benzothiazole...

Frontotemporal Dementias

During the past decade, neurologists and psychiatrists have become increasingly aware that a significant proportion the degenerative dementias are of the non-Alzheimer type. The frontotemporal dementias, characterized by progressive personality changes and language impairment related to a frontotemporal atrophy, account for approximately 5-20 of these diseases (Jackson 1996 Sleegers 2004). The first pathological description of a particular form of frontotemporal dementia (FTD) was made by Arnold Pick in the early 20th century, but the first clearly indexed cases of patients with FTD were reported in 1987 by Gustafson in Lund-Sweden (Gustafson 1987), and in 1988 by Neary et al. in Manchester-United Kingdom (Neary 1988). The clinical and pathological nosology was further clarified in 1994 and the term frontotemporal dementia adopted during a consensus conference bringing both the teams of Lund and Manchester (The Lunds and Manchester groups 1994). The frontotemporal dementias in fact...

Design of structures against neurodegeneration of Alzheimers type

Neurodegenerative diseases like senile dementia of Alzheimer's type (SDAT) are among the greatest challenges in pharmacochemistry It is estimated that there will be about 4 x 107 sufferers from this disorder by 2020.18 SDAT, cardiovascular disorders, and cancer are the first three causes of morbidity worldwide At present, there is no effective treatment for SDAT. The applied pharmacotherapy is based on the cholinergic hypothesis . 19 These drugs are of limited benefit, quite toxic, and fail to inhibit the progress of the disease . Furthermore, there is a challenge because the pathogenesis of SDAT is essentially not known . However, there is a series of patho-biochemical changes in the demented brain that could be used as a base for a rational design of drug molecules for SDAT. In addition to the cholinergic deficit, the patho-biochemical changes related to the present work are inflammation, oxidative stress, hypercholesterolemia,20 and reduced presence of the nerve growth factor (NGF)...

Frontotemporal Dementia and Picks Disease

Frontotemporal dementias, including Pick's disease, are associated with focal atrophy of the frontal and or temporal lobes. They are characterized by considerable gliosis and the loss of cortical neurons. Astrocytosis, Pick bodies (inclusion bodies) and Pick cells (ballooned neurons) are present in a subset of the patients. The term describes a range of similar conditions, with different pathologies. The etiology of these diseases is largely unknown. Patients with frontal atrophy display a change of behavior and personality. Obsessive- compulsive and socially inappropriate behavioral patterns are characteristic. At the same time, motor and sensory functions stay intact. Patients with an affected temporal lobe display severe semantic impairment. They are often unable to remember words or understand less frequently used words. As in frontal dementia, other neuronal functions and memory remain relatively intact.

Homocysteine And Dementia

The utility of standard laboratory tests in the work-up of dementia and the true prevalence of potentially reversible etiologies has been examined by (1) 'Low-intake' hypothesis cobalamin deficiency develops secondarily to impaired nutritional intake due to dementia. (3) The 'etiological' hypothesis the cobalamin deficiency itself contributes to the dementia. Homocysteine metabolism is absolutely dependent on five B-complex vitamins Bj, B2, B6, B12 and folate. Total homocysteine is a useful indicator of a subtle and early cobalamin-deficient state, as tissues cannot utilize this amino acid in the usual manner. Homocysteine has been shown to be associated with cardiovascular disease,88 such as heart attack and stroke. It is also an important emerging risk factor for AD and cognitive dysfunction in the elderly.89 Several associations also have been observed for cognitive impairment in the elderly.90 Whether vitamin B12 deficiency can alter the clinical presentation of DAT or contribute...

Pharmacotherapy for Long Term Care Residents With Dementia Associated Behavioral Disturbance

Summary This journal article summarizes Federal guidelines for benzodiazepine and antipsychotic drug use in long-term care residents with dementia. The Nursing Home Reform Amendments of the Omnibus Budget Reconciliation Act of 1987 (OBRA 87) have resulted in close supervision of the use of unnecessary drugs for residents in Medicare and Medicaid certified nursing homes. They require documenting the behavioral indication for psychotropic drugs, monitoring their safety and efficacy, drug holidays, behavioral management instead of drugs when possible, and systematic dose reductions unless clinically contraindicated. Long-acting benzodiazepines generally are not recommended for use in older patients. Short-acting benzodiazepines may be used for anxiety, insomnia, and dementia-associated agitated states that represent a danger to the patient or others. Antipsychotics may be used for dementia with psychotic features, continuous crying or screaming that impairs functional status, and...

Use of Galantamine in the Treatment of Alzheimers Disease

Galantamine is the last acetylcholinesterase inhibitor to be approved for the treatment of mild to moderate Alzheimer's disease. It is claimed that the nicotinic modulating ability of galantamine enhances cholinergic neurotransmission and thus makes it a more potent cholinesterae inhibitor. Whether or not the mechanism of allosteric modulation of presynaptic nicotinic receptors enhances cholinergic neurotransmission leading to greater efficacy, this is a unique mechanism not shared by the other cholinesterase inhibitors. Similar to the other cholinesterase inhibitors, studies of galantamine so far have shown modest efficacy in the areas of cognition, activities of daily living, and behavioral disturbance. In one of the earlier studies investigating the efficacy of galantamine in mild to moderate Alzheimer's patients, Tariot and colleagues enrolled 978 patients in a randomized, placebo-controlled, double-blind trial. Patients were randomized to receive either placebo, or galantamine...

Alzheimer Disease

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that gradually destroys a person's memory and ability to learn, make judgments, communicate with the social environment and carry out daily activities. In the course of the disease, short-term memory is affected first, caused by neuronal dysfunction and cell death in the hippocampus and amygdala. As the disease progresses further, neurons also die in other cortical regions of the brain. At that stage, sufferers often experience dramatic changes in personality and behaviour, such as anxiety, suspiciousness or agitation, as well as delusions or hallucinations. AD prevalence in the different age groups is 1 (65-69 years), 3 (70-74 years), 6 (75-79 years), 12 (80-84 years), and 25 (85 & over) 1 . As the society ages, the number of Alzheimer's disease patients will increase by 27 by 2020, 70 by 2030, and nearly 300 by 2050, unless science finds a way to slow the progression of the disease or prevent it. Alzheimer's...

Vascular Dementia

Multi-infarct dementia Vascular dementia is the second most common form of dementia after Alzheimer's disease (AD) in older adults. The term refers to a group of syndromes caused by different mechanisms all resulting in vascular lesions in the brain. Early detection and accurate diagnosis are important, as vascular dementia is at least partially preventable.

