Category: Alzheimer’s

Researchers using two brain-imaging technologies have found that apparently normal older individuals with brain deposits of amyloid beta — the primary constituent of the plaques found in the brains of Alzheimer's disease patients — also had changes in brain structure similar to those seen in Alzheimer's patients. Results of the study, which has received early online publication in the Annals of Neurology, may help identify individuals who could be candidates for therapies to prevent the development of dementia.

"Our findings support the theory that Alzheimer's disease begins many years before symptoms appear and that amyloid plaque is an early sign of this process," says Keith Johnson, MD, Massachusetts General Hospital (MGH) Imaging, senior author of the study. "We see that when amyloid deposits are present, even in cognitively normal individuals, the degenerative changes of Alzheimer's are underway. Long-term studies to track these changes and observe how they evolve are ongoing."

Definitive diagnosis of Alzheimer's disease requires finding amyloid plaques and neurofibrillary tangles in the brain at autopsy. In recent years it has been possible to detect amyloid in living brains by PET scanning with an imaging agent known as Pittsburgh Compound B (PiB). Plaques have been observed in the brains of apparently healthy individuals, as well as those with dementia, but whether the presence of plaques indicates the early stages of Alzheimer's disease is not yet known.

High-resolution magnetic resonance imaging studies have identified characteristic changes in brain structure — thinning of key cortical regions and reduced volume of structures such as the hippocampus — in persons with mild cognitive impairment, in individuals known to carry gene mutations that directly cause Alzheimer's disease and in diagnosed Alzheimer's patients. A recent study reported similar brain changes in some cognitively normal elders but did not distinguish those who had amyloid deposits from those who did not.

The current study involved 87 cognitively normal older individuals and 32 patients diagnosed with mild Alzheimer's — matched for age, gender and education — who had enrolled in the long-term Harvard Aging Brain Study. Participants underwent both high-resolution MR imaging of brain structure and PET scanning with PiB to detect amyloid plaques. The results showed that those cognitively normal individuals who had amyloid plaques also had structural changes similar to but less pronounced than the neurodegenerative changes seen in the symptomatic patients. Structural changes were most evident in areas comprising what is called the default network, which is known to be affected early in the course of Alzheimer's disease.

"If amyloidosis — deposits of amyloid plaques — in the brains of clinically normal people is associated with Alzheimer's-like neurodegeneration, then amyloidosis itself may signify 'preclinical' AD," say Johnson, an associate professor of Radiology at Harvard Medical School. "We need to learn more about how long it takes a normal person with amyloid to develop AD, whether there are critical 'second hit' factors that convert amyloidosis to Alzheimer's disease, and if there are measures that can halt the process of neurodegeneration."

Alex Becker, PhD, of MGH Imaging, is lead author of the Annals of Neurology report. Additional co-authors are Jeremy Carmasin, Jacqueline Maye, Bruce Fischl, MD, and Douglas Greve, PhD, MGH Imaging; Trey Hedden, PhD and Deepti Putcha, Martinos Center for Biomedical Imaging at MGH; Dorene Rentz, PsyD, Gad Marshall, MD, and Reisa Sperling, MGH and Brigham and Women's Neurology; Randy Buckner, PhD, MGH Psychiatry; Stephen Salloway, MD, Brown University; and Donald Marks, MD, Tufts University School of Medicine. The study was supported by grants from the National Institutes of Health, Massachusetts Alzheimer's Disease Research Center, Howard Hughes Medical Institute, the Alzheimer's Association and the Charles Farnsworth Trust.

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Journal Reference:

1. J. Alex Becker, Trey Hedden, Jeremy Carmasin, Jacqueline Maye, Dorene M. Rentz, Deepti Putcha, Bruce Fischl, Douglas N. Greve, Gad A. Marshall, Stephen Salloway, Donald Marks, Randy L. Buckner, Reisa A. Sperling, Keith A. Johnson. Amyloid-β associated cortical thinning in clinically normal elderly. Annals of Neurology, 2011; DOI: 10.1002/ana.22333

A drug used to treat asthma has been shown to help reduce the formation of amyloid beta, a peptide in the brain that is implicated in the development of Alzheimer's disease, according to researchers at Temple University's School of Medicine.

The researchers published their findings in the American Journal of Pathology.

