The results from a new study by neurological researchers from the Rush Alzheimer's Disease Center at Rush University Medical Center suggest that people who were emotionally neglected as children may have a higher risk of stroke in later adulthood.

"Studies have shown that children who were neglected emotionally in childhood are at an increased risk of a slew of psychiatric disorders. However, our study is one of few that looked at an association between emotional neglect and stroke," said study author Robert S. Wilson, PhD, a neuropsychologist at Rush.

The findings are published in the September 19, online issue of Neurology, the medical journal of the American Academy of Neurology.

For the study, 1,040 participants in the Memory and Aging Project who did not have dementia and were 55 years of age or older took a survey measuring physical and emotional abuse before the age of 18. The retrospective survey questions focused on whether the participant felt loved by their parents or caregiver when they were younger, were made to feel afraid or intimidated and whether they were punished with a belt or other object. Questions about parental divorce and the family's financial needs were also included.

Over a period of three and a half years, 257 people in the study died, of which 192 had a brain autopsy to look for signs of stroke. Forty of the participants had evidence of a stroke based on their medical history or an examination. A total of 89 people had signs of a stroke based on the autopsy results.

The study found that the risk of stroke was nearly three times higher in those people who reported a moderately high level of childhood emotional neglect than those who reported a moderately low level. The results stayed the same after considering factors such as diabetes, physical activity, smoking, anxiety and heart problems.

"Interestingly, the autopsy showed emotional neglect was associated with the presence of cerebral infarctions," said Dr. David A. Bennett, director of the Rush Alzheimer's Disease Center and co-author of the study. "The results add to a growing body of evidence suggesting that early life factors such as traumatic childhood experiences influence the development of physical illness and common chronic conditions of old age."

Wilson noted that a limitation of the study is that neglect was reported from memory many years after occurrence, so participants may not have remembered events accurately.

The study was supported by the National Institutes of Health and the Illinois Department of Public Health.

A new guideline released by the American Academy of Neurology may help doctors in making the diagnosis of Creutzfeldt-Jakob disease. The guideline is published in the September 19, 2012, online issue of Neurology®, the medical journal of the American Academy of Neurology.

Creutzfeldt-Jakob disease is a rare, always fatal brain disorder that involves quickly progressing dementia. New cases appear in about one person per million each year worldwide and confirming the diagnosis is challenging. People with the disease can have a wide range of symptoms. Many other conditions can cause similar symptoms, and with some of these conditions the dementia can be treated.

The guideline focused only on the diagnosis of sporadic Creutzfeldt-Jakob disease.

While several tests are available to help diagnose sporadic Creutzfeldt-Jakob disease, a brain biopsy is the most accurate test that can be performed on a person living with the disease. Brain biopsy is potentially dangerous.

The guideline examined the diagnostic accuracy of testing for a protein called 14-3-3 in the spinal fluid. The guideline authors reviewed all of the available evidence on the test, which included samples of 1,849 people with suspected sporadic Creutzfeldt-Jakob disease from nine studies.

They found that in cases where doctors strongly suspect Creutzfeldt-Jakob to be the cause of the dementia, the test can be helpful in reducing the uncertainty of the diagnosis. However, the test is not accurate enough to diagnose the disease with certainty or to rule it out completely. The test has a sensitivity of about 92 percent and a specificity of about 80 percent. Sensitivity is the percentage of patients with the disease who have a positive test result, and specificity is the percentage of patients who do not have the disease and who are correctly identified as having a negative test result.

The guideline determined that the 14-3-3 protein test can be useful when the probability of the person having Creutzfeldt-Jakob disease is between 20 percent and 90 percent.

"This means that if the physician considers the likelihood of Creutzfeldt-Jakob disease to be extremely low or extremely high, then testing for 14-3-3 protein would not be useful regardless of the result," said guideline author Taim Muayqil, MBBS, FRCPC, of King Saud University in Riyadh, Saudi Arabia, and a member of the American Academy of Neurology.

Muayqil noted that only doctors experienced in diagnosing dementia should determine whether the 14-3-3 protein test is needed and how results should be interpreted.

— Low serum levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) are associated with Alzheimer's Disease in men, but not women, according to a recent study accepted for publication in The Endocrine Society's Journal of Clinical Endocrinology & Metabolism (JCEM).

IGF-1 and IGFBP-3 are involved in longevity and could be beneficial to cognition, especially in Alzheimer's disease where experimental studies have shown that IGF-1 opposes the main pathological processes of Alzheimer's disease. The current study investigated the relationship between IGF-1 and IGFBP-3 serum levels and cognitive impairment, including Alzheimer's disease.

