Estrogen Replacement Therapy and Dementia

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Susie Coon

AD is characterized by the presence of numerous senile plaques and neurofibrillary tangles accompanied by neuronal loss. The extracellular senile plaques are composed of amyloid beta-peptides. The intracellular neurofibrillary tangles are composed of highly phosphorylated tau proteins. The amyloid cascade hypothesis (Yamada et al., 1999) proposes that amyloid beta-peptides trigger a neurotoxic cascade, thereby causing neurodegeneration and AD.AD is also associated with apolipoprotein E genes (APOE) on chromosome 19. There are three major alleles of APOE: APOE2, APOE3, and APOE4. APOE4 is a susceptible gene of AD or risk factor in familial forms of AD. APOE4 binds to amyloid beta-peptides and promotes amyloid fibril formation.

Many areas in the brain have been found to play a role in AD. Neurons in the hippocampal formation, neocortex, medial septum, diagonal band of Broca, and nucleus basalis magnocellularis are severely affected by AD and are thought to contribute to the cognitive decline associated with AD-related dementia. These areas are important in learning and memory and attentional processes.
Positive Effects of Estrogen Replacement Therapy on AD

Postmenopausal women who receive ERT are 40-60% less likely to be diagnosed with Alzheimer's. Estrogen Replacement Therapy (ERT) has been found to both reduce the risk of developing AD and slow its progression in many studies. Women who receive ERT perform better on cognitive tasks than untreated women, which suggests that estrogen lessens the severity of AD. A study by Asthana et al., (1999) looked at the effects of 17 beta-estradiol, the most potent form of estrogen, on several cognitive domains typically impaired in patients with AD. Subjects, all women with mild-moderate AD were randomly placed in one of two groups. The first group received 0.05 mg/day of 17-b-estradiol and the second group received a placebo, both via a skin patch for 8 weeks. Before treatment, and then every two to three weeks following treatment, a battery of tests were administered which targeted several cognitive domains, including memory, attention, and language that are characteristically impaired by AD. It was found that treatment with estradiol improved aspects of attention and verbal memory, but did not improve language. The authors speculate that the beneficial effects of estrogen may be restricted to certain cognitive domains. Moreover, estrogen-induced enhancements in both memory and attention diminished when treatment was terminated. The results indicate that short-term administration of estrogen has the potential to enhance cognition for postmenopausal women. Numerous other studies have found similar results.

The Mechanisms of ERT in AD

ERT elicits its positive effects in the treatment of Alzheimer's in many ways. Numerous studies have documented the different effects of estrogen by looking at one effect at a time. But it seems to be agreed upon that the effects of estrogen do not act independently of one another. The most well known and documented is estrogen's effect on cholinergic neurons. Estrogen also promotes neuronal growth and cerebral blood flow, reduces the generation of amyloid beta-peptides, and increases the expression of APOE mRNA.

Enhancement of Cholinergic Projections to the Hippocampus and Cortex

Studies have shown an association between AD and the reduction in the number of basal forebrain cholinergic neurons. There are also corresponding reductions in choline acetyltransferase (ChAT) activity, high-affinity choline uptake (HACU), and acetlycholine (ACh) production in the hippocampus and cortex. Continuous estrogen replacement results in increases in ChAT activity within specific regions of the rat basal forebrain, hippocampus, and frontal cortex. Gibbs and Aggarwal (1998) suggest that ERT may enable the neurons to maintain elevated levels of acetylcholine release during periods of increased demand, while at the same time, having relatively little impact on basal cholinergic tone. These effects may have very little impact on a young, healthy brain, but they are significant in AD because of the reduction in cholinergic cells and greater demand on remaining cells.

It is unclear exactly how estrogen influences basal forebrain cholinergic neurons. It has been found that cholinergic neurons contain high-affinity estrogen binding sites indicative of estrogen receptors. It has more recently been suggested that estrogen may directly influence the cholinergic neurons by binding to intracellular receptors followed by direct steroid-mediated effects on gene transcription (Gibbs Aggarwal, 1998). The possibility that estrogen may affect cholinergic neurons indirectly must also be considered.


Cholinergic neurons in the medial septum and nucleus basalis magnocellularis are also affected by nerve growth factor (NGF), which is produced in the hippocampus and cortex. NGF has been shown to promote both the survival and function of basal forebrain cholinergic neurons during development and adulthood. There is evidence that estrogen can significantly affect the expression of ChAT and NGF receptors in specific basal forebrain cholinergic neurons, and therefore exert and effect on both cholinergic and NGF-related systems. The effects of estrogen on basal forebrain cholinergic neurons could result from effects of estrogen on NGF and NGF receptor cells.

Increases in cholinergic function are dose-dependent in determining effects of estrogen on cognitive processes. For example, one study found that increases in cholinergic function was not maintained in response to uninterrupted treatment with high levels of estradiol, and another found beneficial effects following low-dose but not high-dose, or short-term but not long-term, estrogen treatment (Gibbs Aggarwal, 1998). Short-term treatment seems to be the consensus, but an optimal dose has not been agreed upon.

Estrogen also regulates brain derived growth factor (BDNF).

Promotion of Neuronal Growth

Brinton et al. (1997) found that 17-b-estradiol induced an increase in the fine structure of rat hippocampal neurons within 5 minutes of exposure.