In previous studies, the Temple researchers discovered that 5-lipoxygenase, an enzyme long known to exist in the brain, controls the activation state of gamma secretase, another enzyme that is necessary and responsible for the final production of amyloid beta. When produced in excess, amyloid beta causes neuronal death and forms plaques in the brain. The amount of these amyloid plaques in the brain is used as a measurement of the severity of Alzheimer's.

In their current study, led by Domenico Praticò, an associate professor of pharmacology in Temple's School of Medicine, the researchers tested the drug Zileuton, an inhibitor of 5-lipoxygenase typically used to treat asthma, in a transgenic mouse model of Alzheimer's disease. At the end of the treatment they found that this drug, by blocking the 5-lipoxygenase, reduced gamma secretase's production of amyloid beta and the subsequent build up of amyloid plaques in the brain by more than 50 percent.

Praticò said that gamma secretase is present throughout the body and, despite its role in the development of amyloid plaques, plays a significant role in numerous important functions. Direct inhibitors of gamma secretase are known, he said, but blocking the enzyme completely may cause problems such as the development of cancer. Unlike classical gamma secretase inhibitors, Zileuton only modulates the protein expression levels, which keeps some of its vital functions in tact while blocking many of its bad effects, which in this case is the development of the amyloid plaques.

Praticò and his colleagues have begun working with researchers in Temple's Moulder Center for Drug Discovery Research to create more potent inhibitors that can target 5-lipoxygenase in the brain and increase the ability to reduce amyloid plaque formation and the development of Alzheimer's. Because Zileuton is already FDA approved, it is known that 5-lipoxygenase inhibition is an acceptable target that is not associated with overt toxicity and therefore not harmful to patients. The new drug derivative might be expected to advance to clinical trials relatively easily.

"This drug is already on the market and, most importantly, is already FDA-approved, so you don't need to go through an intense drug discovery process," said Praticò. "So we could quickly begin a clinical trial to determine if there is a new application for this drug against a disease where there is currently nothing."

The study was funded by the National Institutes of Health and the Alzheimer's Association.

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Journal Reference:

1. Jin Chua and Domenico Pratic. Pharmacologic Blockade of 5-Lipoxygenase Improves the Amyloidotic Phenotype of an Alzheimer's Disease Transgenic Mouse Model: Involvement of γ-Secretase. The American Journal of Pathology, Volume 178, Issue 4, April 2011, Pages 1762-1769 DOI: 10.1016/j.ajpath.2010.12.032

UCLA researchers have identified a new biomarker that could help them track how effectively the immune system is able to clear the brain of amyloid beta, which forms the plaques considered one of the hallmarks of Alzheimer's disease.

The pilot study, currently published online in the Journal of Alzheimer's Disease, demonstrates how the immune gene MGAT3, which is essential in clearing amyloid beta, is expressed differently in different Alzheimer's patients. The finding may be useful in providing more highly individualized disease prognoses in the future.

It may also help researchers understand which patients will respond to therapy with vitamin D3 and curcumin, a chemical found in turmeric spice, both of which were shown in previous studies by this UCLA research team to help stimulate specific immune system cells to clear amyloid beta in a laboratory test.

Genes hold instructions to create proteins that determine all bodily processes, from moving blood through the veins to stimulating the immune system. The genome of each cell, which is made up of hereditary information, sends out messages to "turn on" various genes according to actual needs.

In earlier research, the UCLA team showed that Alzheimer's patients may have a defect in messaging from the MGAT3 gene, which could help explain why this population cannot effectively clear amyloid beta.

In the current study, researchers used a blood-based biomarker to identify three abnormal ways of processing MGAT3 gene information, which could lead to different disease prognoses.

"Alzheimer's disease robs a person of identity and is a huge burden for families, caregivers and society," said study author Dr. Milan Fiala, a researcher at the David Geffen School of Medicine at UCLA and the Veterans Affairs Greater Los Angeles Healthcare System. "This is one of the first studies demonstrating the role of the immune system in helping track Alzheimer's disease prognosis and the impact of therapies."

For the study, scientists drew blood samples from 20 Alzheimer's disease patients and 20 healthy controls and then isolated critical immune cells from the blood called macrophages, which are responsible for gobbling up amyloid beta and other waste products in the brain and body.