"At this time, no curative treatment is available for Alzheimer's disease so focus on modifiable associated factors is of major importance," said Emmanuelle Duron, MD, PhD, of Broca Hospital in Paris, France and lead author of the study. "Our research shows a possible usefulness of IGF-1 in Alzheimer's disease treatment, especially in early stages."

In this multicentric cross-sectional study, researchers measured IGF-1 and IGFBP-3 serum levels in 694 elderly subjects (218 men and 476 women). Of the study participants, 481 had memory complaints and were diagnosed with Alzheimer's disease or mild cognitive impairment. Duron and her colleagues found that IGF-1 and IGFBP-3 serum levels were significantly associated with cognitive status in men, but not in women.

"Our cross-sectional association does not mean a causal relationship," notes Duron. "Our results justify a longitudinal study to evaluate whether circulating IGF-1/IGFBP-3 are predictive of cognitive decline according to gender."

Other researchers working on the study include: Benoit Funalot, Nadege Brunel, Cecile Viollet, Jacques Epelbaum and Yves le Bouc of Institut National de la Santé et de la Recherche Médicale (INSERM) in Paris France; Joel Coste and Laurent Quinquis of Hotel Dieu in Paris, France; Joel Belmin of Charles Foix Hospital in Seine, France; Pierre Jouanny of Centre Hospitalo in Amiens, France; Florence Pasquier of Hopital Roger Salengro in Lille, France; Jean-Marc Treluyer of France Unite de Recherche Clinique in Paris, France; and Olivier Hanon of Broca Hospital in Paris, France.

Two proteins previously found to contribute to ALS, also known as Lou Gehrig's disease, have divergent roles. But a new study, led by researchers at the Department of Cellular and Molecular Medicine at the University of California, San Diego School of Medicine, shows that a common pathway links them.

The discovery reveals a small set of target genes that could be used to measure the health of motor neurons, and provides a useful tool for development of new pharmaceuticals to treat the devastating disorder, which currently has no treatment or cure.

Funded in part by the National Institutes of Health and the California Institute for Regenerative Medicine (CIRM), the study will be published in the advance online edition of Nature Neuroscience on September 30.

ALS is an adult-onset neurodegenerative disorder characterized by premature degeneration of motor neurons, resulting in a progressive, fatal paralysis in patients.

The two proteins that contribute to the disease — FUS/TLS and TDP-43 — bind to ribonucleic acid (RNA), intermediate molecules that translate genetic information from DNA to proteins. In normal cells, both TDP-43 and FUS/TLS are found in the nucleus where they help maintain proper levels of RNA. In the majority of ALS patients, however, these proteins instead accumulate in the cell's cytoplasm — the liquid that separates the nucleus from the outer membrane, and thus are excluded from the nucleus, which prevents them from performing their normal duties.

Since the proteins are in the wrong location in the cell, they are unable to perform their normal function, according to the study's lead authors, Kasey R. Hutt, Clotilde Lagier-Tourenne and Magdalini Polymenidou. "In diseased motor neurons where TDP-43 is cleared from the nucleus and forms cytoplasmic aggregates," the authors wrote, "we saw lower protein levels of three genes regulated by TDP-43 and FUS/TLS. We predicted that this, based on our mouse studies, and found the same results in neurons derived from human embryonic stem cells."

In 2011, this team of UC San Diego scientists discovered that more than one-third of the genes in the brains of mice are direct targets of TDP-43, affecting the functions of these genes. In the new study, they compared the impact of the FUS/TLS protein to that of TDP-43, hoping to find a large target overlap.

"Surprisingly, instead we saw a relatively small overlap, and the common RNA targets genes contained exceptionally long introns, or non-coding segments. The set is composed of genes that are important for synapse function," said principal investigator Gene Yeo, PhD, assistant professor in the Department of Cellular and Molecular Medicine and the Institute for Genomic Medicine at UC San Diego and a visiting professor at the Molecular Engineering Laboratory in Singapore. "Loss of this common overlapping set of genes is evidence of a common pathway that appears to contribute to motor neuron degeneration."

In an effort to understand the normal function of these two RNA binding proteins, the scientists knocked down the proteins in brains of mice to mimic nuclear clearance, using antisense oligonucleotide technology developed in collaboration with ISIS Pharmaceuticals. The study resulted in a list of genes that are up or down regulated, and the researchers duplicated the findings in human cells.

"If we can somehow rescue the genes from down regulation, or being decreased by these proteins, it could point to a drug target for ALS to slow or halt degeneration of the motor neurons," said Yeo.

These proteins also look to be a central component in other neurodegenerative conditions. For example, accumulating abnormal TDP-43 and FUS/TLS in neuronal cytoplasm has been documented in frontotemporal lobar dementia, a neurological disorder that has been shown to be genetically and clinically linked to ALS, and which is the second most frequent cause of dementia after Alzheimer's disease.