This suggests that the effect of 17-b -estradiol was mediated by a process that could be independent of estrogen nuclear receptor activation. Increased cell growth was specific to 17-b-estradiol, as increased outgrowth did not occur in response to other steroids. Nine other estrogenic steroids were tested. Five of the estrogenic steroids had no effect on neuronal growth in the cortex. The five that increased neuronal growth in the occipital lobe were 17-b-estradiol, equilin, estriol, mestranol, and estrone. This suggests that neuronal growth in the occipital lobe is steroid specific with certain estrogens inducing effects while other estrogens are without effects. Equilin produced highly significant increases in occipital nerve cell growth. It also produced effects in nerve cells from frontal and temporal lobes. Nerve cells in the parietal lobe showed some growth, but the results were not significant.
It was also found that the growth-promoting effects of equilin are dependent upon activation of the NMDA glutamate receptor. Phosphorylation by the protein kinase A increases the amplitude of glutamate-induced current. This increase in NMDA-mediated current could account for the neurotrophic effects of both 17-b-estradiol and equilin.

Reduction in amyloid beta-peptides

It has been found that estrogen diminished amyloid beta-peptide release in cultures from rodent and human fetal cerebral cortex. ERT reduces amyloid beta-peptides, which contributes to the ability of ERT to protect against AD. The amyloid beta-peptide25-35 fragment has been shown to be the toxic portion of the amyloid beta-peptide1-40. This peptide causes cell death in primary neuronal cultures. Simpkins et al., 1997 exposed brain cells to amyloid beta-peptide25-35 for four days. Amyloid beta-peptide25-35 fragment caused a dose-dependent reduction in these cells ranging from 36% to 83%. The addition of beta-estradiol, the major form of circulating estrogen in the body, reduced the fragment toxicity by 83% and 51% in two different studies. The exact mechanisms are unknown.

Increased Production of APOE Protein

Apolipoprotein (APOE) has been implicated in the transport of cholesterol and phospholipids for the repair, growth, and maintenance of membranes that occur during development or after injury. It is also involved in maintenance of dendritic complexes. APOE is present in the senile plaques of AD brains. Of the various APOE isoforms, E2, E3, and E4 differ by one unit of net charge. APOE4 has been associated with increased risk for AD. While some studies have found that APOE4 inhibits neuronal growth, a recent study shows that APOE3 and APOE4 have a protective effect against the toxicity of amyloid aggregates.

Part of the effect of estrogen could be related to the regeneration of injured brain induced by the neurotrophic action of APOE itself, which is independent of the isoform expressed. It is also possible that ERT could override the possible reduction in naturally occurring estrogen, and in this way induce the synthesis of APOE in astrocytes and glial cells. This would result in a positive response in the regeneration of neurons, especially at the cholinergic level in the basal forebrain and hippocampus. It is also possible that estrogen can modulate the expression of APOE receptors either directly or indirectly, enhancing the NGF-mediated pathway that induces APOE.


Stone et al. (1998) suggest that estradiol increases compensatory synaptic sprouting by upregulating local transporters of cholesterol and other hydrophobic membrane components. Thus, estradiol could increase synaptic sprouting by increased production of APOE protein or increased uptake of APOE-containing lipoproteins. Increased APOE production or uptake in response to estrogen could improve the effects of AD through two pathways: increased compensatory synaptic sprouting and increased ChAT activity.

More Web Resources on ERT and Alzheimer's

The Foundation for Better Health Care

The Foundation for Better Health Care provides resources on various topics of women's health

Alzheimer Research Forum on Estrogen

References

Asthana, S., Craft, S., Baker, L. D., Raskind, M. A., Birnbaum, R. S., Lofgreen, C. P., Veith, R. C., Plymate, S. R. (1999). Cognitive and neuroendocrine response to transdermal estrogen in postmenopausal women with Alzheimer's disease: Results of a placebo-controlled, double-blind, pilot study. Psychoneuroendocrinology, 24, 657-677.



Brinton, R. D., Yamazaki, R. S. (1998). Advances and challenges in the prevention and treatment of Alzheimer's disease. Pharmaceutical Research, 15, 386-398.



Brinton, R. D., Proffitt, P., Tran, J., Luu, R. (1997). Equilin, a principle component of the estrogen replacement therapy Premarin, increases the growth of cortical neurons via an NMDA receptor-dependent mechanism. Experimental Neurology, 147, 211-220.



Gibbs, R. B., Aggarwal, P. (1998). Estrogen and basal forebrain cholinergic neurons: Implications for brain aging and Alzheimer's disease-related cognitive decline. Hormones and Behavior, 34, 98-111.



Green, P. S., Gridley, K. E., Simpkins, J. W. (1998). Nuclear estrogen receptor-independent neuroprotection by estratrienes: A novel interaction with glutathione. Neuroscience, 84, 7-10.



Inestrosa, N. C., Marzolo, M. P., Bonnefont, A. B. (1998). Cellular and molecular basis of estrogen's'neuroprotection: Potential relevance for Alzheimer's disease. Molecular Neurobiology, 17, 73-86.