They incubated the immune cells overnight with amyloid beta to test the cells' ability to "turn on" MGAT3. They also added a synthetic form of curcumin to some of the cells to gauge the effect it had on MGAT3 expression and the absorption of amyloid beta.

Based on the results, the researchers identified three groups of Alzheimer's patients.

Type 0 patients: This group had very low expression of MGAT3 and very low absorption rates of amyloid beta.

Type I patients: This group also had low expression of MGAT3 and low amyloid beta absorption rates, but the strength of the MGAT3 message and the absorption of amyloid beta increased when researchers stimulated the macrophages with synthetic curcumin.

Type II patients: This group initially had high amyloid beta absorption rates, but when scientists added synthetic curcumin, MGAT3 expression lessened and absorption was reduced.

In addition, researchers found that for Type I and Type II patients, the clearing of amyloid beta was dependent on vitamin D3, a type of vitamin D that occurs naturally in these cells. When they blocked vitamin D3 use by the macrophages in the laboratory, they found that absorption of amyloid beta suffered.

"These findings demonstrate three very different levels of immunity and possible reactions to natural therapies of vitamin D3 and curcumin," Fiala said. "These differences could point to a new way to track the progression of Alzheimer's disease and the effectiveness of these natural therapies based on an individual patient's immunity."

Fourteen of the 20 Alzheimer's disease patients have been followed for two years, and researchers noted that those who were Type 0 had a worse two-year prognosis regarding the loss of their ability to live independently than the other two types of patients.

Fiala said that 45 percent of the Alzheimer's patients in the study were Type 0 in their MGAT3 immunity expression, while only 10 percent of the healthy controls fell into this patient type. The effects of vitamin D3 and curcumin have not yet been adequately investigated in Type 0 patients.

The healthy control group, made up of university professors, business people and Alzheimer's caregivers, displayed varying results in their ability to absorb amyloid beta. Overall, the university professors demonstrated good to excellent absorption of amyloid beta, and the caregivers displayed lower absorption rates. Fiala notes that the stress of caring for Alzheimer's patients may also affect the caregivers' immunity.

Fiala added that a larger clinical trial needs to be completed to validate findings from this pilot study. He said that while vitamin D3 seems to be helpful to most people, the benefits of synthetic curcumin are more individualized, depending on the patient. In the future, a commercially available test may be able to check for MGAT3 immunity.

During the study, researchers also noted that one Type II patient who underwent hip surgery experienced temporary cognitive dysfunction related to the general surgery anesthesia, which is a phenomenon that can occur. Researchers checked the patient's MGAT3 immunity and found that the patient's ability to clear amyloid beta had declined after surgery but improved in later months, along with cognitive function, possibly due to the vitamin D3 supplementation the patient had undertaken — although this was not a part of the study.

According to Fiala, this might be an example of how vitamin D3 may help improve amyloid beta clearance. He noted that this is early laboratory research and that no dosage of vitamin D or curcumin can be recommended at this time. Larger studies with more patients are planned.

The study was funded by the Alzheimer's Association.

Additional authors include Michelle Mahanian, Mark Rosenthal, Eric Tse, Tiffany Cho and Rachel Weitzman, Department of Medicine, Greater Los Angeles VA Medical Center and David Geffen School of Medicine at UCLA; Matthew T. Mizwicki, Department of Biochemistry, University of California, Riverside; James Sayre, Department of Biostatistics, University of California School of Public Health, Los Angeles and Verna Porter, Department of Neurology, David Geffen School of Medicine at UCLA.

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Journal Reference:

1. Milan Fiala, Michelle Mahanian, Mark Rosenthal, Matthew T. Mizwicki, Eric Tse, Tiffany Cho, James Sayre, Rachel Weitzman, Verna Porter. MGAT3 mRNA: A Biomarker for Prognosis and Therapy of Alzheimer's Disease by Vitamin D and Curcuminoids. Journal of Alzheimer's Disease, March 02, 2011 DOI: 10.3233/JAD-2011-101950

It is no surprise to scientists that the largest social network on the web is called Facebook. Identifying people by their face is fundamental to our social interactions, one of the primary reasons vision researchers are trying to find out how our brain processes facial identity.

