Alzheimer's and marijuana

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• IOS Press

PREVENTION & THERAPY NEWS:
The hippocampus is the brain's memory and learning center. In a big study of 26,000 people, the hippocampus did not get along with marijuana. Marijuana lowered blood flow to levels unseen in any other group. Find out why this strongly suggests higher vulnerability to Alzheimer’s. 

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As the U.S. races to legalize marijuana for medicinal and recreational use, a large scale brain imaging study gives reason for caution. Published in the Journal of Alzheimer’s Disease, researchers using single photon emission computed tomography (SPECT), a sophisticated imaging study that evaluates blood flow and activity patterns, demonstrated abnormally low blood flow in virtually every area of the brain, in nearly 1,000 marijuana users compared to healthy controls.

Marijuana, Alzheimer's & the Hippocampus

The marijuana users' low blood flow patterns included areas known to be affected by Alzheimer’s pathology such as the hippocampus. 

Low Blood Flow

Low blood flow in the hippocampus in marijuana users reliably distinguished marijuana users from controls. The right hippocampus during a concentration task was the single most predictive region in distinguishing marijuana users from their normal counterparts. Marijuana use is thought to interfere with memory formation by inhibiting activity in this part of the brain. 

According to one of the co-authors on the study Elisabeth Jorandby, M.D., “As a physician who routinely sees marijuana users, what struck me was not only the global reduction in blood flow in the marijuana users brains, but that the hippocampus was the most affected region due to its role in memory and Alzheimer’s disease."

May Be Harbingers of Brain Damage

She continued, "Our research has proven that marijuana users have lower cerebral blood flow than non-users. Second, the most predictive region separating these two groups is low blood flow in the hippocampus on concentration brain SPECT imaging. This work suggests that marijuana use has damaging influences in the brain – particularly regions important in memory and learning and known to be affected by Alzheimer’s.” 

Dr. George Perry, Editor in Chief of the Journal of Alzheimer’s Disease said, “Open use of marijuana, through legalization, will reveal the wide range of marijuana’s benefits and threats to human health. This study indicates troubling effects on the hippocampus that may be the harbingers of brain damage.” 
MORE INFORMATION:

• Amen DG, Darmal B, Raji CA, Bao W, Jorandby L, Meysami S, Raghavendra CS (2017) Discriminative Properties of Hippocampal Hypoperfusion in Marijuana Users Compared to Healthy Controls: Implications for Marijuana Administration in Alzheimer’s Dementia. J Alzheimers Dis, doi: 10.3233/JAD-160833.
• Figure legend: Example of a volume rendered brain SPECT image (top down view) of a healthy control compared to an 18-year old daily user of marijuana. While the control subject has symmetric activity, the marijuana user shows overall decreased perfusion.

SOURCE:

• IOS Press

Why marijuana makes you more vulnerable to Alzheimer’s.

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

• IOS Press

As the U.S. races to legalize marijuana for medicinal and recreational use, a new, large scale brain imaging study gives reason for caution. Published in the Journal of Alzheimer’s Disease, researchers using single photon emission computed tomography (SPECT), a sophisticated imaging study that evaluates blood flow and activity patterns, demonstrated abnormally low blood flow in virtually every area of the brain, in nearly 1,000 marijuana users compared to healthy controls. The marijuana users' low blood flow patterns included areas known to be affected by Alzheimer’s pathology such as the hippocampus. 

Continued below image...

IMAGE LEGEND: Example of a volume rendered brain SPECT image (top down view) of a healthy control compared to an 18-year old daily user of marijuana. While the control subject has symmetric activity, the marijuana user shows overall decreased perfusion. 

All data were obtained for analysis from a large multi-site database, involving 26,268 patients who came for evaluation of complex, treatment resistant issues to one of nine outpatient neuropsychiatric clinics across the United States (Newport Beach, Costa Mesa, Fairfield, and Brisbane, CA, Tacoma and Bellevue, WA, Reston, VA, Atlanta, GA and New York, NY) between 1995-2015. Of these, 982 current or former marijuana users had brain SPECT at rest and during a mental concentration task compared to almost 100 healthy controls. Predictive analytics with discriminant analysis was done to determine if brain SPECT regions can distinguish marijuana user brains from controls brain. Low blood flow in the hippocampus in marijuana users reliably distinguished marijuana users from controls. The right hippocampus during a concentration task was the single most predictive region in distinguishing marijuana users from their normal counterparts. Marijuana use is thought to interfere with memory formation by inhibiting activity in this part of the brain. 