Researchers have discovered a way to generate new human neurons from another type of adult cell found in our brains. The discovery, reported in the October 5th issue of Cell Stem Cell, a Cell Press publication, is one step toward cell-based therapies for the treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's.

"This work aims at converting cells that are present throughout the brain but themselves are not nerve cells into neurons," said Benedikt Berninger, now at the Johannes Gutenberg University Mainz. "The ultimate goal we have in mind is that this may one day enable us to induce such conversion within the brain itself and thus provide a novel strategy for repairing the injured or diseased brain."

The cells that made the leap from one identity to another are known as pericytes. Those cells, found in close association with the blood vessels, are important for keeping the blood-brain barrier intact and have been shown to participate in wound healing in other parts of the body.

"Now, we reason, if we could target these cells and entice them to make nerve cells, we could take advantage of this injury response," Berninger says.

Further testing showed that those newly converted neurons could produce electrical signals and reach out to other neurons, providing evidence that the converted cells could integrate into neural networks.

"While much needs to be learnt about adapting a direct neuronal reprogramming strategy to meaningful repair in vivo, our data provide strong support for the notion that neuronal reprogramming of cells of pericytic origin within the damaged brain may become a viable approach to replace degenerated neurons," the researchers write.

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Journal Reference:

1. Marisa Karow, Rodrigo Sánchez, Christian Schichor, Giacomo Masserdotti, Felipe Ortega, Christophe Heinrich, Sergio Gascón, Muhammad A. Khan, D. Chichung Lie, Arianna Dellavalle, Giulio Cossu, Roland Goldbrunner, Magdalena Götz, Benedikt Berninger. Reprogramming of Pericyte-Derived Cells of the Adult Human Brain into Induced Neuronal Cells. Cell Stem Cell, 2012; 11 (4): 471 DOI: 10.1016/j.stem.2012.07.007

With baby boomers approaching the age of 65 and new cases of Alzheimer's disease expected to increase by 50 percent by the year 2030, Georgia Tech researchers have created a tool that allows adults to screen themselves for early signs of dementia. The home-based computer software is patterned after the paper-and-pencil Clock Drawing Test, one of health care's most commonly used screening exams for cognitive impairment.

"Technology allows us to check our weight, blood-sugar levels and blood pressure, but not our own cognitive abilities," said project leader Ellen Yi-Luen Do. "Our ClockMe System helps older adults identify early signs of impairment, while allowing clinicians to quickly analyze the test results and gain valuable insight into the patient's thought processes."

ClockReader is the actual test and is taken with a stylus and computer or tablet. The participant is given a specific time and instructed to draw a clock with numbers and the correct minute and hour hands. Once completed, the sketch is emailed to a clinician, who uses the ClockAnalyzer Application to score the test. The software checks for 13 traits. They include correct placement of numbers and hands without extra markings. People with cognitive impairment frequently draw clocks with missing or extra numbers. Digits are sometimes drawn outside of the clock. The time is often incorrect.

In addition to scoring automatically and consistently, ClockAnalyzer records the duration of the test and the time between each stroke. The software also replays the drawing in real-time, allowing a clinician to watch the drawing being created to observe any behavior abnormality.

"The traditional paper-and-pencil test is usually overseen by a technician and later scored by a clinician, who scores the test based only on the finished drawing," said Do, a professor in Georgia Tech's Colleges of Computing and Architecture. "By looking at the sketch, the scorer is not able to decipher whether the person struggled to remember certain numbers while drawing the clock. The ClockMe system's timing software highlights those delays."

And, because they're saved electronically, the drawings can be used to easily compare a person's cognitive ability progress or regression over time. Do's research found that traditional tests are often filed in a folder and are rarely used for future comparison.

The ClockMe system was initially tested at the Emory Alzheimer's Disease Research Center in Atlanta, where it's currently being used in addition to the traditional paper-and-pencil test. Despite a lack of computer literacy, all of the elderly patients who used the software during the study said they had no problems with the pen-based, computer technology.

"For this reason, as well as the ability to send the drawings directly to clinicians for convenient scoring, we envision ClockMe as a viable tool for home-based screening," said Do. "America's health care costs are expected to soar as baby boomers become senior citizens. If a screening tool can be used at home, unnecessary trips to clinics can be eliminated and medical expenses can be saved."

Do and her colleagues are hoping to commercialize the project in the future. Their research was published in September's Journal of Ambient Intelligence and Smart Environments.

This project is supported by the National Science Foundation (NSF) (Award Number SHB-1117665).