In a study recently published in the Journal of Vision, scientists used an original approach — a method that "shakes" the brain gently and repeatedly by making an image appear and disappear at a constant rate — to evaluate its sensitivity to perceiving facial identity. The technique is called steady-state visual evoked potential (SSVEP).

"If we measure global human brain activity when one face is viewed, it cannot be differentiated from brain activity when another face is viewed," said author Bruno Rossion, PhD, a researcher at the Institute of Psychology and Institute of Neuroscience, Université Catholique de Louvain, Belgium. "This is why we relied on a method in which brain activity is compared between repetition of the same face and the presentation of different faces in succession."

During the experiment, 12 participants were presented with a series of faces appearing at a frequency of 3.5 faces per second. The result showed the brain signal at that specific frequency only was much larger when a sequence of different faces was presented at that rate than when an identical face was repeated.

The research team was positively surprised by the resulting large size of the difference between the two conditions, obtained only after one minute and a half of testing, and was equally astonished that the difference in conditions did not exist when the faces were inverted. The study also confirmed that the region for face perception lies primarily in the posterior part of the brain's right hemisphere.

The ability to recognize a face is a common problem in cases of sudden onset of posterior brain damage, neurodegenerative disorders like Alzheimer disease and other forms of dementia and social disorders such as autism. Rossion points out that an advantage of using this highly sensitive SSVEP methods is that it can be used and compared objectively in different human populations — adults, infants, children, neurological patients, people with long-life face recognition impairments or autism — without requiring complex instructions and a long testing duration.

"Face recognition involves the most complex aspects of perception and memory and, for this reason, understanding how it works has large-scale implication," Rossion adds. "Ultimately, through a better understanding of this function, we will make tremendous progress in our understanding of how the brain works in general, develop tools to detect its dysfunction and hopefully help remedy it."

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Journal Reference:

1. B. Rossion, A. Boremanse. Robust sensitivity to facial identity in the right human occipito-temporal cortex as revealed by steady-state visual-evoked potentials. Journal of Vision, 2011; 11 (2): 16 DOI: 10.1167/11.2.16

Shining a laser light on cells and then clicking off the light makes the cells "breathe in" surrounding water, providing a potentially powerful delivery system for chemotherapy drugs, as well as a non-invasive way to target anti-Alzheimer's medicines to the brain.

That's the conclusion of a report in ACS's The Journal of Physical Chemistry Letters.

Andrei Sommer's group, with Emad Aziz and colleagues note using this technique before to force cancer cells to sip up anti-cancer drugs and fluorescent dyes. Pulses of laser light can also change the volume of water inside cells in a way that plumps up wrinkles and makes skin look younger, the researchers found in an earlier study. "The potential applications of the technique range from anticancer strategies to the design principles of nano-steam engines," the report states. Using the so-called Liquidrom ambient approach, developed by Aziz's group, the researchers combined for the first time laser irradiation with soft X-rays obtained from a cyclotron radiation source to explore the molecular structure of interfacial water layers under ambient conditions.

The researchers now showed that laser light aimed at a cell causes the water inside the cell to expand. When the light goes off, the volume of water collapses again, creating a strong pull that also sucks in the water surrounding the cell. This "breathing in and out" of the water molecules can pull chemotherapy drugs into a cell faster than they would normally penetrate, the researchers found. "In other words, we discovered a powerful method to kill cancer cells by pumping anti-cancer drugs into them via laser light," said Sommer.

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Journal Reference:

1. Andrei P. Sommer, Kai F. Hodeck, Dan Zhu, Alexander Kothe, Kathrin M. Lange, Hans-Jörg Fecht, Emad F. Aziz. Breathing Volume into Interfacial Water with Laser Light. The Journal of Physical Chemistry Letters, 2011; : 562 DOI: 10.1021/jz2001503

Cell biologists pondering the death of neurons — brain cells — have now shown that by eliminating one ingredient from the cellular machinery, they prolonged the life of neurons stressed by a pesticide chemical. The finding identifies a potential therapeutic target to slow changes that lead to neurodegenerative disorders such as Parkinson's and Alzheimer's diseases.

The researchers, from The University of Texas Health Science Center San Antonio, found that neurons lacking a substance called caspase-2 were better able to withstand pesticide-induced damage to energy centers known as mitochondria.