According to one of the co-authors on the study Elisabeth Jorandby, M.D., “As a physician who routinely sees marijuana users, what struck me was not only the global reduction in blood flow in the marijuana users brains, but that the hippocampus was the most affected region due to its role in memory and Alzheimer’s disease. Our research has proven that marijuana users have lower cerebral blood flow than non-users. Second, the most predictive region separating these two groups is low blood flow in the hippocampus on concentration brain SPECT imaging. This work suggests that marijuana use has damaging influences in the brain – particularly regions important in memory and learning and known to be affected by Alzheimer’s.” 

Dr. George Perry, Editor in Chief of the Journal of Alzheimer’s Disease said, “Open use of marijuana, through legalization, will reveal the wide range of marijuana’s benefits and threats to human health. This study indicates troubling effects on the hippocampus that may be the harbingers of brain damage.” 

Dementia and HS aging

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University of Kentucky Sanders-Brown Center on Aging

3 important dementia studies focus on HS-AGING. It's a type of dementia almost as common as Alzheimer's in the 85+ group. Yet few people have heard of it. Why? What makes it different? 

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In those who live to a very advanced age (beyond the age of 85) HS-AGING (hippocampal sclerosis in the elderly) is almost as prevalent as Alzheimer's. Remarkably, HS-Aging appears to be a completely separate disease from Alzheimer's, although it is almost always diagnosed as Alzheimer's disease while people are alive.

Three important papers authored by Dr. Peter Nelson and others at the University of Kentucky Sanders-Brown Center on Aging, explore the neuropathology behind this little-understood brain disease.

HS-AGING, much like Alzheimer's disease, causes symptoms of dementia, such as cognitive decline and impaired memory. Although Alzheimer's disease is probably the most recognized cause of dementia, HS-AGING also causes serious cognitive impairment in many older adults.

Overview of 3 New Studies on HS-AGING:

1. The first paper, published in the Journal of Alzheimer's Disease, draws from a very large sample population and shows that presently, around 20% of all dementia cases are diagnosed as HS-AGING at autopsy, although almost none are given that diagnosis during life. That means that the presence of this disease is currently almost unknown by the health care providers who are seeing patients.
2. A second study, "Arteriolosclerosis that affects multiple brain regions," appears in a recent issue of the journal Brain, and looks at small blood vessels in patients with HS-Aging and describes a specific change, called "arteriolosclerosis," which is present in patients with HS-Aging. This small blood vessel change may provide a new therapeutic target to alter the progression of the disease.
3. Finally, the third paper, "Hippocampal sclerosis of aging, a prevalent and high morbidity brain disease," appears in Acta Neuropathologica and offers an overview of HS-AGING for patients and researchers. This paper reviews the relevant scientific literature and also presses home the point that HS-AGING is a very common disease that exerts a strongly adverse impact on public health.

It is important for physicians and scientists to understand the unique pathology of HS-AGING, and to be able to differentiate it from other diseases, as it is only by making an accurate diagnosis that clinicians can hope to treat people who present with signs of cognitive decline. These current studies represent a leap forward in the knowledge base about HS-AGING, and represent potential new paths to explore for diagnosis and treatment of this serious, but under-appreciated brain disease.

In people over 95, a type of dementia called HS-Aging is about as common as Alzheimer's. Yet few people have heard of it. Why? What makes it different?

What is HS-Aging?

HS-Aging stands for "Hippocampal Sclerosis in Aging People".

Alzheimer's and HS-Aging are types of dementia. In people over 95, their prevalence is about equal.

HS-Aging is Not Well Known. Everyone Has Heard of Alzheimer's. Why?

There are hundreds of types of dementia. In people aged 65 to 95, 60% of dementia cases are Alzheimer's. That is why Alzheimer's is so well-known.

At age 95, the balance shifts and HS-Aging becomes about as common as Alzheimer's.

Few people have heard of HS-Aging. The main reason is because it is often mis-diagnosed as Alzheimer's. Why?