Preface to the Series

The editors have chosen topics from both important therapeutic areas and from work that advances the discipline of medicinal chemistry. For example, cancer, metabolic syndrome and Alzheimer's disease are fields in which academia and industry are heavily invested to discover new drugs because of their considerable unmet medical need. The editors have therefore prioritized covering new developments in medicinal chemistry in these fields. In addition, important advances in the discipline, such as fragment-based drug design and other aspects of new lead-seeking approaches, are also planned for early volumes in this series. Each volume thus offers a unique opportunity to capture the most up-to-date perspective in an area of medicinal chemistry.

AD Symptoms and Neutodegeneration

AD is a chronic progressive neurodegenerative disease. The progression of symptoms varies from patient to patient but can be roughly divided into three stages mild, moderate and severe (Mayo Clinic, http health alzheimers-stages AZ00041). The progression of symptoms can be ascribed to the sequential and progressive loss of neuronal functions and synaptic connections, and neuronal cell death in different regions of the brain. In the mild stage AD is first manifested with loss of memory as neurons in the region for memory formation, the hippocampus, are first affected. Patients may forget words and names with increasing frequency and get lost even in familiar places. Some believe that these incipient cases of AD are equivalent to a clinical condition known as mild cognitive impairment (MCI). Not all MCI patients will convert to AD a 36 month study shows that the conversion rate from amnestic MCI to AD is about 16 per year 2 . In the moderate stage cortical regions...

Apoptosis Characterization

To change shape and becomes very contorted in comparison to the normal nucleus. The nucleus and the cell then begin to split up into many, small, membrane-bound structures, called apoptotic bodies. The apoptic bodies are phagocytized by neighboring cells or by macrophages, which occurs fairly rapidly over the next few hours. In general, cells that die by becoming shrunken and dark, such as red neurons in stroke models, neurofibrillary tangles in Alzheimer's disease,

Neurofibrillary tangles amyloid deposition FREE radicals AND neurotoxicity

Replacement strategies are aimed at alleviating clinical symptoms (memory loss), not at preventing the development of the disease. Discovering drugs that can inhibit the progression of AD will therefore largely require an understanding of the molecular causes and mechanisms underlying the neurodegenerative processes responsible for the neurochemical deficits and neuronal losses observed. Both the regional distribution and the amount of neurofibrillary tangles (which are composed of paired helical filaments, PHFs) correlate with the degree of dementia.42 It has been shown that PHFs are composed of protein tau, a protein normally associated with the microtubular network of the cell. Tau isolated form PHFs (AD) appear to be in a hyperphosphorylated state when compared to normal soluble tau. The region of tau that normally binds to the microtubule contains a serine residue (Ser-262), which is of particular interest because phosphorylation of this residue has only been observed in tau...

Acetylcholine app processing and neurotrophic and neuroprotective effects

Dephosphorylation and potentiated the neurotrophic effects of NGF in PC12(MI) cells.67 These findings suggest that cholinergic replacement therapy, or any agents favoring phosphorylation via depolarization or second-messenger systems, might beneficially affect the metabolism of APP and eventually slow the course of the disease. Testing this hypothesis would obviously require long-term treatment of Alzheimer patients in an early stage of the disease with well-tolerated cholinergic drugs. It remains to be established whether cholinergic hypoactivity caused by the loss of cholinergic nerve terminals contributes to plaque formation via reduced activation of cholinergic mt receptors and PKC.

Basics of Cholinesterase Inhibitors

There are currently four cholinesterase inhibitors approved by the US Food and Drug Administration for the treatment of Alzheimer's disease. They are tacrine, donepezil, rivastigmine, and galantamine. Although each of the cholinesterase inhibitor behaves uniquely, the main mechanism of action shared by all the cholinesterase inhibitors as a class is reversible inhibition of acetylcholinesterase and with some, butyrylcholinesterase. Tacrine is nonselective for all forms of acetylcholinesterases. Both rivastigmine and galantamine are selectively active in the central nervous system, with ri-vastigmine probably most centrally selective, with minimal activity in periphery. Donepezil has more peripheral action 6 . All cholinesterase inhibitors are readily absorbed across the gastrointestinal tract. Tacrine was the first acetylcholinesterase inhibitors to be approved by the FDA in 1993. However, hepatotoxicity and the need for frequent dosing limited the usage of this drug. Donepezil was...

Early Experimental Data Implicating Neuroinflammatory Processes

The classical view of the brain as an immunologically privileged site primarily due to its effective selectivity and the relative impermeability of the blood-brain barrier has made it difficult to consider the notion that inflammatory processes, also classically considered to be a domain of the circulatory system, occur in the brain. But the early findings by the McGeer and Rogers groups, starting as early as 1987, on the expression of immune system antigens (16), the presence of reactive microglia (17), and the activation of the classical compliment pathway in Alzheimer's disease (AD) brain (18) strongly implicated neuroinflammatory processes. In addition, their early demonstrations that rheumatoid patients taking antiinflammatory drugs had delayed appearance of AD symptoms (19) also strongly suggested the importance of neuroinflammatory events in the dementia associated with the disease. The early demonstrations that proinflammatory cy-tokines were shown to be elevated in...

Brain Anatomical Changes Associated with the Use of Cholinesterase Inhibitors

Using positron emission tomography, or PET scanning, Nordberg and colleagues were able to show higher cholinergic activity in the brains of patients afflicted with Alzheimer's disease who were taking tacrine 59 . In another study, using PET, Mega and colleagues looked at brain metabolism in patients with Alzheimer's disease who were taking galantamine. Their data show that patients who had improved in the areas of cognition and behavior also showed significant activation in the striatalthalamofrontal regions on PET scanning 60 . However, this study had several limitations. First of all, this was a small prospective, open-label study involving only 19 patients. Furthermore, it may be difficult to attribute the changes on PET solely due to the administration of galantamine, as patients who did not exhibit improvement in cognition but were also receiving galantamine did not show this change on PET. In a similar study using PET technology to assess the impact of cholin-esterase inhibition...

Combination Treatment of Cholinesterase Inhibitors with Memantine

Besides the Cholinesterase inhibitors, one of the current treatments available for the treatment of Alzheimer's disease is memantine. Since this chapter is devoted to Cholinesterase inhibitors, discussion of memantine will only be in the context of its combination treatment with cholinesterase inhibitors. Memantine has a distinct mechanism of action. It is a noncompetitive N-methyl-D-aspartate receptor antagonist. As more data become available from recent research, it is now known that other neurotransmitters, besides acetylcholine, are involved in Alzheimer's disease. In the glutamate hypothesis, excessive activation of NMDA by glutamate is implicated in neurotoxicity and neuronal ischemia. Normally, NMDA receptors are activated by glutamate, which is an excitatory neurotransmitter in the brain. Thus, by blocking this excessive activation, memantine may have a neuroprotective effect 67 . Currently in the United States, memantine is approved for treatment in moderate to severe...