Schneider, L. S., Farlow, M. R., Pogoda, J. M. (1997). Potential role for estrogen replacement in the treatment of Alzheimer's dementia. The American Journal of Medicine, 103, 46S-50S.



Simpkins, J. W., Green, P. S., Gridley, K. E., Singh, M., de Fiebre, N. C., Rajakumar, G. (1997). Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer's disease. The American Journal of Medicine, 103, 19S-25S.



Stone, D. J., Rozovsky, I., Morgan, T. E., Anderson, C. P., Finch, C. E. (1998). Increased synaptic sprouting in response to estrogen via an apolipoprotein E-dependent mechanism: Implications for Alzheimer's disease. The Journal of Neuroscience, 18, 3180-3185.



Xu, H., Gouras, G. K., Greenfield, J. P., Vincent, B., Naslund, J., Mazzarelli, L., Fried, G., Jovanovic, J. N., Seeger, M., Relkin, N. R., Liao, F., Checler, F., Buxbaum, J. D., Chait ,B. T., Thinakaran, G., Sisodia, S. S., Wang, R., Greengard, P., Gandy, S. (1998). Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nature Medicine, 4, 447-451.



Yamada, K., Ren, X., Nabeshima, T. (1999). Perspectives of pharmacotherapy in Alzheimer's disease. The Japanese Journal of Pharmacology, 80, 9-14.

Is hearing loss related to dementia

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New York Times

Dr. Frank Lin, an otolaryngologist and epidemiologist at Johns Hopkins School of Medicine, describes this phenomenon as “cognitive load.” Cognitive overload is the way it feels. Essentially, the brain is so preoccupied with translating the sounds into words that it seems to have no processing power left to search through the storerooms of memory for a response

Over the past few years, Dr. Lin has delivered unwelcome news to those of us with hearing loss. His work looks “at the interface of hearing loss, gerontology and public health,” as he writes on his Web site. The most significant issue is the relation between hearing loss and dementia.

In a 2011 paper in The Archives of Neurology, Dr. Lin and colleagues found a strong association between the two. The researchers looked at 639 subjects, ranging in age at the beginning of the study from 36 to 90 (with the majority between 60 and 80). The subjects were part of the Baltimore Longitudinal Study of Aging. None had cognitive impairment at the beginning of the study, which followed subjects for 18 years; some had hearing loss.

“Compared to individuals with normal hearing, those individuals with a mild, moderate, and severe hearing loss, respectively, had a 2-, 3- and 5-fold increased risk of developing dementia over the course of the study,” Dr. Lin wrote in an e-mail summarizing the results. The worse the hearing loss, the greater the risk of developing dementia. The correlation remained true even when age, diabetes and hypertension — other conditions associated with dementia — were ruled out.

In an interview, Dr. Lin discussed some possible explanations for the association. The first is social isolation, which may come with hearing loss, a known risk factor for dementia. Another possibility is cognitive load, and a third is some pathological process that causes both hearing loss and dementia.

In a study last month, Dr. Lin and colleagues looked at 1,984 older adults beginning in 1997-8, again using a well-established database. Their findings reinforced those of the 2011 study, but also found that those with hearing loss had a “30 to 40 percent faster rate of loss of thinking and memory abilities” over a six-year period compared with people with normal hearing. Again, the worse the hearing loss, the worse the rate of cognitive decline.

Both studies also found, somewhat surprisingly, that hearing aids were “not significantly associated with lower risk” for cognitive impairment. But self-reporting of hearing-aid use is unreliable, and Dr. Lin’s next study will focus specifically on the way hearing aids are used: for how long, how frequently, how well they have been fitted, what kind of counseling the user received, what other technologies they used to supplement hearing-aid use.

What about the notion of a common pathological process? In a recent paper in the journal Neurology, John Gallacher and colleagues at Cardiff University suggested the possibility of a genetic or environmental factor that could be causing both hearing loss and dementia — and perhaps not in that order. In a phenomenon called reverse causation, a degenerative pathology that leads to early dementia might prove to be a cause of hearing loss.

The work of John T. Cacioppo, director of the Social Neuroscience Laboratory at the University of Chicago, also offers a clue to a pathological link. His multidisciplinary studies on isolation have shown that perceived isolation, or loneliness, is “a more important predictor of a variety of adverse health outcomes than is objective social isolation.” Those with hearing loss, who may sit through a dinner party and not hear a word, frequently experience perceived isolation.

Other research, including the Framingham Heart Study, has found an association between hearing loss and another unexpected condition: cardiovascular disease. Again, the evidence suggests a common pathological cause. Dr. David R. Friedland, a professor of otolaryngology at the Medical College of Wisconsin in Milwaukee, hypothesized in a 2009 paper delivered at a conference that low-frequency loss could be an early indication that a patient has vascular problems: the inner ear is “so sensitive to blood flow” that any vascular abnormalities “could be noted earlier here than in other parts of the body.”

A common pathological cause might help explain why hearing aids do not seem to reduce the risk of dementia. But those of us with hearing loss hope that is not the case; common sense suggests that if you don’t have to work so hard to hear, you have greater cognitive power to listen and understand — and remember. And the sense of perceived isolation, another risk for dementia, is reduced.