When dementia is seen in the elderly, the default diagnosis is Alzheimer's. This is caused by many factors, among them:

• Patients often do not want to go through extensive testing for a variety of reasons.
• There is no simple test. The differences between dementias can be subtle. Therefore, distinguishing between dementias is often technically challenging.
• Cost comes into play. For example, F18 dementia scans can run thousands of dollars. Therefore, many a diagnosis is made based on incomplete information.

With these realities, it is common for a diagnosis to default to the most common dementia, which is Alzheimer's.

As a result, people with dementias such as HS-Aging often live out their lives thinking they have Alzheimer's.

How does HS-Aging differ from Alzheimer's?

Alzheimer's and HS-Aging both damage the hippocampus. It seems that HS-Aging hits harder than Alzheimer's, causing greater disturbances to memory.

HS-Aging describes a brain under attack from a protein called TDP-43. It causes sclerosis, or the hardening of tissues. In the case of HS-Aging, TDP-43 proteins harden brain tissue in the hippocampus (sometimes called the memory-processing center), causing the loss of a large number of crucial brain cells. It is called Hippocampal Sclerosis because the brain's hippocampus is the focus of the attack.

Alzheimer's, on the other hand, is an attack on the brain by plaques (made from beta-amyloid) and tangles (made of tau proteins). Researchers speculate that the plaques clump together and "choke" brain cells, while the tangles strangle them from within.

How does HS-Aging differ from regular HS?

Regular Hippocampal Sclerosis (HS) occurs in younger people where brain tissue hardening is associated with epilepsy. HS-Aging is a similar hardening, but it occurs in the elderly with different consequences. It is caused by a long life of physical wear-and-tear on the brain, similar to vascular dementia. As a matter of fact, once people hit 95, the combined occurrences of HS-Aging PLUS vascular dementia actually outstrip Alzheimer's.

Why does the type of dementia matter?

As explained above, the biochemistry of each dementia differs significantly. This implies different medications are required to fight the chemicals causing the dementia. A person's response to medicines and supplements will be entirely different, depending on the disease.

Importantly, new F18 imaging techniques have recently been introduced that let doctors see if a person with dementia has the plaques associated with Alzheimer's. Using this technique helps doctors tell the difference between Alzheimer's and HS-Aging. This is particularly crucial in the world of clinical trials, where participants must closely match the experimental drugs they are testing.

CTE Research Leading to Rapid Improvements in HS-Aging Treatments

When we talk about dementia in aging athletes, it is usually the type of dementia called CTE (Chronic Traumatic Encephalopathy). Recent studies showed athletes in contact sports like football are 19 times more likely than average to develop dementia. As a result, there has been a huge burst of research on CTE treatment.

CTE treatment has a lot in common with HS-Aging treatment. With the new attention both of these dementias are now receiving, there is good reason to hope for effective new treatments in the immediate future.

MORE INFORMATION: 
Study #1 above was done with the collaboration of the National Alzheimer's Coordinating Center (or "NACC"; the first author of this study, Willa Brenowitz, is based in Washington state and works with NACC), enabling Nelson and colleagues to incorporate data from dozens of federally funded Alzheimer's Disease Centers around the country. These centers are funded by the National Institute on Aging, part of the National Institutes of Health. The research was supported by NIA grant numbers U01 AG016976 and P30 AG028383.

Study #2 above was based on analyses that were boosted through collaboration with the larger NACC-based dataset. Further, the first author, Dr. Janna Neltner, provided critical expertise in digital pathologic measurement of the brain. 

SOURCE:
University of Kentucky Sanders-Brown Center on Aging

Research illuminates why stimulating environment may protect against Alzheimer's disease

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

Medical News

 

"Use it or lose it." The saying could apply especially to the brain when it comes to protecting against Alzheimer's disease. Previous studies have shown that keeping the mind active, exercising and social interactions may help delay the onset of dementia in Alzheimer's disease.

Now, a new study led by Dennis Selkoe, MD, co-director of the Center for Neurologic Diseases in the BWH Department of Neurology, provides specific pre-clinical scientific evidence supporting the concept that prolonged and intensive stimulation by an enriched environment, especially regular exposure to new activities, may have beneficial effects in delaying one of the key negative factors in Alzheimer's disease.
The study will be published online on March 6, 2013 in Neuron.
Alzheimer's disease occurs when a protein called amyloid beta accumulates and forms "senile plaques" in the brain. This protein accumulation can block nerve cells in the brain from properly communicating with one another. This may gradually lead to an erosion of a person's mental processes, such as memory, attention, and the ability to learn, understand and process information.
The BWH researchers used a wild-type mouse model when evaluating how the environment might affect Alzheimer's disease. Unlike other pre-clinical models used in Alzheimer's disease research, wild-type mice tend to more closely mimic the scenario of average humans developing the disease under normal environmental conditions, rather than being strongly genetically pre-disposed to the disease.
Selkoe and his team found that prolonged exposure to an enriched environment activated certain adrenalin-related brain receptors which triggered a signaling pathway that prevented amyloid beta protein from weakening the communication between nerve cells in the brain's "memory center," the hippocampus. The hippocampus plays an important role in both short- and long-term memory.
The ability of an enriched, novel environment to prevent amyloid beta protein from affecting the signaling strength and communication between nerve cells was seen in both young and middle-aged wild-type mice.

"This part of our work suggests that prolonged exposure to a richer, more novel environment beginning even in middle age might help protect the hippocampus from the bad effects of amyloid beta, which builds up to toxic levels in one hundred percent of Alzheimer patients," said Selkoe. Moreover, the scientists found that exposing the brain to novel activities in particular provided greater protection against Alzheimer's disease than did just aerobic exercise. According to the researchers, this observation may be due to stimulation that occurred not only physically, but also mentally, when the mice moved quickly from one novel object to another.
"This work helps provide a molecular mechanism for why a richer environment can help lessen the memory-eroding effects of the build-up of amyloid beta protein with age," said Selkoe. "They point to basic scientific reasons for the apparent lessening of AD risk in people with cognitively richer and more complex experiences during life."
Source: Brigham and Women's Hospital

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.

Remarkable recent discoveries in Alzheimer’s disease

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Examiner

• 
  

Medscape Medical News reported on the latest published research in Alzheimer’s disease on November 7, 2012 indicating individuals carrying a mutant gene for Alzheimer’s disease demonstrate markers 20 years before onset of memory changes. In addition to markers in the cerebral spinal fluid, the individuals show structural changes in the brain other than the amyloid plaques and tangles commonly found in patients with the disease.

Dr. Eric M. Reiman, the first author on this recent study, published his results in Lancet Neurology on November 6, 2012. His research group from the Banner Alzheimer’s Institute in Phoenix, Arizona studied about 5000 people who carry the gene mutation that produces Alzheimer’s disease as early as age 45 years in Colombia.

Reiman and colleagues compared carriers of the gene with non-carriers and found structural differences in area of the brain called the hippocampus as well as less grey matter in some parietal lobes in individuals with the Alzheimer’s gene mutation. The parietal lobe resides at the top of the head after the frontal lobe and before the occipital lobe at the back of the head. The researchers used magnetic resonance imaging to uncover the changes in the parietal lobe. These changes occurred 20 years before the onset of memory loss. By knowing these alterations exist early, researchers can study treatments and measure for differences at these sites.

According to the Center for Disease Control and Prevention, Alzheimer’s disease causes the most common form of dementia that produces loss of thought control, memory and language. The disease usually affects men and women over the age of 60 years. The cause of Alzheimer’s disease remains presently unknown. Most scientists think several factors such as genetic, environmental and lifestyle contribute to the development of the disease. The discovery of changes in the parietal lobe and hippocampus add significantly to progress in the research.

The National Institute on Aging describes the importance of clinical research for uncovering causes, treatment modalities and disease prevention in Alzheimer’s disease. Patients or families interested in becoming involved in research trials can go the Clinical Trials.gov website for more information. The research trial website lists trials available in all 50 states and 181 countries.

Researchers move closer to delaying dementia

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UQ News

Scientists at UQ's Queensland Brain Institute are one step closer to developing new therapies for treating dementia.



QBI's Dr Jana Vukovic said the work was aimed at understanding the molecular mechanism that may impair learning and memory in the aging population.


“Aging slows the production of new nerve cells, reducing the brain's ability to form new memories,” said Dr Vokovic, who performed the work in the laboratory of Professor Perry Bartlett, the Director of QBI at The University of Queensland.


"But our research shows for the first time that the brain cells usually responsible for mediating immunity, microglia, have an inhibitory effect on memory during aging.


“Furthermore, they have shown that a molecule produced by nerve cells, fractalkine, can reverse this process and stimulate stem cells to produce new neurons.”


The discovery, published in The Journal of Neuroscience today, came after QBI scientists observed that the increased production of new neurons in mice that were actively running was due to the release of fractalkine in the hippocampus – the brain structure responsible for specific types of learning and memory.

Professor Bartlett said it had been known for some time that exercise increased the production of new nerve cells in the hippocampus in young and even aged mice.

“But this study found that it is fractalkine that appears to be specifically mediating this effect by making the microglia produce factors that activate the stem cells that produce new nerve cells,” he said.

“Once the cells are activated they divide and produce new cells, which underpin the animal's ability to learn and form memories.



"This means that fractalkine may form the basis for the development of future therapies.

“The discovery is especially exciting because we have found that older animals suffering cognitive decline showed significantly lower levels of fractalkine.

“We are seeking ways of increasing fractalkine levels in patients with cognitive decline, and hoping this may be a new frontline therapy in treating dementia.”


Dr Vukovic said that until relatively recently, it was thought the adult brain was incapable of generating new neurons.

“But work from Professor Bartlett's laboratory over the past 20 years has demonstrated that the brains of adult animals, including humans, retain the ability to make new nerve cells,” she said.


“The challenge is to find out how to stimulate this production in the aged animal and human where production has slowed.”

The latest work was a significant step toward achieving this goal, she said.


The article published today is titled Microglia modulate hippocampal neural precursor activity in response to exercise and aging. Its authors are Jana Vukovic, Michael J. Colditz, Daniel G. Blackmore, Marc J. Ruitenberg, Perry F. Bartlett

Genes that influence hippocampal volume identified

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London: Researchers have uncovered four loci that seem to be associated with decreasing the volume of the hippocampus.

The hippocampus is the region of the brain that plays an important role in the formation of specific, new memories, which is an ability that patients with Alzheimer’s disease lose.

The findings by an international team of researchers led by Boston University School of Medicine (BUSM) may have broad implications in determining how age, Alzheimer’s disease and other diseases impact the function and integrity of the hippocampus.

Previous research has shown that the hippocampus is one of the brain regions involved with short and long-term memory processes and that it shrinks with age.

It also is one of the first regions to exhibit damage from Alzheimer’s disease, which can cause memory problems and disorientation.

“One of the problems with studying the genetics of a disease like Alzheimer’s, which becomes symptomatic later in life, is that many people die of other causes before they reach the age at which they might have manifested the clinical dementia associated with the disease,” said Sudha Seshadri, MD, professor of neurology at BUSM and a senior author of the study.

“To get around this issue, we have been studying the genetics of traits that we know are associated with a high future risk of Alzheimer’s disease but that can be measured in everyone, often 10 to 20 years before the age when most persons develop clinical symptoms.”

The potential genetic traits are called endophenotypes, and hippocampal volume is one such trait. The hippocampus shrinks before and during the progression of Alzheimer’s disease, but other factors, such as vascular risk factors and normal aging, also lead to the decrease in size.

“Our research team wanted to pinpoint the genetic causes of changes in the hippocampal volume in a sample of apparently normal older persons,” said Seshadri.

The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium allowed the researchers to gather data on hippocampal volume from 9,232 people who did not have dementia. They identified four genetic loci, including seven genes in or near these loci that appear to determine hippocampal volume.

The results show that if one of the genes is altered, the hippocampus is, on average, the same size as that of a person four to five years older. These results were replicated in two large European samples that included a mixed-age sample that included some participants with cognitive impairment.

“The findings indicate that these loci may have broad implications for determining the integrity of the hippocampus across a range of ages and cognitive capacities,” said Seshadri.

One of the genes identified by the researchers was also shown to play a role in memory performance in a different data sample.

The identified genetic associations indicate that certain genes could influence cell death by apoptosis, brain development and neuronal movement during brain development, and oxidative stress.

Additionally, the researchers found that the genes play a role in ubiquitination, which is a process by which damaged proteins are removed, whereas other genes code for enzymes targeted by new diabetes medications.

“Future studies need to further explore these genetic regions in order to better understand the role of these genes in determining hippocampal volume,” added Seshadri.