Recent Recommendations by the National Institute of Clinical Excellence

Of cholinesterase inhibitors in the treatment of dementia. In their most recent recommendation from January 2007, NICE states that cholinesterase inhibitors should only be used in patients with moderate dementia, those with MMSE of 10-20 91 . In those with mild or severe dementia, the panel did not think that the medications made enough of a difference. This has affected hundreds of thousands of patients with Alzheimer's disease in Great Britain. Opponents of this recommendation are worried that patients with Alzheimer's disease will be discriminated against by the health care system 92 . Not only will the insurance companies stop reimbursing for cholinesterase inhibitors in patients with mild or severe Alzheimer's disease, patients might not be as forthcoming about their illness or seek treatment since now it would be harder to have access to one of the few treatments currently available for Alzheimer's disease. In addition, opponents of this study are also quick to point out that...

Concluding Remarks

Current evidence suggests that oxidative stress is a key component in all forms of glutamate neurotoxicity. In particular, the formation of O2 and its decay pathways in a cellular setting seem to be critical determinants of glutamate neuro-toxicity. Mitochondria appear to be the primary source of reactive oxygen species during excitotoxicity although methodological difficulties make it difficult to make any sound conclusions. More quantitative analysis of oxidant generation following glutamate treatment and analysis of oxidative damage needs to be performed to better assess the involvement of reactive oxygen species in glutamate neurotoxicity. Because glutamate is believed to play an important role in the neurodegeneration associated with Alzheimer's disease, Huntington's disease, epilepsy, and cerebral ischemia, understanding the complex free radical chemistry involved in glutamate neurotoxicity will hopefully advance therapeutic strategies for many neurodegenerative disorders.

Epidemiological Studies of Cholesterol and AD

Initial interest in cholesterol and Alzheimer's disease stemmed from a lengthy historical backdrop. One of the first studies linking cholesterol to AD stemmed from an observation that senile plaques were quite prevalent in the brains of non-demented patients who had died from coronary heart disease 21 , a population known to possess elevated cholesterol levels. Additional studies soon followed demonstrating that the ApoE4 allele of the ApoE cholesterol transporter was a major risk factor for AD 13-16 . Is there a clear association between cholesterol and Alzheimer's disease Although a few studies have observed an association between elevated cholesterol, dementia and AD 22,23 , the majority of cross-sectional studies typically report no association or lower levels of cholesterol in patients with AD compared to controls or VaD patients 24-30 . In two longitudinal population-based studies, higher midlife cholesterol levels were reported to be associated with an increased risk of AD...

Epidemiological Studies of AD and Statin

HMG-CoA reductase is the first enzyme in the cholesterol synthesis pathway and inhibition essentially blocks de novo synthesis of cholesterol 40 . As expected, the first HMG-CoA reductase inhibitors were shown to be efficient inhibitors of cholesterol 41,42 . Today, statins are one of the most prescribed medications for lowering blood cholesterol. In 2000, two seminal epidemiological studies were published raising hopes that statins may have some utility in the prevention of dementia presumably through cholesterol lowering mechanisms. These studies utilized a case-control and a nested case-control analysis to examine the relationship between statin use and the prevalence of dementia. One study utilized hospital patient databases in Illinois and Arizona to examine prevalence of AD in over 57 000 patients 60 yrs or older. Initial results suggested that the prevalence of probable AD in lovastatin and pravastatin (but not simvastatin) users was significantly lower compared...

Statins and Cognition

Preliminary enthusiasm in statins and cognition had been tempered by negative findings from two large cardiovascular studies examining the effects of statins on mortality and cardiovascular events where cognition was assessed as a secondary outcome. In 2002, the Foundation Heart Protection study evaluated effectiveness of 40 mg simvastatin in 20,536 elderly adults, including 5,806 between the age of 70-80 years. A telephone interview for cognitive status was used to assess cognition over the 5-year study period, and no differences in cognition was observed between placebo vs. statin treated groups 64 . The second large, Prospective Study of Pravastatin in the Elderly (PROSPER) evaluated pravastatin use in 5804 70-80 year-old cardiovascular patients at risk for dementia for 3.2 years. A number of cognitive tests were assessed including mini mental state exam (MMSE), Stroop and word learning digit recall memory tests. Again, no effect on cognition was noted 65 . The prior results are in...

SHydroxycholesterol Cerebrosterol

Previously, a prospective placebo-controlled, randomized intent-to-treat study had been run to test atorvastatin for benefit in the treatment of mildmoderate AD patients. Preliminary results from the Alzheimer's disease cholesterol lowering trial (ADCLT) has been described in detail 73 . In brief, 67 AD subjects were randomized to either 80 mg atorvastatin or placebo and treated for one year. Blood for biomarker analysis was collected at baseline, 3, 6, 9 and 12 months post-dosing. To determine whether atorvastatin might impact brain cholesterol, a subset of samples was analyzed by GCMS for changes in 24S-hydroxycholesterol (also known as cerebrosterol). Statistical analysis utilizing a repeated measures approached identified no statistical differences in 24S-hydroxycholesterol concentration over time between atorvastatin and placebo treated groups. However, 24S-hydroxycholesterol levels were slightly increased at 9 and 12 months in the placebo group and were unchanged at the same...

Of Calcium Homeostasis In Acute

Huntington's disease (HD) is an age-related disorder characterized by choreic movements and progressive dementia. This disease is hereditary, resulting from expansion in a CAG trinucleotide repeat in the coding region of the huntington gene on chromosome 4. This mutation results in degeneration of a subset of GABAergic neurons in the basal ganglia. Production of genetically engineered mice in which the gene has been ''knocked out'' results in embryonic lethals, indicating that HD is not the result of a loss of function mutation but rather is due to the gain of function by the protein (55,56). B. Alzheimer's Disease Alzheimer's disease (AD) is currently the most prevalent cause of progressive intellectual failure in older individuals. A primary pathological feature of Alzheimer's disease is the increased age-related formation of extracellular deposits in the cerebral cortex and hippocampus of affected individuals known as amyloid plaques, named for the presence of aggregates of a 40-...