An international research team led by the Spanish National Research Council (CSIC) and researchers from Kiel University revealed the atomic‐level structure of the human peptidase enzyme meprin β (beta). The enzyme is related to inflammation, cancer and Alzheimer's Disease and is involved in cellular proliferation and differentiation. The knowledge of the enzyme structure will allow for the development of a new medication type different from those known up to now.

The study was published in the current issue of the Proceedings of the National Academy of Sciences.

"Now that we know how meprin β looks, how it works and how it relates to diseases, we can search for substances that stop its enzyme activities when they become harmful," explains Xavier Gomis-Rüth, researcher at the Molecular Biology Institute of Barcelona, who led the project. Meprin β is an enzyme that is anchored in the outer wall of cells. Its normal function in the human metabolism is to cut off certain proteins, e.g. growth factors, that are also anchored in the cell wall. In this way meprin β releases protein fragments into the environment surrounding the cells — a natural and normal process, as long as it occurs at a certain intensity. However, under specific circumstances, meprin β may function abnormally, and, for example, releases too many protein fragments. The protein pieces than overdo their natural task in the cell surroundings, causing disorder in the human body. Such disorder typically occurs when inflammation, cancer or Alzheimer's Disease get started.

In their study, the scientists found out that meprin β consists of two identical molecules building a dimeric structure with a cleft in the middle. "We also discovered that the active site cleft is something like the scissor of the enzyme, the actual place where the proteins are cleaved," explains Christoph Becker-Pauly, researcher at the Institute of Biochemistry at Kiel University, and principle investigator of the Kiel Collaborative Research Center 877 „Proteolysis as a Regulatory Event in Pathophysiology." Molecular biologist Gomes-Rüth points out to the next research goal: "We now need to find a substance that fits right into the cleft and will thus block the cleaving activity of meprin β." Such a substance could be the key to new therapeutical drugs against inflammation, cancer or Alzheimer's Disease.

The research has been carried out in collaboration with scientists from Max Planck Institute for Biochemistry and Johannes Gutenberg University Mainz (Germany) as well as University of Bern (Switzerland).

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Journal Reference:

1. J. L. Arolas, C. Broder, T. Jefferson, T. Guevara, E. E. Sterchi, W. Bode, W. Stocker, C. Becker-Pauly, F. X. Gomis-Ruth. Structural basis for the sheddase function of human meprin   metalloproteinase at the plasma membrane. Proceedings of the National Academy of Sciences, 2012; 109 (40): 16131 DOI: 10.1073/pnas.1211076109

Research shows that managing and treating vascular disease risk factors are not only beneficial to preventing heart disease and stroke, but also common forms of dementia.

Dr. Gustavo C. Roman, director of the Nantz National Alzheimer Center at the Methodist Neurological Institute in Houston, summed up decades of dementia-related research in a review paper in Alzheimer's Disease and Associated Disorders. Roman said although more definitive research is needed, focusing on the following risk factors can go a long way to helping reduce the risk of vascular dementia and mixed dementia (the combination of vascular dementia and Alzheimer's disease). By 2050, 11 to 16 million Americans will suffer some form of dementia.

Hypertension: Controlling blood pressure reduces the risk of stroke and heart disease. Studies are also beginning to show that hypertension increases the likelihood that people with mild cognitive impairment will eventually have dementia later in life.

Hyperlipidemia: Epidemiological studies show that in addition to cardiovascular disease, high blood pressure and diabetes, high blood cholesterol is an important risk factor for dementia, including Alzheimer's.

Smoking: Not only is smoking associated with increased risk of lung cancer, cardiovascular disease and emphysema, but it also adversely affects blood flow to the brain which can lead to cognitive decline and dementia.

Diabetes: Studies have already linked the obesity epidemic to increased risk of high blood pressure, metabolic syndrome, cardiovascular disease, stroke, renal failure, peripheral vascular disease, obstructive sleep apnea, and type 2 diabetes mellitus. In fact, people with this form of insulin resistant diabetes are two-to-three times more likely to face an Alzheimer's diagnosis, in part because of vascular complications.

Diet and Exercise: An overall healthy lifestyle decreases risk of dementia as people age, particularly vascular dementia. Here, the focusis on a low body mass index (25 or lower), healthy diet (based on dairy, meat, fish, fruits, vegetables, cereals, low alcohol, and the ratio of monounsaturated to saturated fat), and aerobic exercise.

Hyperhomocysteinemia: Homocysteine is an amino acid in the blood, and high blood levels are linked to an increased risk of developing Alzheimer disease. People who already exhibit signs of dementia and test positive for high levels of homocysteine are more likely to respond well to large doses of B vitamins. Research has proven that taking large doses of B-complex vitamins can reduce the rate of brain shrinkage by half in elderly people with memory problems and slow the progression of dementia.