Master switch

Caspase-2 appears to be a master switch that can trigger either cell death or survival depending on the amount of cellular damage, the team found. Neurons that lacked caspase-2 showed an increase in protective activities, including the efficient breakdown of obsolete or used proteins. This process, called autophagy, delays cell death.

"This research shows, for the first time, that in the absence of caspase-2 neurons increase autophagy to survive," said study co-author Marisa Lopez-Cruzan, Ph.D., investigator in the cellular and structural biology department at the Health Science Center.

Role of energy centers

Evidence suggests that mitochondrial dysfunction plays an important role in neuronal death in conditions such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) and Huntington's disease.

"Identifying initiators in the cell death process is important for determining therapeutic approaches to provide the maximum protection of neurons during neurodegenerative conditions," said senior author Brian Herman, Ph.D., vice president for research and professor of cellular and structural biology at the Health Science Center.

Young adult mice

The team studied neurons from young adult mice. This was intended to model the early changes that take place in neurodegenerative diseases.

The research is in the March 11 issue of the Journal of Biological Chemistry.

Dr. Lopez-Cruzan, director of Dr. Herman's laboratory, came up with the idea that caspase-2 protects cells from mitochondrial stress. Meenakshi Tiwari, Ph.D., postdoctoral fellow, expanded upon the initial work and is first author of the paper.

The work was supported by the National Institute on Aging and is part of a second National Institutes of Health MERIT award to Dr. Herman.

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Journal Reference:

1. M. Tiwari, M. Lopez-Cruzan, W. W. Morgan, B. Herman. Loss of Caspase-2-dependent Apoptosis Induces Autophagy after Mitochondrial Oxidative Stress in Primary Cultures of Young Adult Cortical Neurons. Journal of Biological Chemistry, 2011; 286 (10): 8493 DOI: 10.1074/jbc.M110.163824

A team of scientists at the University of California, San Francisco (UCSF) has developed a new model for how inherited genes contribute to a common but untreatable and incurable neurodegenerative disease. The disease, frontotemporal lobar degeneration, is the second most common cause of dementia before age 65, after Alzheimer's disease.

Based on experiments in worms and mice, the UCSF team's work explains in part why the brain deteriorates in frontotemporal lobar degeneration, which may have implications for the understanding of several neurodegenerative disorders, including Alzheimer's and Parkinson's, as well as different forms of cancer.

"If our findings hold up," said Aimee Kao, an assistant adjunct professor in the Department of Neurology at UCSF, "they may suggest a new way to think about how to treat neurodegenerative diseases." Kao is first author on the study, led by Cynthia Kenyon, PhD, a professor of biochemistry and biophysics at UCSF and director of UCSF's Larry L. Hillblom Center for the Biology of Aging.

Disease Caused By Loss of Neurons

Generally scientists have blamed the mental decline associated with neurodegenerative diseases on the loss of neurons associated with the accumulation of insoluble protein in the brain — sticky plaques that interfere with and ultimately kill the brain's neurons.

In frontotemporal lobar degeneration, this loss of neurons happens in the frontal lobe — the part of the brain involved in such higher mental functions as art appreciation and emotional empathy. People with this disease can suffer from progressive difficulties with language, undergo personality and behavioral changes, and usually die within a decade of diagnosis.

The new work suggests that the accumulation of insoluble protein may not be the only cause of cognitive decline in frontotemporal lobar degeneration. Another mechanism could involve how the body deals with injured neurons in the brain.

A significant percentage of patients with frontotemporal lobar degeneration have mutations in the gene that produces a protein called progranulin. Scientists have known that people with these genetic mutations produce too little progranulin protein, but up to now it was unclear what role this played in disease development.

Now the work of the UCSF team suggests that progranulin regulates the speed with which dying cells are cleared.

The Speed of Brain Cell Death

Cells in the brain — as in the rest of the human body — die through a process known as apoptosis, or programmed cell death. In a sense, apoptosis is the cellular equivalent of a controlled implosion.

Rather than explode a condemned building in a crowded city and scatter its dust and rubble across surrounding neighborhoods, implosions minimize the fallout. Likewise, apoptosis of neurons prevents them from exploding and damaging the surrounding brain tissue, instead withering them away in protective fashion.

In their paper, Kao, Kenyon and their colleagues show that progranulin normally slows the process of apoptosis. In its absence, however, apoptotic cells are cleared more quickly, probably by neighboring cells, which engulf them.

Using a sophisticated microscope, the UCSF team showed that mutations to the progranulin gene caused cells in the microscopic roundworm C.elegans that were undergoing this programmed cell death to be cleared in about half the time, as compared to normal worms. They also found something similar in engulfing cells called macrophages that were taken from mice. When these cells lacked progranulin, they engulfed other, dying cells even faster.

"In both worms and cultured macrophages," Kao said, "the absence of progranulin cause more rapid clearance of dying cells."

Based on these findings, the team hypothesized that lack of progranulin may affect the ability of cells to recover from an injury. When individual cells are injured, the damage may or may not be fatal. Given enough time, the damaged cell could recover. However, if local engulfing cells are over-eager to remove the damaged cell, the cell may have too little time to recover. If this scenario occurred in the brain, then over time, the cumulative cell loss could lead to neurodegenerative disease.

These findings also have implications in the treatment of cancer, since some aggressive forms of breast, brain and bladder cancer produce increased levels of progranulin.

"These cancers may be using progranulin as a sort of 'invisibility shield' to hide from the surveillance of the immune system," Kao said. "Thus, progranulin could represent a druggable target in both neurodegeneration and some forms of cancer."

The study was published online in the journal Proceedings of the National Academy of Sciences.

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Journal Reference:

1. A. W. Kao, R. J. Eisenhut, L. H. Martens, A. Nakamura, A. Huang, J. A. Bagley, P. Zhou, A. de Luis, L. J. Neukomm, J. Cabello, R. V. Farese, C. Kenyon. A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1100650108

Neurodegenerative diseases like Alzheimer's and Parkinson's are partly attributable to brain inflammation. Researchers at Karolinska Institutet now demonstrate in a paper published in Nature that a well-known family of enzymes can prevent the inflammation and thus constitute a potential target for drugs.

Research suggests that microglial cells — the nerve system's primary immune cells — play a critical part in neurodegenerative diseases, such as Alzheimer's and Parkinson's. The over-activation of these cells in the brain can cause inflammation, resulting in neuronal death.

Scientists at Karolinska Institutet and Seville University, working in collaboration with colleagues at Lund University, have now found a way to prevent the activation of the microglia and consequently the inflammation they cause. The key is the blocking of enzymes called caspases, which the team has shown control microglial activation.

"The caspases are a group of enzymes known for causing cell death," says Associate Professor Bertrand Joseph, who headed the study. "That they also serve as signal molecules that govern that activity of other cells was an unexpected discovery that gives them an entirely new physiological role."

By studying cell cultures and mice, the researchers show that certain caspases (3, 7 and 8) activate rather than kill microglial cells, which triggers an inflammatory reaction. Mice given caspase inhibitors displayed fewer activated microglia and less inflammation and cell death in the surrounding neurons.

They also examined samples from deceased Alzheimer's and Parkinson's patients and discovered a higher incidence of activated caspases in their microglial cells.

"We'll now be examining whether the substances that inhibit the caspases can be candidates for useful drugs in the treatment of certain neurological diseases," says Dr Joseph.

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Journal Reference:

1. Miguel A. Burguillos, Tomas Deierborg, Edel Kavanagh, Annette Persson, Nabil Hajji, Albert Garcia-Quintanilla, Josefina Cano, Patrik Brundin, Elisabet Englund, Jose L. Venero, Bertrand Joseph. Caspase signalling controls microglia activation and neurotoxicity. Nature, 2011; DOI: 10.1038/nature09788

A devastating vascular disorder of the brain called CADASIL, which strikes young adults and leads to early dementia, often is misdiagnosed as multiple sclerosis, Loyola University Health System researchers report.

CADASIL occurs when a thickening of blood vessel walls blocks blood flow in the brain. Migraine headaches are an early symptom of this condition, which progresses to strokes and mini-strokes, depression, apathy, motor disability and executive dysfunction (an inability to plan and organize everyday activities.) The final symptom is dementia.

CADASIL is caused by mutations of a single gene called NOTCH 3. If an individual carries the mutated gene, he or she inevitably will develop the disease, and there's a 50 percent chance that each of the individual's children will inherit the mutation and the disease.

Researchers conducted an exhaustive series of genetic, physical and psychological tests and exams on 11 CADASIL patients. "We found a delay in the detection of this pathology and previous diagnostic errors in some patients and their relatives," researchers wrote. "Multiple sclerosis was the most frequent misdiagnosis."

The study is published in Revista de Neurologia (Journal of Neurology) in Spain.

The study was a subset of a larger study to determine whether the Alzheimer's disease drug donepezil (trade name, Aricept®) can help in CADASIL patients. This larger study found there generally was no benefit to the drug.

CADASIL stands for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. It was realistically portrayed by one of the main characters in the critically acclaimed 2004 movie "The Sea Inside."

"It is a terrible disease that runs in families, and, unfortunately, we as yet don't have effective treatments," said Dr. José Biller, senior author of the study and chairman of the Department of Neurology of Loyola University Chicago Stritch School of Medicine.

There are several reasons why CADASIL is misdiagnosed as MS. Both diseases tend to strike young adults. There are similarities in brain MRIs, and both diseases can cause focal neurologic signs and symptoms.

While there currently are no effective treatments, researchers are making significant progress in better understanding CADASIL, Biller said. "The field is exploding, and there is hope down the road that there will be new treatments for these patients," Biller said.

Other authors of the study are Dr. Sarkis Morales-Vidal; Christopher Randolph, PhD; Linda Chadwick, BSN, RN; and first author Dr. Rocío Vázquez do Campo.

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Journal Reference:

1. R. Vázquez do Campo, S. Morales-Vidal, C. Randolph, L. Chadwick, J. Biller. CADASIL: a case series of 11 patients. Revista de Neurologia, 2011; 52: 202-210 

 Despite international variation in prevalence rates of bipolar spectrum disorder, the severity and associated disorders are similar and treatment needs are often unmet, especially in low-income countries, according to a report in the March issue of Archives of General Psychiatry.

"Bipolar disorder (BP) is responsible for the loss of more disability-adjusted life-years than all forms of cancer or major neurologic conditions such as epilepsy and Alzheimer disease, primarily because of its early onset and chronicity across the life span," the authors write as background information in the article. "Few prior international studies of BP have included information on severity or disability associated with this condition."

Kathleen R. Merikangas, Ph.D., of the National Institute of Mental Health, Genetic Epidemiology Research Branch, Bethesda, Md., and colleagues conducted cross-sectional, face-to-face, household surveys to describe the prevalence, symptom severity, patterns of co-existing illnesses, and patterns of service utilization for bipolar spectrum disorder (BPS) in the World Health Organization World Mental Health Survey Initiative. Surveys of 61,392 community adults were carried out in the United States, Mexico, Brazil, Colombia, Bulgaria, Romania, China, India, Japan, Lebanon, and New Zealand.

"In a combined sample of 61,392 adults from 11 countries, the total lifetime prevalences were 0.6 percent for BP-I, 0.4 percent for BP-II, and 1.4 percent for sub-threshold BP, yielding a total BPS prevalence estimate of 2.4 percent worldwide," the authors report.

The severity of symptoms was greater for depressive than manic episodes. Approximately 74.0 percent of respondents with depression and 50.9 percent of respondents with mania reported severe role impairment.

Three-quarters of those with BPS also met criteria for at least one other disorder. Anxiety disorders, especially panic attacks, were the most common comorbid condition.

The surveys found that treatment needs for BPS are often unmet. "Less than half of those with lifetime BPS received mental health treatment, particularly in low-income countries, where only 25.2 percent reported contact with the mental health system," the authors write.

The authors believe their findings document the magnitude and major impact of BP worldwide and underscore the urgent need for increased recognition and treatment facilitation.

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Journal Reference:

1. K. R. Merikangas, R. Jin, J.-P. He, R. C. Kessler, S. Lee, N. A. Sampson, M. C. Viana, L. H. Andrade, C. Hu, E. G. Karam, M. Ladea, M. E. Medina-Mora, Y. Ono, J. Posada-Villa, R. Sagar, J. E. Wells, Z. Zarkov. Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative. Archives of General Psychiatry, 2011; 68 (3): 241 DOI: 10.1001/archgenpsychiatry.2011.12