Future Directions

This is an exciting period for MAO research and its effects on behavior. Since MAO-A KO mice display elevated levels of aggressive behavior (17), these mice provide an excellent model to study the mechanism of aggression. Recently, Cases et al. (37) showed atypical localization of 5-HT immunolabeling in the developing brain of MAO-A KO mice. The molecular role of 5-HT during development can be further studied in these mice. MAO-B can metabolize the main metabolite of histamine, telehistamine (38). Studies with MAO-A and MAO-B KO mice will clarify the physiological role of MAO-B in histamine catabolism. PEA can significantly alter behavior and may be important in disease. Several lines of evidence suggest that increased levels of PEA are associated with the manic phase of bipolar disease (39) and with schizoaffective disorders (40). We have demonstrated that H2O2 generated during MAO-catalyzed oxidation of neurotransmitters may cause oxidative damage to mitochondrial DNA (19). Thus,...

Neurofibrillary Tangles

Neurofibrillary tangles are found within neurons of the cerebral cortex and hippocampus and consist of insoluble intracellular fibrils that are comprised of hyperphosphorylated forms of tau, a microtubule-associated protein 20,21 . The microtubules are essential for axonal transport and the structural stability of neuronal processes. Therefore, it is believed that impaired axonal transport contributes to neuronal degeneration that typifies the disease. Neurofibrillary tangles are not unique to Alzheimer's disease and can be found in a variety of other neurologic disorders.

Subunits Associated with Complex Phenotypes

While many reports find an association between the C825T allele of GNB3 and other features of the metabolic syndrome, including obesity, insulin resistance, auto-nomic nervous changes, and dyslipidemia (58-61), the results are not unanimous (62-65). The polymorphism has also been implicated in Alzheimer's disease (66), sudden death (67), and tumor progression (68,69) and as a pharmacogenetic marker for drug response (57,70-73). The mechanisms linking the C825T polymorphism to clinical outcomes have not been identified. The GNB3 polymorphisms, however, may become useful markers for disease risk and altered drug response.

Nitric Oxide Overproduction and Oxidative Stress in Human Idiopathic Parkinsons Disease

Neurodegenerative diseases are a complex group of neurological disorders that present a common hallmark the selective death of circumscribed groups of neurons. In accord, Parkinson's disease (PD) is characterized by a massive loss of melanized dopaminergic neurons in the pars compacta of the substantia nigra with a significant reduction of the striatal dopamine (DA) content (1) (Fig. 1). Cell death should be related to the activation of proapoptotic pathways.

Neurodegenerative Diseases A Growing Burden In The Aging Population

Neurodegenerative diseases are initially characterized by subtle changes in the normal function of neurons, which is followed by overt neuronal dysfunction and cell death in later stage of the disease. Age is the single most important risk factor for the development of many neurodegenerative disorders including Parkinson's (PD) and Alzheimer's disease (AD). In 2006, 26.6 million people were living with Alzheimer's disease worldwide. According to the American Alzheimer's Association, this number is set to exceed 100 million by 2050, at which time one in 85 people will be living with the disease, due to rapidly ageing populations and longer life expectancy. Patients with neurodegenerative diseases not only suffer emotionally and physically but also represent a significant financial and

Other Suggested Mechanisms For

Although sporadic ALS is believed not to be a primary genetic disease, genetic susceptibility might be relevant furthermore, it is not excluded that the number of ALS patients turning out to be part of FALS families will increase as epidemiological studies advance. As mentioned above, mutations in the SOD1 gene account only for about 20 of familial ALS, indicating that genes other than SOD1 must be involved in FALS. The genes coding for five glutamate receptor subunits designated GluR1-GluR5 have been localized in the human genome and GluR5 maps between the loci for Alzheimer APP and SOD1 genes on chromosome 21. However, linkage between GluR5 and FALS has been conclusively excluded other members of the family are still good candidates (17). Also good candidates are the genes encoding for neurofilament proteins, since a typical feature of ALS motoneurons is represented by the accumulation of neurofilaments leading to axon swelling (49). In this respect, it must be mentioned that mice...

Inhibitors of GSK30 structure physical chemistry mechanism of action potency and selectivity

Although a significant proportion of those articles actually focused on describing GSK-3P inhibitors claim their use in Alzheimer's disease as well as in other indications (principally type II diabetes mellitus), there are relatively few examples where Alzheimer's disease appears to be the principal focus. For example, a simple cross-referencing of the 330 PCT international patent applications with the term tau reveals only 58 filings.

Efficacy of Lithium on Tau and Beta Amyloid

Lithium reduces the phosphorylation of tau in primary neurons 69-71 . Studies performed in Sf9 cells overexpressing FTDP-17 tau, a tau mutation resulting in tau aggregate formation resembling PHFs, display a reduction in the amount of polymer in response to lithium treatment. This suggests that phosphorylation of FTDP-17 tau by GSK-3 induces a conformational change favouring the formation of fibrillar polymers 72 . Thus, this finding implies that inhibition of GSK-3 not only regulates the phosphorylation status of tau but also tau assembly into filaments. As described above, an abnormal phosphorylation of tau is believed to have an important role in the destabilisation ofmicrotubules, which contributes to the disruption of microtubule structures in tangle-bearing neurons. Lithium has the ability to restore the stability of microtubules in 3T3 cells co-transfected with tau and GSK-3P 73 . Thus, inhibition of GSK-3 not only inhibits fibril formation but also can recover the microtubule...

Potential Strategies For Radical Scavenging

One of the main pathological features of PD is the appearance of abundant deposition of iron at the site of neurodegeneration, but the basis of the increased iron levels remains unclear (8). Iron has the capacity to promote oxidation reactions and the formation of cytotoxic free radicals (9). A marked increase in the concentration of iron in affected brain areas has been confirmed for PD, Huntington's disease, supra nuclear palsy, multiple system atrophy, as well as Alzheimer's disease (10). The late state of PD is characterized by an accumulation of iron in substantia nigra pars compacta (11). This raises the possibility that therapies designed to chelate iron and prevent it from participating in oxidation reactions may protect vulnerable neurons and slow the rate of disease progression in patients suffering from neurodegenerative disorders. Iron chelators have been demonstrated to effectively prevent iron-catalyzed reactions from taking place and to correspondingly limit free...