A critical factor may be the way hearing aids are used. A user must practice to maximize their effectiveness and they may need reprogramming by an audiologist. Additional assistive technologies like looping and FM systemsmay also be required. And people with progressive hearing loss may need new aids every few years.

Increasingly, people buy hearing aids online or from big-box stores like Costco, making it hard for the user to follow up. In the first year I had hearing aids, I saw my audiologist initially every two weeks for reprocessing and then every three months.

In one study, Dr. Lin and his colleague Wade Chien found that only one in seven adults who could benefit from hearing aids used them. One deterrent is cost ($2,000 to $6,000 per ear), seldom covered by insurance. Another is the stigma of old age.

Hearing loss is a natural part of aging. But for most people with hearing loss, according to the National Institute on Deafness and Other Communication Disorders, the condition begins long before they get old. Almost two-thirds of men with hearing loss began to lose their hearing before age 44. My hearing loss began when I was 30.

Forty-eight million Americans suffer from some degree of hearing loss. If it can be proved in a clinical trial that hearing aids help delay or offset dementia, the benefits would be immeasurable.

“Could we do something to reduce cognitive decline and delay the onset of dementia?” he asked. “It’s hugely important, because by 2050, 1 in 30 Americans will have dementia.

“If we could delay the onset by even one year, the prevalence of dementia drops by 15 percent down the road. You’re talking about billions of dollars in health care savings.”

Should studies establish definitively that correcting hearing loss decreases the potential for early-onset dementia, we might finally overcome the stigma of hearing loss. Get your hearing tested, get it corrected, and enjoy a longer cognitively active life. Establishing the dangers of uncorrected hearing might even convince private insurers and Medicare that covering the cost of hearing aids is a small price to pay to offset the cost of dementia.

Mysterious brain clumps behind dementia identified

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The Dementia Caregiver's Little Book of Hope [Kindle Edition

FoxNews

By Tanya Lewis

Certain forms of dementia may be caused by a gene mutation that makes proteins in the brain clump together, a new study finds.

MORE FROM LIVE SCIENCE:

• Top 10 Mysterious Diseases
• 7 Diseases You Can Learn from a Genetic Test
• Living With Alzheimer’s in the US (Infographic)

The most common cause of frontotemporal dementia and a motor neuron disease called amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) is a genetic mutation that creates extra copies of a DNA sequence, but the actual mechanism of the diseases is unknown. A team of researchers has now found that proteins, molecules that normally help cells function, are being produced from the mutated gene and appear to be causing the clumping seen in both those diseases.

The findings, described online Feb. 7 in the journal Science, could explain how these diseases arise and might even be treated.

About 10 percent of FTLD (frontotemporal lobar degeneration) and ALS patients have a mutation in the C9orf72 gene, which contains a short repeated DNA sequence. Healthy people have about 25 repeats of this sequence, but there are hundreds of repeats in these patients. Their brains exhibit telltale clumps of proteins in the hippocampus and cerebellum regions.

While proteins in other forms of dementia are known, patients with this mutation have clumps of other, unknown proteins, said study co-author Dieter Edbauer, a neuroscientist at Ludwig Maximilian University of Munich, in Germany. The mutated gene lacks the label that normally tells cells to start making a protein, and is located in a stretch of the DNA that isn't normally active.

Protein mystery

Edbauer and his colleagues hypothesized that if the gene were somehow activated, it would cause three different proteins to be made, and these proteins would aggregate in cells and cause disease.

To test their hypothesis, the researchers took both diseased and healthy brain tissue from deceased patients and filtered it through a fine mesh. Clumps of brain tissue from the patients got stuck in the mesh. By making antibodies (proteins produced by the body to target and fight off foreign invaders) that recognized the three specific proteins, the scientists were able to determine that these were the proteins in the clumps.  

"This study helps to resolve a major question about how C9orf72 mutations cause FTD and ALS," said neurologist Adam Boxer of the University of California, San Francisco, who was not involved in the study.

"It suggests that these mutations can lead to creation of a new toxic protein that aggregates and accumulates in cells, similar to other neurodegenerative diseases such as Huntington's and Alzheimer's, which are also associated with toxic protein aggregates," Boxer told LiveScience. [10 Odd Facts About the Brain]

Others agree that the findings, if replicated, will be important. "It would be good to confirm their results using an independent method," said neuropathologist Ian Mackenzie of Vancouver General Hospital and the University of British Columbia, in Canada.

Understanding the diseases

There are several possible explanations for how the proteins are being made. One is that the ribosome, the cellular machinery that reads genetic instructions to make proteins, is misreading the mutated gene. Another possibility is that the repeated sequence is forming a hairpin shape that attracts the ribosome and tells it to make proteins.

It's unclear whether the clumps are causing the diseases or are simply markers. If the protein clumps are in fact responsible, scientists might be able to treat the disease by getting rid of those proteins, Edbauer said.

FTD and ALS are characterized by personality changes, language abnormalities and movement disorders, which often appear before the age of 65. There is currently no cure.

NEW STUDY SAYS SMOKING POT COULD HELP CURE DEMENTIA

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The Dementia Caregiver's Little Book of Hope [Kindle Edition

SYDNEY MORNING HERALD (Australia)

Worldcrunch

SYDNEY – Australian scientists have discovered that cannabis could help reverse dementia.

