Alzheimer's-Where why and how

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Columbia University Medical Center, via Newswise.

3 ROOTS OF ALZHEIMER'S: 

Columbia University researchers have pinpointed 3 discoveries about Alzheimer's:

• Where it starts
• Why it starts there
• How it spreads.

Learn why this can help researchers treat Alzheimer's sooner and better

discoveries about Alzheimer's:

• Where it starts
• Why it starts there
• How it spreads.

Learn why this can help researchers treat Alzheimer's sooner and better. 

---

Using high-resolution functional MRI (fMRI) imaging in patients with Alzheimer's disease and in mouse models of the disease, Columbia University Medical Center (CUMC) researchers have clarified three fundamental issues about Alzheimer's: where it starts, why it starts there, and how it spreads. In addition to advancing understanding of Alzheimer's, the findings could improve early detection of the disease, when drugs may be most effective. The study was published today in the online edition of the journalNature Neuroscience.

Alzheimer's disease starts in the entorhinal cortex (yellow). Using fMRI in mouse (left) and human (right) brains, the researchers provide evidence that the disease spreads from the entohrinal cortex (yellow) to other cortical regions (red) -- the perirhinal cortex and posterior parietal cortex. (Credit: Usman Khan/lab of Scott A. Small, MD, Columbia University Medical Center.)

"It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex," said co-senior author Scott A. Small, MD, Boris and Rose Katz Professor of Neurology, professor of radiology, and director of the Alzheimer's Disease Research Center. "But this study is the first to show in living patients that it begins specifically in the lateral entorhinal cortex, or LEC. The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected."

The study also shows that, over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular, the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation. The researchers suspect that Alzheimer's spreads "functionally," that is, by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.

A third major finding of the study is that LEC dysfunction occurs when changes in tau and amyloid precursor protein (APP) co-exist. "The LEC is especially vulnerable to Alzheimer's because it normally accumulates tau, which sensitizes the LEC to the accumulation of APP. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer's," said co-senior author Karen E. Duff, PhD, professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute.

In the study, the researchers used a high-resolution variant of fMRI to map metabolic defects in the brains of 96 adults enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP). All of the adults were free of dementia at the time of enrollment.

"Dr. Richard Mayeux's WHICAP study enables us to follow a large group of healthy elderly individuals, some of whom have gone on to develop Alzheimer's disease," said Dr. Small. "This study has given us a unique opportunity to image and characterize patients with Alzheimer's in its earliest, preclinical stage."

The 96 adults were followed for an average of 3.5 years, at which time 12 individuals were found to have progressed to mild Alzheimer's disease. An analysis of the baseline fMRI images of those 12 individuals found significant decreases in cerebral blood volume (CBV) -- a measure of metabolic activity -- in the LEC compared with that of the 84 adults who were free of dementia.

A second part of the study addressed the role of tau and APP in LEC dysfunction. While previous studies have suggested that entorhinal cortex dysfunction is associated with both tau and APP abnormalities, it was not known how these proteins interact to drive this dysfunction, particularly in preclinical Alzheimer's.

To answer this question, explained first author Usman Khan, an MD-PhD student based in Dr. Small's lab, the team created three mouse models, one with elevated levels of tau in the LEC, one with elevated levels of APP, and one with elevated levels of both proteins. The researchers found that the LEC dysfunction occurred only in the mice with both tau and APP.

The study has implications for both research and treatment. "Now that we've pinpointed where Alzheimer's starts, and shown that those changes are observable using fMRI, we may be able to detect Alzheimer's at its earliest preclinical stage, when the disease might be more treatable and before it spreads to other brain regions," said Dr. Small. In addition, say the researchers, the new imaging method could be used to assess the efficacy of promising Alzheimer's drugs during the disease's early stages.

The paper is titled, "Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease." The other contributors are Li Liu, Frank Provenzano, Diego Berman, Caterina Profaci, Richard Sloan and Richard Mayeux, all at CUMC.

The study was supported by grants from National Institutes of Health (AG034618, AG025161, AG07232, AG037212, NS074874, and HL094423.

Source:

Columbia University Medical Center, via Newswise.