Lithium and Long Term Potentiation

In conclusion, lithium is a moderate inhibitor of GSK-3, which in pre-clinical studies has been shown to influence pathophysiological mechanisms of Alzheimer's disease, i.e. both decreasing the hyperphosphorylation of tau and reducing the metabolism of beta amyloid. However, the action of lithium is complicated by the diverse actions associated with this compound. Due to the toxic effects associated with long-term use of lithium and therapeutically higher concentrations to decrease GSK-3 activity, it may not be considered as a prime candidate for treatment of Alzheimer's disease.

Antioxidant Vitamins

Alzheimer's Disease fenses against free radical damage in 55 patients with AD and 24 age-matched controls. There was a statistically significant decrease in the serum levels of vitamins A, C, and E among other things in the AD group. However, most of the deficiencies were found in the malnourished subgroup of the AD patients. Furthermore, one study suggests that among patients with AD serum vitamin E levels are associated with better results on cognitive measures, especially among female patients who had overall higher levels (65). In contrast, Ahlskog et al. (66) found no significant differences in serum levels of vitamin E between AD patients and controls. Cerebrospinal fluid (CSF) levels of vitamin E were found to be decreased in two studies comparing AD patients and controls (67,68). Again, weight and body mass index were found to be significantly lower in AD patients in one of these studies (67), suggesting that CSF and serum vitamin E concentrations in these patients may be...

Pharmacokinetic Properties of ARA014418

In summary, AR-A014418 is a potent and specific GSK-3 inhibitor capable of intervening with both tau phosphorylation and beta-amyloid-induced toxicity. AR-A014418 is also the only published specific GSK-3 inhibitor with documented in vivo efficacy consistent with an Alzheimer's disease modifying mode of action. Thus, AR-A014418 represents an important research tool to study the therapeutic potential of GSK-3 inhibition in neurological disease.

Author Index Volumes

Alzheimer's Disease. 2 137-174 Blake JF, see Wallace EM (2007) 1 65-114 de Bono JS, see ten Holte P (2007) 1 273-311 Boschelli DH (2007) Bcr-Abl Kinase Inhibitors. 1 387-424 Bradbury RH (2007) Overview. 1 1-17 Brodney MA, see Lau L-F (2007) 2 1-24 Burrows J, see Bhat RV (2007) 2 137-174 Bush AI, see White AR (2007) 2 107-136 Jiang Q, Mandrekar S, Landreth G (2007) PPARy Agonists for the Treatment of Alzheimer's Lau L-F, Brodney MA (2007) Therapeutic Approaches for the Treatment of Alzheimer's Soares HD, Sparks DL (2007) Beyond Cholesterol Statin Benefits in Alzheimer's Disease. 2 53-80 Signaling by Small-Molecule Inhibitors of ErbB, Raf, andMEK. 1 65-114 White AR, Bush AI (2007) Metal Complexing Agents for the Treatment of Alzheimer's Disease. 2 107-136

Free Radicals and Antioxidants in Neurological Disorders

Molecular and Cellular Aspects of Oxidative Damage in Alzheimer's Disease 313 Mark A. Smith and George Perry 16. Free Radical-Mediated Disruption of Cellular Ion Homeostasis, Mitochondrial Dysfunction, and Neuronal Degeneration in Sporadic and Inherited Alzheimer's Neurotoxicity in Alzheimer's Disease 359

Petra Kapkova Vildan Alptuzun Eberhard Heller Eva Kugelmann Gerd Folkers and Ulrike Holzgrabe

One of the most prominent features of Alzheimer's disease (AD) is a significant deficit in cholinergic transmission in certain brain areas.1,2 The concentrations of acetylcholine (ACh) decrease by nearly 90 in patients with AD. Therefore, one main focus of AD treatment is the use of agents that increase the availability of intrinsic ACh by inhibiting the acetylcholinesterase (AChE) enzyme. This may restore the cholinergic function in the brain and significantly reduce the severity of dementia. Another key feature in brain pathology of patients with AD is the progressive deposition of the amyloid p (Ap) peptide in fibrillar form.3

Therapeutic Potential of GSK3 Inhibitors

The current therapeutics for Alzheimer's disease are limited to drugs that provide only marginal symptomatic benefit in the clinic. This is achieved by attenuating cognitive deficits through inhibiting acetylcholinesterase and increasing the levels of the neurotransmitter ACh or by antagonists for the NMDA receptor. However, this type of therapy does not affect the underlying pathology or halt the progressive neuritic dystrophy and neuronal damage. In addition, over time these therapies become ineffective. Therefore, there is an urgent medical need to develop agents which delay or reverse the progression of Alzheimer's disease. The doses of lithium given in bipolar patients will at best cause about 25 inhibition of total GSK-3 activity 71 . Given the observation that lithium reduces GSK-3 activity and tau phosphorylation at therapeutically relevant concentrations, lithium has been tested for its ability to slow down the progression of Alzheimer's disease. In a retrospective study...

The Cholinergic Treatment Hypothesis

Loss of basal forebrain cholinergic neurons is a significant feature of the disease and appears to be correlated with the memory deficits. Experimental lesions of cholinergic systems also produce memory deficits in animals. Treatments for the memory loss in AD have therefore focused on cholinergic replacement approaches (the cholinergic hypothesis). Much research has been devoted to the design and testing of acetylcholinesterase inhibitors (AChE-I) as a means of preserving acetylcholine (ACh) in synapses where large numbers of cholinergic nerve terminals have been lost. Tacrine is the first drug to be approved for symptomatic treatment of memory impairment in Alzheimer patients. Although the drug produces small but significant benefit in approximately 40 of patients,4 its marginal level of efficacy and high level of liver toxicity is likely to restrict its use to a small group of patients. Several chemical analogues of tacrine have been reported to be in advanced stages of clinical...

Targeting Amyloid Pathologies

Unisci Puntini Stampare

Into clinical trials with numerous others in preclinical development 79-81 . A major concern over using y-secretase inhibitors is inhibition of signal transduction mediated by many other y-secretase substrates. For instance, inhibition of Notch signaling by y-secretase inhibitors may affect differentiation of tissues regulated by Notch. Indeed, y-secretase inhibitors have been shown to induce morphological changes in the gastrointestinal tract and alter differentiation of intestinal globet cells and lymphocytes 82-84 . A subset of y-secretase inhibitors, known as the y-modulators, can selectively inhibit A 42 production without significantly diminishing A 40 or processing of Notch 85 . It is hoped that these compounds may circumvent the potential liabilities of conventional y-secretase inhibitors. The most advanced compound of this type is R-flurbiprofen (Flurizan) (Fig. 2) which is currently in Phase III clinical trials although there are conflicting data on its effect on modulating...

Defect In Mitochondrial Oxidative

Insomnia Pharmacological

Ton's disease, and Alzheimer's disease. However, the extent to which these decreases cause a disturbance in oxidative phosphorylation and energy homeostasis in the brain is not known. Davey et al. (45) examined the relative contribution of individual mitochondrial respiratory chain complexes to the control of NAD-linked substrate oxida-tive phosphorylation in synaptic mitochondria. Titration of complex I, III, and IV activities with specific inhibitors generated threshold curves that showed the extent to which a complex activity could be inhibited before causing impairment of mitochondrial energy metabolism. Complex I, III, and IV activities were de creased by approximately 25 , 80 , and 70 , respectively, before major changes in rates of oxygen consumption and ATP synthesis were observed. These results suggest that, in mitochondria of synaptic origin, complex I activity has a major control of oxidative phosphorylation, such that when a threshold of 25 inhibition is exceeded, energy...

Etiology and Environmental Risk Factors for AD

In addition to aberrant internal metabolism, external insult such as traumatic brain injury can increase the risk of AD 63-65 . The mechanisms by which head trauma may augment the risk of AD is unknown. Repetitive head trauma experienced by professional boxers may lead to punch drunk syndrome or dementia pugilistica later in life 66 . This syndrome is characterized by progressive dementia and parkinsonism and the presence of senile plaques and neurofibrillary tangles 67,68 . Aft deposition has been detected in the brains of victims of even a single head injury 69 . In preclinical models head trauma can exacerbate the formation of plaques or tangles, induce neu- In addition to the risk factors, epidemiological studies have revealed protective factors associated with AD. An engagement in physical, mental and social activities has been shown to reduce the risk of developing AD. The mechanisms for the associations are not well understood. Physical exercise or caloric restriction may...

Antioxidants In Neuroprotection In Vitro

There are numerous links between the female sex hormone estrogen and neurode-generative diseases in general and AD in particular. It is well known that women are twice as likely to develop AD than men (42,43) and that the loss of estrogens during menopause may play a role in an age-associated cognitive decline (44). Increasing the level of estrogens by estrogen replacement therapy may lower the risk of getting AD for postmenopausal women (45,46). Estrogen is a steroidal compound that binds to cognate receptors upon penetration of the cellular membrane, and these activated estrogen receptors comprise transcription factors that translocate into the nucleus. There estrogen receptors bind to estrogen-responsive elements in the promoter regions of certain target genes activating the transcription of these genes. It is known that estrogen affects neurons through this estrogen receptor-dependent hormonal effect by activating the transcription of certain receptors of neurotrophins such as...

Morphological Aspects And Protein Components Of Rosenthal Fibers

Cuando Acabara Mundo Realmente

The parallels between RFs of Alexander's disease and the intracellular inclusions of common neurodegenerative diseases (e.g., neurofibrillary tangles, Lewy bodies) are striking. Common to these inclusions are extreme insolubility of accumulating protein, resistance to detergents and proteases, ubiquitination, high lysine content, absence of mutation, and accumulation with disease in a region-specific manner that correlates with clinical deficits (7,11,12,21). In neurodegenerative diseases such as Alzheimer's disease, increasing data indicate that oxidative post-translational modifications confer these characteristics (22-24). Thus, it may also be that similar posttranslational protein modifications in RFs confer the biochemical properties necessary for their insolubility and, therefore, accumulation, and that such accumulation is intimately related to disease expression and pathogenesis. The Maillard reaction resulting in AGEs is potentiated by reactive oxygen species and does not...

Implications For New Therapeutic Treatments For Neurodegenerative Diseases

Our data demonstrating enhanced protein oxidation in AD brain (47) combined with our recent observations demonstrating the presence of increased protein nitration products (15) strongly indicate that neuroinflammatory processes may be important factors in the progression of the neuropathology and the dementia of the disease. Thus we conclude that enhanced signal transduction processes are interrelated with the transition from the normal brain to one that is suffering from a neurodegenerative condition. Figure 6 presents this concept. In the broadest terms, then, compounds that suppress pathological signal transduction processes in brain may be an effective therapeutic. In this context, PBN derivatives could be useful.

Preface to Volume

It was one hundred and one years ago that Alois Alzheimer presented at a scientific meeting a case of progressive dementia in a 51-year-old patient Auguste D. Postmortem analysis revealed two pathologies, namely, senile plaques and neurofibrillary tangles. These findings were published the following year in 1907. In 1910 Emil Kraepelin, Alzheimer's mentor, named this disease after its discoverer. The two initial pathological findings remain the postmortem diagnostic features of Alzheimer's disease (AD) today. At the time, however, Kraepelin made the distinction between AD and senile dementia ( 65 years old) despite their similarities in pathologies and clinical symptoms 1, 2 . In 1976 Robert Katzman argued in an editorial in the April issue of Archives of Neurology that this distinction be removed. AD has thus morphed from a rare orphan disease to one with a much bigger socioeconomic threat. This nosological shift has brought AD into the lime light and exponentially and thankfully...

Tau Pathologies

Although believed to be downstream of Aft, tau pathologies may play an important role in the deterioration of neuronal health in AD. NFTs have been classified into six stages (I-VI) by Braak and Braak 15 . The different stages describe the progression of tau pathologies from the transentorhinal region (I-II) to the limbic region (III-IV) and finally to the cerebral cortex (V-VI). During stages I-II the affected subject remains clinically silent. Stages III-IV pathologies are found in incipient AD when there is loss of cognitive functions and subtle personality changes. In the final stages of V-VI patients have fully developed AD. The sequential evolution of tau pathologies and its correlation with neurodegeneration and clinical manifestations suggests that tau pathologies, although not the ultimate trigger of AD, may play a prominent role in the demise of neurons. In fact, genetic mutations on tau have been shown to be sufficient to cause neurodegeneration in frontotemporal dementia...


Fig. 4 Possible scenarios of symptomatic, disease modifying and mixed treatment on cognitive functions of AD patients. A Symptomatic treatment provides a rapid boost to cognitive functions. Upon withdrawal of treatment, cognitive functions return to the same level of the untreated group. B Disease modifying treatments can be divided into those slowing, halting and reversing disease progression. The figure shows a disease slowing progression which does not provide any immediate improvement in cognitive functions but slows the rate of cognitive decline. Upon withdrawal of treatment, cognitive functions are still higher than the untreated group. C Mixed symptomatic and disease modifying treatment provides both a rapid boost to cognitive functions as well as a long lasting effect even upon treatment withdrawal. Mixed treatment may be achieved by combining symptomatic and disease modifying treatments while certain target mechanisms alone may produce mixed treatment effects Fig. 4 Possible...


Tacrine is the first acetylcholinesterase inhibitor approved for treatment of Alzheimer's disease. Tacrine is short-acting, and is a reversible inhibitor of both acetylcholinesterase and butyrylcholinesterase 7,8 . Tacrine is highly protein bound, rapidly absorbed orally, however absorption is reduced with food intake. Due to the side effect of hepatotoxicity, tacrine is no longer a popular drug. It increases serum glutamic-oxaloacetic transaminase (SGOT), and serum glutamic-pyruvic transaminase (SGPT) in 25-30 of patients. Patients with signs of jaundice confirmed by elevated total bilirubin should not be on tacrine. Liver enzymes should be monitored weekly for at least the first 18 weeks, then, they should be monitored once every 3 months. Liver enzymes tend to increase during the first 6-12 weeks 9,10 .


Donepezil was the second cholinesterase inhibitor approved in the US 6 . It is currently the only acetylcholinesterase approved by the FDA for the treatment of severe Alzheimer's disease. Donepezil is a reversible, noncompetitive cholinesterase inhibitor. It has a high binding specificity for brain acetyl-cholinesterase, with little to no affinity for butylcholinesterase. Compared with the other cholinesterase inhibitors in this class, donepezil may be better tolerated, with less gastrointestinal side effects. The long half-life of this medication allows once a day dosing (See Table 3).

By Nitric Oxide

It has been shown that certain neurons expressing the nNOS are resistant to NMDA neurotoxicity, and this is also observed in neuronal diseases, such as Alzheimer's, or in situations of ischemia (54), in spite of the fact that these neurons have glutamate receptors (55,56). The explanation for this resistance to neu-rotoxicity of the very neurons that produce NO came about recently, using an NO-resistant PC12 cell line, which permitted determining that the presence of high levels of manganese-SOD (MnSOD) in these cells accounts for the resistance of the nNOS-containing cells to NMDA- and NO-induced toxicity (57). In primary cortical cultures, the MnSOD is colocalized with nNOS in the neurons and, thus, the MnSOD is strategically localized to protect the NO-producing cells against the toxic effect of NO. Furthermore, nNOS-containing neurons from mice lacking the gene for MnSOD are very sensitive to the toxic effects of NMDA and NO (29,57). The protection offered by MnSOD is highly...


Clinical symptoms of AD include cognitive impairment, memory loss and disorientation. Increasing evidence suggests that risk for AD can be influenced by life style choices such as diet and exercise that directly affect metabolism. Moreover, concurrent metabolic diseases such as diabetes, metabolic syndrome, atherosclerosis and other types of cardiovascular disease are associated with an increased risk for AD 23,24 . Thus, the physiological status of peripheral organ systems impacts the central nervous system and affects biological processes that are critical to the pathogenesis of AD. The relationships between insulin resistance, inflammation, cholesterol homeostasis and PPARy in AD are summarized in Fig. 2.

Energy Metabolism

Utilization is impaired in brain regions involved in memory and cognition in AD patients. Significantly, familial AD patients exhibited impaired cerebral glucose metabolism in advance of symptomatic onset and in the absence of detectable structural changes in the brain 92 . It is now possible to employ positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to evaluate glucose metabolism as an early biomarker for AD. Additionally, several independent studies have shown a link between the Apoe4 allele and glucose utilization in the brain. These studies detect an Apoe4 dose-dependent impairment in glucose utilization in brain regions affected by the disease 93-97 . Bookheimer and colleagues have found, using fMRI, that memory recall tasks stimulated glucose utilization in regions affected by Alzheimer's disease and this effect was more pronounced in ApoeE4 carriers in comparison to those who expressed the Apoe3 allele 98 . Significantly, PGC-1a knockout mice...


Striatal dopamine neurons may be particularly vulnerable to oxidative stress because of an intrinsic stress already placed on them associated with dopamine metabolism via monoamine oxidase, which produces H2O2 and oxidation of dopamine by other enzymatic or nonenzymatic mechanisms. The glutathione system, which is responsible for removing H2O2 and maintaining protein thiols in their appropriate redox state in the cytosol and mitochondrion, is an important protective mechanism for minimizing oxidative damage. Both alterations in the glutathione system and deficits in mitochondrial metabolism have been observed in patients with PD. The cause effect relationship among energy impairment, glutathione reduction, and loss of dopamine neurons in PD is not clear. Regardless of whether these events are initiating factors in the disease, there is ample evidence to show that derangements in oxidative phosphorylation and glutathione are present during the progression of the disease and may have an...

GSK3 and Amyloidosis

Overexpress active GSK-3P in the CNS have increased levels of beta amyloid 40 . It is believed that proteolytic processing of APP occurs by the sequential activities of P- and y-secretases, which results in the release of the beta amyloid peptide. In earlier studies, the role of GSK-3 in APP processing was attributed to an interaction with the y-secretase complex activity and presenilin-1 (PS1), a component of the y-secretase complex. PS1 was shown to directly bind GSK-3P and tau in co-immunoprecipitation experiments from human brain samples 42 . A different mechanism has been suggested by Akiyama et al., who propose that GSK-3 acts on the P-secretase pathway via blocking of Pinl interaction with phosphorylated C99Thr668, which leads to decreased turnover of C99, a product of P-secretase cleavage of APP 43 . Thus, it is tempting to speculate that GSK-3 may be the key intersection point at which Alzheimer's disease-related tau hyperphosphorylation and beta amyloid formation converge.


Differential effects of statins on apolipoproteins are well known 156,157 . Statins can reduce apolipoprotein B with little effects on ApoA-I. Indeed, some suggest the ratio of ApoB ApoA-I may be better predictors of cardiovascular risk factors than cholesterol LDL ratios 156 and assessment of lipoproteins in AD may prove to be a better approach to understanding dementia risk. Apolipoprotein CIII is believed to delay lipolysis of apoB lipopro-teins and can cause hypertriglyceridemia. Apo C-III induces monocyte adherence to vascular endothelium, an early essential event in atherosclerosis 158 . Excessive apolipoprotein CIII, is a known risk factor for coronary heart disease 159 and a weak genetic association between apolipoprotein CIII and Alzheimer's has been reported 160 . Sporadic genetic associations on proteins involved in lipid metabolism appear to be a consistent theme in the literature and lend credence to the hypothesis that aberrant lipid metabolism contributes to AD...