Researchers from Neuroscience Research Australia (NRA) believe one of the main active ingredients in cannabis – cannabidiol – could reverse some of the symptoms of memory loss, reports the Sydney Morning Herald.

Tim Karl, a senior NRA researcher says that cannabidiol has anti-inflammatory, antioxidant and other effects that could be beneficial for the brain.

According to Karl, “Back in the day cannabis was used for medical purposes, I'm talking 200 years, 100 years back, then at some point people discovered it had other effects and, as quite often happens in our society, people decided it was a bad drug.” 

He told the Sydney Morning Herald that even though “most of the components [of marijuana] are detrimental – they worsen your cognitive performance and have psychoactive effects – cannabidiol seems to not have any of these negative effects.”

The researchers injected cannabidiol into mice that had been bred with Alzheimer’s-like symptoms. They found that the mice showed drastic improvements during tests where they had to remember objects and other mice. The research will be presented at the annual meeting of the Australian Neuroscience Society this week.

Researchers hope to learn if aspirin can fight dementia

ThCaregivers and healthcare professionals, here is some great information

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The Dementia Caregiver's Little Book of Hope [Kindle Edition

e University of Texas Health Science Center is looking for more people to help them find answers to this question.

The Regional Academic Health Center in Harlingen is one of about 30 sites in the country where the study is being conducted, Dr. Sara Espinoza, the local principal investigator, said.

The study is called Aspirin in Reducing Events in the Elderly. The study’s principal investigator is Dr. Richard Grimm, medical director of the Berman Center for Outcomes and Clinical Research in Minneapolis.

“We know that aspirin prevents heart disease and stroke in middle-aged people,” said Espinoza, an associate professor of medicine at the UT Health Science Center in San Antonio. “There is some evidence that aspirin may prevent dementia or cognitive impairment.”

Past studies suggest that aspirin, as an anti-inflammatory drug, could be a protective for dementia, she said.

The study includes persons 65 and older who are in good health. Some will be given aspirin; others will take a placebo. They will then be monitored annually for five years. Harlingen residents participating in the study are tested and examined at the RAHC’s Clinical Research Unit.

Espinoza said the study has far-reaching effects because conditions such as dementia, including Alzheimer’s disease, could be caused by inflammation.

Diabetes is considered an inflammatory condition, and that can lead to disability. Therefore, the study is also being conducted to see if aspirin can reduce the possibility of people becoming disabled to the point where they are unable to care for themselves.

The study is also being conducted at sites in Australia, begun about two years ago. Espinoza said the study’s operators intend to enroll people in the program until December, but the deadline could be extended.

The South Texas site, which includes the RAHC as an extension of the University of Texas Health Science Center in San Antonio, has about 219 subjects enrolled, Espinoza said, with 25 to 30 enrolled in Harlingen.

Travis M. Whitehead writes for the Valley Morning Star in Harlingen. 

 ASPIRIN STUDY

>> Persons interested in participating in the study can call 1 (877) 524-3265 or visit www.ASPREE.org.

Dementia aggression difficult to control

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The Dementia Caregiver's Little Book of Hope [Kindle Edition

Carol Bursack

It’s likely that someday a physician will be able to order a blood test which will identify the exact medication needed to balance a person’s brain chemistry. Unfortunately, we are a long way from that ideal. Doctor and other professionals try their best to find a medication that will help, but finding the optimum medication is difficult.

Zyprexa (olanzapine) is an atypical antipsychotic medication. Exactly how it works isn’t known, though it’s thought to work by changing the actions of certain chemicals in the brain. The drug is generally used to treat the symptoms of psychotic conditions such as schizophrenia and bipolar disorder (manic depression), but doctors can use it for other illnesses if they think it may help the patient. Many doctors use atypical antipsychotic medications for dementia symptoms with varying results. Sleepiness is one of the most common side effects.

Problem behavior would be difficult for anyone to handle alone. You may need to consider in-home caregiving help or a good nursing home. You’d still be her caregiver, but you’d be part of a team. With people to help with medication management and aggression issues, you’d be able to focus more on your personal relationship with your love one. Remember that you need to consider your own health as well as your loved one's.

Alzheimer's Disease and 8 Potential Natural Treatments

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The Dementia Caregiver's Little Book of Hope [Kindle Edition

EmaxHealth

Alzheimer’s disease is one of the most challenging and serious health problems facing the world’s population, and research into prevention and treatment remains a high priority. Among the studies are those exploring potential natural treatments for this devastating disease.

What’s new in natural treatments for Alzheimer’s?

Although scientists have not yet uncovered a cure or an effective way to prevent or treat Alzheimer’s disease, every research endeavor reveals something investigators can use to help them reach their goal. A case in point is new research from the University of Leeds (UL), in which scientists identified the process by which two chemicals found in two natural substances—red wine and green tea—may interfere with the progression of Alzheimer’s disease.

Even though the research is still in the laboratory stage, the study’s lead researcher, Professor Nigel Hooper of the Faculty of Biological Sciences of UL, noted that “this is an important step in increasing our understanding of the cause and progression of Alzheimer’s disease.”