The study will be published online in Nature Genetics.

ANI

New research targets treatment for dementia

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From Surabhi Gupta(PTI)

People suffering from dementia can heave a sigh of relief as neuroscientists in Australia have discovered a fundamental component of the process that regulates memory formation.

Neuroscientists at the Queensland Brain Institute (QBI) of The University of Queensland discovered the component in the hippocampus � a part of the brain commonly associated with memory function.

The discovery explains, for the first time, how new nerve cells form in this area of the brain associated with learning and memory � which deteriorate in people with stroke and dementia, QBI Director Professor Perry Bartlett told PTI.

"The hippocampus is the region of the brain involved in important functions such as learning and memory, and loss of neuronal production in the hippocampus is associated with a range of neurodegenerative conditions. It is particularly evident in ageing dementia," Bartlett said.

"Surprisingly, however, studies so far have failed to identify a resident stem cell population in the hippocampus that''s capable of providing the renewable source of these essential nerve cells."
Research by Professor Bartlett and his QBI colleagues, Dr Tara Walker and Dr Dhanisha Jhaveri (a recipient of the Indian National Science Academy''s award for Young Scientist of the Year 2003), has identified the resident populations of stem cells in the hippocampus.

Even more importantly, this research has discovered how it can be activated to produce new neurons.

The discovery of the presence of precursors in the adult brain which have the potential to produce neurons via a process called neurogenesis, will help immensely in the case of dementia patients, Bartlett said.

"For the first time, we''ve been able to identify a mechanism that''s able to regulate production of nerve cells, a step that''s crucial to our understanding of memory and learning," Professor Bartlett said.

"The same mechanism helps regulate growth of healthy brain tissue, so identifying this process is essential for the development of therapeutics to treat conditions such as dementia and depression."
A detailed understanding of the activation process should enable the development of therapeutics that can stimulate the production of new neurons and reverse or prevent the cognitive decline that occurs during ageing dementia, he said.

"These significant advances in determining the molecular regulation of nerve production will also have a major impact on our understanding of more complex areas such as behavior, cognition, neurological disease and mental illness," he added.

He said that the latest research provides further evidence that the mammalian central nervous system has the potential capacity to respond to its outside environment by generating new nerve cells.

The QBI research augments ongoing efforts to identify cellular and molecular mechanisms that can repair compromised brain tissue, and represents another milestone in understanding the fundamental workings of the brain.

Neuroscientist says spatial strategies can reduce risk of dementia

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Véronique Bohbot, PhD., neuroscientist at the Douglas Mental Health University Institute and associate professor at McGill University, leads studies on navigational strategies. She presented her findings at the recent meeting of the Society for Neuroscience in San Diego, which could bring light into how we can make better use of our hippocampus in order to reduce the risk of dementia.

Why it is better to use a spatial strategy - Summary of findings

In her lab, Bohbot and her team used virtual navigation to conduct a series of studies. It was shown that, in healthy older adults:

1) Participants using spatial strategies had reduced risk of dementia as assessed with the MoCA© (The Montreal Cognitive Assessment is a cognitive screening test designed to assist Health Professionals for detection of mild cognitive impairment)

2) Spatial strategies significantly correlated with grey matter in the hippocampus.




3) Only the people who used spatial strategies showed significant fMRI activity in the hippocampus during a virtual navigation task that allowed for both spatial and response strategies.



Two strategies used by our brain



When we find our way in the world, we rely on one of two strategies. One is spatial strategy, in which we build cognitive maps using relationships between landmarks to help us determine where we are but also help us plan where we want to go (for instance, you will memorize the spatial relationship between the market, home and school such that you can take shortcuts when going to novel destinations). The other one is a stimulus-response strategy, which is kind of an auto-pilot mode (after some repetition, you make a series of right and left turns out of habit like going to work every day using the same route. Sometimes you get there out of habit without knowing what you saw on the way). When you use a GPS, you don't necessarily use your spatial memory.



Significant results



"These results are in agreement with the literature showing that the first symptoms of Alzheimer's disease involve problems with spatial orientation as well as the literature that shows that decreased volume in the hippocampus is a risk factor for conversion from mild cognitive impairment to Alzheimer's disease." adds Bohbot.



Source: DOUGLAS MENTAL HEALTH UNIVERSITY INSTITUTE