Cholesterol and Ap

Statins have been reported to improve cognitive endpoints in rodents, and inhibit cognitive decline in the clinic. Interestingly, the majority of rodent studies have failed to describe consistent decreases in total brain cholesterol levels following statin treatment. Although statins possess activities independent of cholesterol lowering, subtle modulation of brain cholesterol trafficking may partially explain effects on neurological function. A growing body of literature report significant overlaps between amyloid and cholesterol trafficking. Indeed, brain cholesterol turnover and APP processing appear to converge to a common endocytic trafficking route within the cell. Based upon recent data implicating statin modulation in cholesterol trafficking within intraneuronal compartments, it is quite possible that statins may exert effects through both cholesterol and APP intracellular trafficking rather than through effects on total brain cholesterol. A brief review of both cholesterol...

Contemporary Neuroscience

Highly Selective Neurotoxins Basic and Clinical Applications, edited by Richard M. Kostrzewa, 1998 Neuroinflammation Mechanisms and Management, edited by Paul L. Wood, 1998 Neuroprotective Signal Transduction, edited by Mark P. Mattson, 1998 Clinical Pharmacology of Cerebral Ischemia, edited by Gert J. Ter Horst and Jakob Korf, 1997 Molecular Mechanisms of Dementia, edited by Wilma Wasco and Rudolph E. Tanzi, 1997 Neurotransmitter Transporters Structure, Function, and Regulation, edited by Maarten E. A. Reith, 1997

Definitions And Applications

Depending on the application, other terms have been applied to biomarkers, which have been used to classify them 3 . Natural history markers are those that measure disease predisposition, severity, or outcome. These are often used to define inclusion or exclusion criteria for patients considered for enrollment into clinical trials, or for stratifying these patient populations. Examples include the genotypes for Factor V Leiden and Apo E as risk factors for thromboembolism and Alzheimer's disease, respectively, and the peptide a-fetoprotein for progression of certain neoplasias.

Membrane Transporters In Therapeutic Drug Responses

PHARMACODYNAMICS TRANSPORTERS AS DRUG TARGETS Membrane transporters are the targets of many drugs. For example, neurotransmitter transporters are the targets for drugs used in the treatment of neuropsychiatric disorders. SERT (SLC6A4) is a target for the selective serotonin reuptake inhibitors (SSRIs), a major class of antidepressant drugs. Other neurotrans-mitter reuptake transporters serve as drug targets for the tricyclic antidepressants, amphetamines (including amphetamine-like drugs used in the treatment of attention deficit disorder in children), and anticonvulsants. These transporters also may be involved in the pathogenesis of neuropsychi-atric disorders, including Alzheimer's and Parkinson's diseases. Transporters that are nonneuronal also may be potential drug targets (e.g., cholesterol transporters in cardiovascular disease, nucleo-side transporters in cancers, glucose transporters in metabolic syndromes, and Na+-H+ antiporters in hypertension).

Complexity And Heterogeneity In Neurodegeneration

Focal or generalized impairment of memory is the defining feature of many disorders which are clinically distinguishable on the basis of associated features within a complex phenotype. Thus, while confusion may arise between normal ageing, early Alzheimer's, and frontotemporal dementia or Pick's disease, few clinicians would have difficulty in distinguishing these conditions from Down's syndrome or familial prion disease. Equally, parkin-sonism, progressive supranuclear palsy, corticobasal degeneration, familial multisystem atrophy and pallidopontonigral degeneration have many features in common, but each is a distinct clinical entity recognizable by its specific phenotype. And yet, each of these disorders shares the accumulation of phosphorylated tau as the central pathological process albeit with subtle molecular differences distinguishing the underlying type I, II or III tauo-pathy.1 It takes an experienced neuropathologist reliably to unravel these various tangles containing...

NAA and Magnetic Resonance Spectroscopy

Finally, it is important to note that there are two distinct NAA research communities one group involved in basic research into the neurochemistry of NAA, and another group which employs MRS techniques for the non-invasive analysis of NAA levels in the brain with respect to clinical applications. NAA levels measured by MRS have been shown to be changed in a number of neurological disorders. These studies have mostly detected decreases in NAA, with the exception of Canavan disease which involves accumulation of NAA in the brain.37 The diseases and disorders in which NAA levels are decreased include stroke,38 Alzheimer's disease,39 epilepsy,40 brain cancer,41 multiple sclerosis42 and AIDS dementia complex.43 Earlier, the decreases in NAA were interpreted to represent irreversible loss of neurons. However, more recent evidence indicates that these decreases also could represent reversible mitochondrial dysfunction.23,24 In support of this view, some evidence has been presented showing...

Looking Farther Ahead The Combination of Conventional and Unconventional

The signaling of the mutant receptor back to normal levels. Similarly, arrestins with anti-proliferative or simply pro-apoptotic signaling bias selectively expressed in cancerous cells by means of appropriate targeting vectors would likely solve the existing problem without creating new ones after all, the ideal therapeutic outcome is the death of every cancer cell in the body. In contrast, it will be necessary to control the effectiveness of arrestin mutants with pro-survival signaling bias, the expression of which in affected neurons may be beneficial in neurodegenerative disorders, such as Alzheimer's and Parkinson's. Excessive signaling shift in that direction may lead to cell dedifferentiation, which would be just as harmful as the disease itself.

Michael C Ashby Michael I Daw and John T R Isaac

acid receptors (AMP ARs) are glutamate-gated ion channels. They are the neurotransmitter receptors that mediate the great majority of fast excitatory synaptic transmission in the mammalian brain and are found throughout the animal kingdom in organisms as diverse as rodents, honeybees, nematode worms, and humans. They are absolutely critical for brain function for example, infusion of a selective AMPAR antagonist into the rat hippocampus in vivo completely silences excitatory transmission in that region (1). AMPARs are also required for adaptive changes in the brain, mediating the expression of forms of long-term and short-term synaptic plasticity that are believed to underlie learning and memory, development, and certain neurologic diseases (2-5). Thus, AMPARs play a central role in brain function, and consequently there is great interest in the development of novel therapies directed at modulating AMPAR function for treatment of neurologic disorders, such as Alzheimer disease and...

Pain And Suffering What Are They

There is no consensus about whether suffering falls within the boundaries of pain medicine - or even within medicine - but the medical neglect of suffering is palpable. Suffering rarely gets an entry in medical textbooks, and only a few authors with medical training discuss it directly.32, 33 In a practical sense, health professionals confront the problems of suffering every day - as suffering emerges during the course of illnesses that range from cancer and depression to Alzheimer's disease. This

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