\Basically, the research team discovered how extracts of resveratrol from red wine and epigallocatechin gallate (EGCG) from green tea can help prevent the death of brain cells. In Alzheimer’s disease, nerve cells in the brain die when amyloid proteins accumulate in the brain, clump together into balls, and attach themselves to nerve cells.

The UL researchers discovered that when they added extracts from red wine and green tea to human and animal brain cells and amyloid balls in the lab, the shape of the balls changed. This prevented the balls from attaching to the nerve cells and thus stopped the cells from dying.

This discovery doesn’t mean everyone should be downing bottles of red wine and green tea. However, it does open the door to more research and “the potential to reveal yet more drug targets,” noted Hooper.

Six more natural treatments for Alzheimer’s
Vitamin D and curcumin. Investigators from a 2012 study conducted at the University of California Los Angeles reported they had discovered mechanisms regulated by vitamin D3 that may promote the clearance of amyloid beta, which is the main ingredient of plaques associated with Alzheimer’s disease. In a previous study by the same research group, they had found some immune system cells in people with Alzheimer’s disease may respond to vitamin D3 and curcumin, a component of the spice turmeric.

In a separate, new study from China, investigators reported on the use of curcumin as a potential treatment for Alzheimer’s disease. In addition to amyloid, their research focused on astrocytes as major factors in early Alzheimer’s development. Star-shaped astrocytes are the most abundant cells in the brain.

The authors explained that in the lab, curcumin has been shown to inhibit amyloid accumulation and speed up the breakup of amyloid plaque, as well as increase expression of a marker important to astrocytes. In addition, curcumin improved the spatial memory (typical of Alzheimer’s) in rat models.

Omega-3 Fatty Acid DHA. A new (February 2013) small study has revealed that the omega-3 fatty acid docosahexaenoic acid (DHA) and vitamin D3 help improve removal of plaque and control inflammation, both critical features in the fight against Alzheimer’s disease.

The researchers found that DHA helps clear plaque in a way slightly different than does vitamin D3. Additional research may help reveal whether correcting deficiencies of DHA and vitamin D will help individuals eliminate amyloid plaque as a way to treat Alzheimer’s disease.

Coffee (caffeine). A study from the University of South Florida College of Pharmacy and the USF Health Byrd Alzheimer’s Institute reported that caffeinated coffee has a positive effect on older adults with mild memory impairment. According to lead author and neuroscientist Dr. Chuanhai Cao, their findings, “along with our earlier studies in Alzheimer’s mice, are very consistent in indicating that moderate daily caffeine/coffee intake throughout adulthood should appreciably protect against Alzheimer’s disease later in life.”

More specifically, the authors identified about three cups of coffee daily as the number necessary to enjoy this benefit. Co-author Dr. Gary W. Arendash, USF department of cell biology, microbiology and molecular biology, went so far as to state that “moderate daily consumption of caffeinated coffee appears to be the best dietary option for long-term protection against Alzheimer’s memory loss.”

Grape seed extract. A number of studies have shown that grape seed extract can interfere with the accumulation of toxic proteins characteristic of Alzheimer’s disease, as demonstrated by a mouse study from the Mount Sinai School of Medicine.

A more recent study from the University of Minnesota noted the impact of grape seed extract given to mouse models of Alzheimer’s disease. Five months of treatment significantly reduced brain levels of amyloid substances known to cause memory impairment. The authors noted they “strongly suggest” that grape seed extract “should be further tested as a potential prevention and/or therapy for AD.”

Vitamin E. The potent antioxidant vitamin E has been identified as having significant ability to help with the prevention and treatment of Alzheimer’s disease, although not all researchers agree. A recent meta-analysis in the Journal of Alzheimer’s Disease explored the results of seven studies that evaluated the use of vitamins C, E, and beta-carotene and the risk of Alzheimer’s disease.

The reviewers concluded that of the three antioxidants, vitamin E showed the most impressive protective effects against Alzheimer’s disease. However, all three did demonstrate an ability to lower the risk of the disease.

It’s true there are no effective treatments for Alzheimer’s disease in either the conventional or alternative/complementary areas of medicine. However, continuing exploration of potential natural treatments as well as medications may lead to effective answers.

SOURCES:
Cashman JR et al. Curcumins promote monocytic gene expression related to B-amyloid and superoxide dismutase clearance. Neurodegenerative Diseases 2012; 10(1-4): 274-76
Li FJ et al. Dietary intakes of vitamin E, vitamin C, and b-carotene and risk of Alzheimer’s disease: a meta-analysis.Journal of Alzheimer’s Disease 2012; 31(2): 253-58
Liu P et al. Grape seed polyphenolic extract specifically decreases aB*56 in the brains of Tg2576 mice. Journal of Alzheimer’s Disease 2011; 26(4): 657-66
Mizwicki MT et al. Genomic and nongenomic signaling induced by 1a,25(OH)2-vitamin D3 promotes the recovery of amyloid-B phagocytosis by Alzheimer’s disease macrophages. Journal of Alzheimer’s Disease 2012; 29(1): 51-62
Rushworth JV et al. Prion protein-mediated toxicity of amyloid-B oligomers requires lipid rafts and the transmembrane LRP1. Journal of Biological Chemistry 2013 Feb 5
Wang Y et al. Curcumin as a potential treatment for Alzheimer’s disease: a study of the effects of curcumin on hippocampal expression of glial fibrillary acidic protein. American Journal of Chinese Medicine 2013; 41(1): 59-70
Wang J et al. Grape derived polyphenols attenuate tau neuropathology in a mouse model of Alzheimer’s disease.Journal of Alzheimer’s Disease 2010; 22(2): 653-61

New hope for dementia sufferers

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Here is a great dementia resource for caregivers and healthcare professionals,

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The Dementia Caregiver's Little Book of Hope [Kindle Edition

Medical Xpress

Researchers are investigating new ways to treat Alzheimer's disease by targeting the blood-brain barrier 

—Research that aims to rid dementia sufferers' brains of toxins could lead to a new treatment that reverses the symptoms of Alzheimer's disease in the future.