---

Journal Reference:

1. Usman A Khan, Li Liu, Frank A Provenzano, Diego E Berman, Caterina P Profaci, Richard Sloan, Richard Mayeux, Karen E Duff, Scott A Small. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nature Neuroscience, 2013; DOI: 10.1038/nn.3606

Brain-Beginning of Alzheimer's

Caregivers, and healthcare professionals,here is some great information

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

Your residents will love the Amazon Kindle Fire

Here is information on being the best caregiver you can be

Here is a way for nurses administrators, social workers and other health care  professionals to get an easyceu or two

Follow alzheimersideas on twitter
The Dementia Caregiver's Little Book of Hope [Kindle Edition]


Source:

Columbia University Medical Center, via Newswise.

ROOTS OF ALZHEIMER'S: 

Columbia University researchers have pinpointed 3 discoveries about Alzheimer's:

• Where it starts
• Why it starts there
• How it spreads.

Learn why this can help researchers treat Alzheimer's sooner and better. 

---

Using high-resolution functional MRI (fMRI) imaging in patients with Alzheimer's disease and in mouse models of the disease, Columbia University Medical Center (CUMC) researchers have clarified three fundamental issues about Alzheimer's: where it starts, why it starts there, and how it spreads. In addition to advancing understanding of Alzheimer's, the findings could improve early detection of the disease, when drugs may be most effective. The study was published today in the online edition of the journalNature Neuroscience.

Alzheimer's disease starts in the entorhinal cortex (yellow). Using fMRI in mouse (left) and human (right) brains, the researchers provide evidence that the disease spreads from the entohrinal cortex (yellow) to other cortical regions (red) -- the perirhinal cortex and posterior parietal cortex. (Credit: Usman Khan/lab of Scott A. Small, MD, Columbia University Medical Center.)

"It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex," said co-senior author Scott A. Small, MD, Boris and Rose Katz Professor of Neurology, professor of radiology, and director of the Alzheimer's Disease Research Center. "But this study is the first to show in living patients that it begins specifically in the lateral entorhinal cortex, or LEC. The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected."

The study also shows that, over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular, the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation. The researchers suspect that Alzheimer's spreads "functionally," that is, by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.

A third major finding of the study is that LEC dysfunction occurs when changes in tau and amyloid precursor protein (APP) co-exist. "The LEC is especially vulnerable to Alzheimer's because it normally accumulates tau, which sensitizes the LEC to the accumulation of APP. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer's," said co-senior author Karen E. Duff, PhD, professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute.

In the study, the researchers used a high-resolution variant of fMRI to map metabolic defects in the brains of 96 adults enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP). All of the adults were free of dementia at the time of enrollment.

"Dr. Richard Mayeux's WHICAP study enables us to follow a large group of healthy elderly individuals, some of whom have gone on to develop Alzheimer's disease," said Dr. Small. "This study has given us a unique opportunity to image and characterize patients with Alzheimer's in its earliest, preclinical stage."

The 96 adults were followed for an average of 3.5 years, at which time 12 individuals were found to have progressed to mild Alzheimer's disease. An analysis of the baseline fMRI images of those 12 individuals found significant decreases in cerebral blood volume (CBV) -- a measure of metabolic activity -- in the LEC compared with that of the 84 adults who were free of dementia.

A second part of the study addressed the role of tau and APP in LEC dysfunction. While previous studies have suggested that entorhinal cortex dysfunction is associated with both tau and APP abnormalities, it was not known how these proteins interact to drive this dysfunction, particularly in preclinical Alzheimer's.

To answer this question, explained first author Usman Khan, an MD-PhD student based in Dr. Small's lab, the team created three mouse models, one with elevated levels of tau in the LEC, one with elevated levels of APP, and one with elevated levels of both proteins. The researchers found that the LEC dysfunction occurred only in the mice with both tau and APP.

The study has implications for both research and treatment. "Now that we've pinpointed where Alzheimer's starts, and shown that those changes are observable using fMRI, we may be able to detect Alzheimer's at its earliest preclinical stage, when the disease might be more treatable and before it spreads to other brain regions," said Dr. Small. In addition, say the researchers, the new imaging method could be used to assess the efficacy of promising Alzheimer's drugs during the disease's early stages.
The paper is titled, "Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease." The other contributors are Li Liu, Frank Provenzano, Diego Berman, Caterina Profaci, Richard Sloan and Richard Mayeux, all at CUMC.

The study was supported by grants from National Institutes of Health (AG034618, AG025161, AG07232, AG037212, NS074874, and HL094423.

---

Journal Reference:

1. Usman A Khan, Li Liu, Frank A Provenzano, Diego E Berman, Caterina P Profaci, Richard Sloan, Richard Mayeux, Karen E Duff, Scott A Small. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nature Neuroscience, 2013; DOI: 10.1038/nn.3606

Where Alzheimer's Begins

Caregivers, and healthcare professionals,here is some great information

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

Your residents will love the Amazon Kindle Fire

Here is information on being the best caregiver you can be

Here is a way for nurses administrators, social workers and other health care  professionals to get an easyceu or two

Follow alzheimersideas on twitter

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

Columbia University Medical Center.

ROOTS OF ALZHEIMER'S: 

Columbia University researchers have pinpointed 3 discoveries about Alzheimer's:

• Where it starts
• Why it starts there
• How it spreads.

Learn why this can help researchers treat Alzheimer's sooner and better. 

---

Using high-resolution functional MRI (fMRI) imaging in patients with Alzheimer's disease and in mouse models of the disease, Columbia University Medical Center (CUMC) researchers have clarified three fundamental issues about Alzheimer's: where it starts, why it starts there, and how it spreads. In addition to advancing understanding of Alzheimer's, the findings could improve early detection of the disease, when drugs may be most effective. The study was published today in the online edition of the journalNature Neuroscience.

Alzheimer's disease starts in the entorhinal cortex (yellow). Using fMRI in mouse (left) and human (right) brains, the researchers provide evidence that the disease spreads from the entohrinal cortex (yellow) to other cortical regions (red) -- the perirhinal cortex and posterior parietal cortex. (Credit: Usman Khan/lab of Scott A. Small, MD, Columbia University Medical Center.)

"It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex," said co-senior author Scott A. Small, MD, Boris and Rose Katz Professor of Neurology, professor of radiology, and director of the Alzheimer's Disease Research Center. "But this study is the first to show in living patients that it begins specifically in the lateral entorhinal cortex, or LEC. The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected."

The study also shows that, over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular, the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation. The researchers suspect that Alzheimer's spreads "functionally," that is, by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.

A third major finding of the study is that LEC dysfunction occurs when changes in tau and amyloid precursor protein (APP) co-exist. "The LEC is especially vulnerable to Alzheimer's because it normally accumulates tau, which sensitizes the LEC to the accumulation of APP. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer's," said co-senior author Karen E. Duff, PhD, professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute.

In the study, the researchers used a high-resolution variant of fMRI to map metabolic defects in the brains of 96 adults enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP). All of the adults were free of dementia at the time of enrollment.

"Dr. Richard Mayeux's WHICAP study enables us to follow a large group of healthy elderly individuals, some of whom have gone on to develop Alzheimer's disease," said Dr. Small. "This study has given us a unique opportunity to image and characterize patients with Alzheimer's in its earliest, preclinical stage."

The 96 adults were followed for an average of 3.5 years, at which time 12 individuals were found to have progressed to mild Alzheimer's disease. An analysis of the baseline fMRI images of those 12 individuals found significant decreases in cerebral blood volume (CBV) -- a measure of metabolic activity -- in the LEC compared with that of the 84 adults who were free of dementia.

A second part of the study addressed the role of tau and APP in LEC dysfunction. While previous studies have suggested that entorhinal cortex dysfunction is associated with both tau and APP abnormalities, it was not known how these proteins interact to drive this dysfunction, particularly in preclinical Alzheimer's.

To answer this question, explained first author Usman Khan, an MD-PhD student based in Dr. Small's lab, the team created three mouse models, one with elevated levels of tau in the LEC, one with elevated levels of APP, and one with elevated levels of both proteins. The researchers found that the LEC dysfunction occurred only in the mice with both tau and APP.

The study has implications for both research and treatment. "Now that we've pinpointed where Alzheimer's starts, and shown that those changes are observable using fMRI, we may be able to detect Alzheimer's at its earliest preclinical stage, when the disease might be more treatable and before it spreads to other brain regions," said Dr. Small. In addition, say the researchers, the new imaging method could be used to assess the efficacy of promising Alzheimer's drugs during the disease's early stages.

Mental Stimulation Postpones, Then Speeds Dementia (part 2)

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Get your subscription to Activity Director Today's e magazine" />

Allison Augbry

His(Yaakov Stern) theory is that mentally engaged people build up a "cognitive reserve" that may help them compensate when the initial brain changes associated with dementia and Alzheimer's begin to develop.

"One simple idea is that perhaps they have more flexibility in how they approach tasks," Stern says. So, if the disease begins to disrupt or damage one network in the brain, they may be able to engage alternative networks in the brain to solve problems or do tasks.

Delay Followed By Speedy Decline

So for those who are mentally engaged, it may take many more years for the symptoms of the disease to appear. But once they do, the course of the disease seems to speed up. Researchers say there's a bit of a silver lining here: knowing that the disease will likely progress more quickly.

"We think this is very good news," Wilson says. "It suggests that cognitive activity extends your period of cognitive independence as long as it possibly can."

And it will likely shorten the battle at the end of life. This means Alzheimer's patients may be less of a burden to caregivers and loved ones.

Mental Stimulation Postpones, Then Speeds Dementia

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

Here is information on being the best caregiver you can be

Here is a way for nurses administrators, social workers and other health care professionals to get an easyceu or two

Here are more interesting dementia brain boosting activities





Get your subscription to Activity Director Today's e magazine" />

Allison Augbry

When it comes to staving off dementia, new evidence suggests that the "use it or lose it" dictum holds true — at least for a while. But it also appears that mentally stimulating lifestyles may speed up dementia once it hits in old age.

"We do think that a cognitively active lifestyle is protective up to some point," says Robert Wilson, a professor of neurological sciences at Rush University Medical Center in Chicago.

But the protection doesn't hold up indefinitely.

New Evidence

Wilson and his colleagues recruited 1,157 people age 65 and older from the Chicago area. When the study began, none of the seniors had dementia. During face-to-face interviews, each was asked how often he or she participated in stimulating activities. "Things such as reading a newspaper, listening to the radio, going to a museum, or playing a board game such as chess or checkers," Wilson says. Then they gave each person a score on a cognitive activity scale. The more frequently people engaged in stimulating activities, the higher their score.

More than a decade later, researchers followed up with cognitive evaluations and diagnostics. They found that among the seniors who didn't have dementia, the rate of cognitive decline was reduced by 52 percent for each point on the cognitive activity scale. But the results were much different for those who developed Alzheimer's disease — their rate of decline increased. The average rate of decline per year increased by 42 percent for each point on the cognitive activity scale.

Findings Fit With Theory Of 'Cognitive Reserve'

"Someone who's brilliant and engages in a lot of activities might reduce their risk of Alzheimer's disease for a while," says Yaakov Stern, professor of clinical neuropsychology at Columbia University

His theory... come back to dementia views soon to see

Direct Relationship Seen Between Plasma Aβ Levels and Cognitive Decline (part 3)

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Here is a way for nurses administrators, social workers and other health care professionals to get an easyceu or two

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Pam Harrison (Medscape Today)

Relatively Rapid Decline

As the authors point out, the relatively rapid cognitive decline seen as a function of high baseline plasma Aβ levels and stable or decreasing Aβ42 in the entire sample is not surprising given that a similar plasma Aβ profile predicted conversion to Alzheimer's disease in the same sample in an earlier study — cognitive decline in more than one domain is a prerequisite for incident Alzheimer's disease.

"We need to further validate these Aβ levels, and we also need to understand how plasma Aβ levels relate to brain levels," Dr. Cosentino cautioned. "But once we have a better understanding of this, testing patients for plasma Aβ levels is an inexpensive and noninvasive way to identify people at greater risk for cognitive decline and Alzheimer's disease, and ultimately, this would be very important in terms of being able to provide preventive treatment when we have such a treatment."

The study was supported by grants from the National Institutes of Health. The authors have disclosed no relevant financial relationships.

Direct Relationship Seen Between Plasma Aβ Levels and Cognitive Decline (part 2)

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

Here is information on being the best caregiver you can be

Here is a way for nurses administrators, social workers and other health care professionals to get an easyceu or two

Here are more interesting dementia brain boosting activities





Get your subscription to Activity Director Today's e magazine" />

Pam Harrison (Medscape Today)

Aging Project

The amyloid cascade hypothesis suggests that Alzheimer's disease develops subsequent to aberrant metabolism of glycoproteins, the precursors to amyloid, the authors write. Aβ40 and Aβ42 then accumulate, and this accumulation is considered the primary trigger for the development of Alzheimer's disease. Previous research indicates that plasma Aβ levels decrease as brain levels increase, suggesting that plasma Aβ level may be used as a biomarker of disease risk.

In this study, participants were drawn from the Washington Heights and Inwood Columbia Aging Project and represented 3 broadly defined ethnic groups: Caribbean Hispanic, black, and white. All participants were free of dementia at the time of the first Aβ sample; at follow-up, 481 patients remained cognitively healthy, 329 were cognitively or functionally impaired but not demented at any point, and 70 developed Alzheimer's disease.

Investigators then determined whether Aβ levels could be linked to either specific cognitive changes that constitute conversion to Alzheimer's disease or whether they corresponded to cognitive change independent of dementia. Cognitive change consisted of a composite score and memory, language, and visuospatial indices.

When researchers examined cognitive change in specific domains by Aβ, they determined that baseline Aβ42 predicted cognitive change in all 3 domains in the overall sample, with those in the highest Aβ quartile "consistently declining faster" than those in the lowest. "Baseline Aβ40 quartile predicted change in memory," the authors add, with those in the second and third quartiles declining faster than those in the lowest quartile.

Baseline Aβ40 quartiles also predicted change in language, with individuals in the highest quartile declining faster than those in the lowest. "Finally, change in Aβ42 predicted change in memory and visuospatial scores, with relatively stable or decreasing Aβ42 predicting faster decline," the researchers add. Among the group who remained cognitively healthy during the study interval, baseline Aβ42 predicted change primarily in memory, with higher baseline levels generally predicting faster decline.

In contrast, baseline Aβ40 was generally unrelated to cognitive change in the same healthy elderly group, and change in Aβ42 was not associated with change in any domain. Finally, change in Aβ40 over time was not related to cognitive change in either the overall sample or the cognitively healthy.

Relatively Rapid Decline

As the authors point out, the relatively rapid cognitive decline seen as

Direct Relationship Seen Between Plasma Aβ Levels and Cognitive Decline

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

Here is information on being the best caregiver you can be

Here is a way for nurses administrators, social workers and other health care professionals to get an easyceu or two

Here are more interesting dementia brain boosting activities





Get your subscription to Activity Director Today's e magazine" />

Pam Harrison (Medscape Today)

There is a direct and linear association between plasma beta-amyloid (Aβ) levels and multiple aspects of cognitive decline over time, including cognitive changes that constitute conversion to Alzheimer's disease, according to new findings from a population-based, ethnically diverse longitudinal sample of older adults.

Stephanie Cosentino, PhD, from the Taub Institute for Research in Alzheimer's Disease and the Aging Brain at Columbia University Medical Center, New York City, and multicenter colleagues found that in their overall sample of 880 adults, individuals in the top 3 quartiles of Aβ42 at baseline had faster declines in cognitive function during 4.5 years of follow-up than those in the lowest quartile. The same observation held largely true for individuals who remained cognitively healthy during the same study interval.

"Individuals in the top 3 Aβ40 quartiles also declined faster than those in the lowest quartile," investigators add, "[whereas] in the healthy elderly individuals, only the highest quartile declined faster than those in the lowest."

Looking at the rate of global cognitive change by change in Aβ, investigators noted that in both the overall cohort and the healthy elderly, individuals with relatively stable or decreasing Aβ42 values had faster cognitive decline than those with increasing Aβ42 values.

In contrast, change in Aβ40 was not associated with cognitive change in either the overall cohort or the healthy elderly.

"What we tend to see in healthy elders is a steady increase in Aβ42 levels over time, so what we are trying to characterize here is the absence of an increase," Dr. Cosentino told Medscape Medical News.

She also noted that previous studies have shown that high initial plasma levels of Aβ and declining levels of Aβ over time are risk factors for Alzheimer's disease, "so changes in Aβ levels provide information about disease risk." In this particular study, changes in the same plasma Aβ levels predicted the rate of cognitive decline in patients who eventually developed dementia.

"This linear association between plasma Aβ and cognitive change increases our ability to use plasma Aβ as a marker of impending cognitive decline and Alzheimer's disease," Dr. Cosentino said, adding that interestingly enough, the same Aβ profile predicted cognitive decline even in those individuals who remained healthy over time.

The study was published online August 9 and will appear in the December issue of the Archives of Neurology.

Aging Project

The amyloid cascade hypothesis suggests that