Researchers are investigating new ways to treat Alzheimer's by targeting the blood-brain barrier, which acts as a door to the brain, and is responsible for pumping toxins in the blood away from the brain. Dr Joseph Nicolazzo, from the Monash Institute of Pharmaceutical Sciences, in collaboration with the University of Washington, is examining pumps at the blood-brain barrier that are known to become dysfunctional in Alzheimer's patients. This diminished pumping action is believed to result in a build-up of the toxin amyloid in the brain, killing nerve cells and leading to memory loss associated with Alzheimer's. The researchers are investigating how to get the pumps working again, to safely filter toxins out of the brain. 

"Alzheimer's is the most common form of dementia affecting 300,000 Australians and 5.4 million Americans," Dr Nicolazzo said. "While there are medications that can assist with memory, there is currently no cure that can reverse the disease. "We hope that unravelling how to get the pumps working again to decrease amyloid build-up in the brain will lead to new drugs that may cure Alzheimer's disease."

Ask a Doctor

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The Dementia Caregiver's Little Book of Hope [Kindle Edition

Now it is simple to ask a foctor about dementia or any other topic by tying in the question in the box on the righ. Then press "ask"

..

Your question will be answered by a top doctor in the field.

Your comments are welcome

Simple Cognitive Test for Those with Dementia

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The Dementia Caregiver's Little Book of Hope [Kindle Edition

Ohio State Medical Center

Here is a simple pen and paper test to access someones cognitive ability

The Ohio State University Medical Center provides this instrument and accompanying interpretive guidelines (collectively the “Instrument”) as an informational service. Use of the Instrument is governed by the terms and conditions provided below. Please read the statements below carefully before accessing or using the Instrument. By accessing or using the Instrument, you agree to be bound by all the terms and conditions herein.

The Instrument cannot substitute for medical advice, diagnosis or treatment by a trained medical professional.  Diagnosis and treatment of human illness should be based collectively on medical history, including family medical history, and a physical examination along with a doctor’s professional judgment and review of all test results. The material contained in the Instrument does not contain standards that are meant to be applied rigidly and followed in virtually all cases. Physicians’ judgment must remain central to the selection of diagnostic tests and therapy options of a specific patient’s medical condition.

Permission is granted to use and redistribute this Instrument for individual clinical or noncommercial educational use only, provided that The Ohio State University and authors of the Instrument are acknowledged in any publications reporting its use, and the name of The Ohio State University or any of its officers, employees, students or board members is not used in any advertising or publicity pertaining to the use or distribution of the Instrument without specific, written prior authorization. Permission to modify or otherwise create derivative works of the Instrument, or redistribute any derivatives of the Instrument is not granted. Those desiring to utilize the instrument for research purposes, incorporate the Instrument into commercial products or use the Instrument for promotional purposes should contact, Technology Licensing and Commercialization, The Ohio State University, 1960 Kenny Road, Columbus, Ohio, 43210-1063, (614) 292-1315.

The Sage Test

Why exercise slows memory loss in Alzheimer’s

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Here is a great dementia resource for caregivers and healthcare professionals,

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Futurity

A stress hormone produced during moderate exercise may protect the brain from memory changes related to Alzheimer’s disease.

The findings, published in the Journal of Alzheimer’s Disease by researchers from the University of Nottingham, may also explain why people who are susceptible to stress are at more risk of developing the disease.

Increasingly there is evidence that physical and mental activity can reduce people’s chances of developing the disease or can slow down its progression but until now it has been unclear how this happens.

A research team, led by Marie-Christine Pardon in the School of Biomedical Sciences, discovered that the stress hormone CRF—or corticotrophin-releasing factor—may have a protective effect on the brain from the memory changes brought on by Alzheimer’s disease.

CRF is most associated with producing stress and is found in high levels in people experiencing some forms of anxiety and depressive diseases. Normal levels of CRF, however, are beneficial to the brain, keeping the mental faculties sharp and aiding the survival of nerve cells.

Studies have shown that people with Alzheimer’s disease have a reduced level of CRF.

Researchers used an experimental drug to prevent the hormone from binding to a brain receptor called CRFR1 in mice with Alzheimer’s disease that were free from memory impairments, therefore blocking the effects of the hormone.

They discovered that the mice had an abnormal stress response with reduced anxiety but increased behavioral inhibition when confronted by a stressful situation—in this case being placed in a new environment—and this is was due to the abnormal functioning of the CRFR1.

This abnormal stress response before the onset of symptoms may explain why people susceptible to stress are more at risk of developing Alzheimer’s.

Pardon and her team also found that interrupting the hormone from binding on to the CRFR1 receptor blocked the improvement of memory normally promoted by exercise. However, in mice with Alzheimer’s a repeated regime of moderate exercise restored the normal function of the CRF system allowing its memory enhancing effects.

The results are in line with the idea that regular exercise is a means of improving one’s ability to deal with everyday stress in addition to keeping mental abilities keen.

The switching on of this particular brain receptor during exercise increased the density of synapses, which makes the connection between nerve cells, the loss of which is thought to be responsible for the early memory loss seen in Alzheimer’s patients.

“This is the first time that researchers have been able to identify a brain process directly responsible for the beneficial effects of exercise in slowing down the progression of the early memory decline characteristics of Alzheimer’s disease,” says Pardon.

“Overall, this research provides further evidence that a healthy lifestyle involving exercise slows down the risk of Alzheimer’s disease and opens avenues for the new interventions targeting the altered CRFR1 function associated with the early stages of the disease.”

Research into Aging (Age UK) and the University of Nottingham funded the study.

Source: University of Nottingham

Converting a Person's Own Cells into Functional Neurons with PTB

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UC San Diego

Repression of a single protein in ordinary fibroblasts is sufficient to directly convert the cells – abundantly found in connective tissues – into functional neurons. The findings, which could have far-reaching implications for the development of new treatments for neurodegenerative diseases like Huntington’s, Parkinson’s and Alzheimer’s, will be published online in advance of the January 17 issue of the journal Cell.

In recent years, scientists have dramatically advanced the ability to induce pluripotent stem cells to become almost any type of cell, a major step in many diverse therapeutic efforts.  The new study focuses upon the surprising and singular role of PTB, an RNA-binding protein long known for its role in the regulation of alternative RNA splicing.

Confocal micrograph of a primary human fibroblast cell grown in  culture stained blue for actin, a highly abundant protein that makes up the cytoskeleton of cells. Energy-producing mitochondria are shown in green. Image courtesy of Matthew Daniels, University of Oxford and Wellcome Images.

In in vitro experiments, scientists at University of California, San Diego School of Medicine and Wuhan University in China describe the protein’s notable regulatory role in a feedback loop that also involves microRNA – a class of small molecules that modulate the expression of up to 60 percent of genes in humans. Approximately 800 miRNAs have been identified and characterized to various degrees.

One of these miRNAs, known as miR-124, specifically modulates levels of PTB during brain development. The researchers found that when diverse cell types were depleted of PTB, they became neuronal-like cells or even functional neurons – an unexpected effect. The protein, they determined, functions in a complicated loop that involves a group of transcription factors dubbed REST that silences the expression of neuronal genes in non-neuronal cells.

According to principal investigator Xiang-Dong Fu, PhD, professor of cellular and molecular medicine at UC San Diego, it’s not known which neuronal signal or signals turn on the loop, which in principle can happen at any point in the circle. But the ability to artificially manipulate PTB levels in cells, inducing them to become neurons, offers tantalizing possibilities for scientists seeking new treatments for an array of neurodegenerative diseases.

It is estimated that over a lifetime, one in four Americans will suffer from a neurodegenerative disease, from Alzheimer’s and Parkinson’s to multiple sclerosis and amyotrophic lateral sclerosis (Lou Gehrig’s disease).

“All of these diseases are currently incurable. Existing therapies focus on simply trying to preserve neurons or slow the rate of degeneration,” said Fu. “People are working with the idea of replacing lost neurons using embryonic stem cells, but there are a lot of challenges, including issues like the use of foreign DNA and the fact that it’s a very complex process with low efficiency.”

Fu explained that REST is expressed in cells everywhere except in neurons. PTB is itself a target of miR-124, but also acts as a break for this microRNA to attack other cellular targets that include REST, which is responsible for repressing miR-124. 

In non-neuronal cells, REST keeps miR-124 down and PTB enforces this negative feedback loop, but during neural induction, miR-124 is induced, which diminishes PTB, and without PTB as a break, REST is dismantled, and without REST, additional miR-124 is produced.  This loop therefore becomes a positive feed forward, which turns non-neuronal cells into neurons.

“If we learn how to manipulate PTB, which appears to be a kind of master regulator, we might eventually be able to avoid some of these problems by creating new neurons in patients using their own cells adjacent deteriorating neurons,” said Fu.

Co-authors are Yuanchao Xue and Yu Zhou, Wuhan University, China and UCSD Department of Cellular and Molecular Medicine; Kunfu Ouyang, Gang Wang and Ju Cheng, UCSD Department of Medicine; Jie Huang, Qijia Wu, Yanzhen Bi, Li Jiang, Zhiqiang Cai, Hui Sun, UCSD Department of Cellular and Molecular Medicine; Hong Ouyang and Kang Zhang, UCSD Institute of Genomic Medicine; Hairi Li and Chaoliang Wei, UCSD Department of Cellular and Molecular Medicine; and Yi Zhang, Wuhan University, China and Center for Genome Analysis, Wuhan, China.

Funding for this research came, in part, from National Institutes of Health grants (GM049369, GM052872 and HG004659) and the China 973 programs.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu