Feeds:
Posts
Comments

Posts Tagged ‘Alzheimers Disease’

MRI Cortical Thickness Biomarker Predicts AD-like CSF and Cognitive Decline in Normal Adults

Posted in Alzheimer's Disease, Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Etiology, Health Economics and Outcomes Research, tagged , , , , , , , , , on July 18, 2012| 2 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

MRI cortical thickness biomarker predicts AD-like CSF and cognitive decline in normal adults

Bradford C. Dickerson, MD and David A. Wolk, MD On behalf of the Alzheimer’s Disease Neuroimaging Initiative

Author Affiliations

From the Frontotemporal Dementia Unit, Department of Neurology, Massachusetts Alzheimer’s Disease Research Center, and Athinoula A. Martinos Center for Biomedical Imaging (B.C.D.), Massachusetts General Hospital and Harvard Medical School, Boston; and Department of Neurology, Alzheimer’s Disease Core Center, and Penn Memory Center (D.A.W.), University of Pennsylvania, Philadelphia.

Correspondence & reprint requests to Dr. Dickerson: bradd@nmr.mgh.harvard.edu

ABSTRACT

Objective: New preclinical Alzheimer disease (AD) diagnostic criteria have been developed using biomarkers in cognitively normal (CN) adults. We implemented these criteria using an MRI biomarker previously associated with AD dementia, testing the hypothesis that individuals at high risk for preclinical AD would be at elevated risk for cognitive decline.

Methods: The Alzheimer’s Disease Neuroimaging Initiative database was interrogated for CN individuals. MRI data were processed using a published set of a priori regions of interest to derive a single measure known as the AD signature (ADsig). Each individual was classified as ADsig-low (≥1 SD below the mean: high risk for preclinical AD), ADsig-average (within 1 SD of mean), or ADsig-high (≥1 SD above mean). A 3-year cognitive decline outcome was defined a priori using change in Clinical Dementia Rating sum of boxes and selected neuropsychological measures.

Results: Individuals at high risk for preclinical AD were more likely to experience cognitive decline, which developed in 21% compared with 7% of ADsig-average and 0% of ADsig-high groups (p = 0.03). Logistic regression demonstrated that every 1 SD of cortical thinning was associated with a nearly tripled risk of cognitive decline (p = 0.02). Of those for whom baseline CSF data were available, 60% of the high risk for preclinical AD group had CSF characteristics consistent with AD while 36% of the ADsig-average and 19% of the ADsig-high groups had such CSF characteristics (p = 0.1).

Conclusions: This approach to the detection of individuals at high risk for preclinical AD—identified in single CN individuals using this quantitative ADsig MRI biomarker—may provide investigators with a population enriched for AD pathobiology and with a relatively high likelihood of imminent cognitive decline consistent with prodromal AD.

 

Copyright © 2011 by AAN Enterprises, Inc.

http://www.neurology.org/content/early/2011/12/21/WNL.0b013e31823efc6c.abstract

 

 

Read Full Post »

THREE new drugs for Alzheimer’s Disease: Two Antibodies against AMYLOID and one IV Immune Globulin

Posted in Alzheimer's Disease, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Etiology, Health Economics and Outcomes Research, Innovations in Neurophysiology & Neuropsychology, International Global Work in Pharmaceutical, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy and Cell Activity, Population Health Management, Genetics & Pharmaceutical, tagged , , , , , , , on July 17, 2012| 3 Comments »

 

Reporter: Aviva Lev-Ari, PhD, RN

A pivotal study of a third drug will end later this year, and results from a small, early test of it will be reported next week at an Alzheimer’s conference in Vancouver, British Columbia.

These three treatments are practically the “last men standing” in late-stage trials, after more than a decade of failed efforts to develop a drug to halt the mind-robbing disease. Current medicines such as Aricept and Namenda just temporarily ease symptoms. There is no known cure.

Experts say that if these fail, drug companies may pull out of the field in frustration, leaving little hope for the millions of people with the disease. An estimated 35 million people worldwide have dementia, which includes Alzheimer’s. In the U.S., experts say about 5 million have Alzheimer’s.

http://www.timesleader.com/stories/Last-drugs-standing,176933#ixzz20uq13yCg

http://www.timesleader.com/stories/Last-drugs-standing,176933

The three drugs and their developers are:

• Bapineuzumab (bap-ih-NOOZ-uh-mab), by Pfizer Inc. and Johnson & Johnson’s Janssen Alzheimer Immunotherapy unit.

• Solanezumab (sol-ah-NAYZ-uh-mab), by Eli Lilly & Co.- Antibody

• Gammagard, by Baxter International Inc. – IV Immune Globulin

http://www.timesleader.com/stories/Last-drugs-standing,176933#ixzz20ulwcTEP

All are given as periodic intravenous infusions; some companies are trying to reformulate them so they could be given as shots. If a major study shows that one of the drugs works, there will be a huge effort to make it more convenient and practical, Thies predicted.

Still, it would probably be very expensive.

The first two on the list are lab-made, single antibodies against amyloid. Gammagard is intravenous immune globulin, or IVIG — multiple, natural antibodies culled from blood. Half a dozen companies already sell IVIG to treat immune system and blood disorders. It takes 130 plasma donations to make enough to treat one patient for a year.

Treating Alzheimer’s with IVIG would cost $2,000 to $5,000 every two weeks, depending on the patient’s weight, said Dr. Norman Relkin, head of a memory disorders program at New York-Presbyterian Hospital/Weill Cornell Medical Center. He consults for some drugmakers and has patents for tests that measure amyloid.

http://www.timesleader.com/stories/Last-drugs-standing,176933#ixzz20uoQU79G

Concern arose when an earlier study found possible bleeding or brain abnormalities in up to 10 percent of patients on the drug. However, most had no symptoms and were able to resume treatment after a brief break, Yuen said. In fact, some researchers think these changes might be a sign the drug is working to clear the amyloid plaque.

The fact that independent monitors have not stopped the new studies has made Dr. Reisa Sperling optimistic the drug will prove to be safe. Director of the Alzheimer’s center at Brigham and Women’s Hospital in Boston, she has consulted for Janssen and Pfizer and enrolled patients in the studies.

Relkin, who is leading the Gammagard study, said that if all three of these drugs fail, “we’re in trouble.” There hasn’t been a new drug even to help symptoms in nine years, he said.

Petersen of the Mayo Clinic agrees.

“If they’re dead-flat negative, the impact on the field and the implication for Big Pharma could be huge,” he said. Companies “may bail” from the field entirely. “They may just say, ‘This nut is too tough to crack.”’

http://www.timesleader.com/stories/Last-drugs-standing,176933#ixzz20upXXNJ6

 

Read Full Post »

New ADNI Project to Perform Whole-genome Sequencing of Alzheimer’s Patients,

Posted in Alzheimer's Disease, Cell Biology, Signaling & Cell Circuits, Etiology, tagged , , , , , , , , , on July 3, 2012| 1 Comment »

Reporter: Aviva Lev-Ari, PhD, RN

NEW YORK (GenomeWeb News) – The Alzheimer’s Association and the Brin Wojcicki Foundation yesterday announced a partnership aimed at obtaining the whole-genome sequences of people with AD.

The Alzheimer’s Association and the Wojcicki Foundation are funding the project, which seeks to perform whole-genome sequencing on more than 800 people enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), generating at least 165 terabytes of new genetic data.

Once the genomes are sequenced, the raw data will be made available to scientists worldwide to investigate new targets for risk assessment and new therapies and to gain new understanding into the disease, which afflicts an estimated 5.4 million Americans.

“The current ADNI database already includes detailed, long-term assessments of neuropsychological measures, standardized structural and functional imaging, and precise biomarker measures from blood and spinal fluid,” said Robert Green of Brigham and Women’s Hospital and Harvard Medical School, and who will coordinate the sequencing work within ADNI. “Adding whole-genome sequences to this rich repository will allow investigators all over the world to discover new associations between these disease features and rare genetic variants, offering new clues to diagnosis and treatment.”

The new project is an extension of ADNI, a public-private research project launched in 2004 with the goal of identifying biomarkers of AD in body fluids, structural changes in the brain, and measures of memory, in order to improve early diagnosis of the disease and develop better treatments. The National Institutes of Health leads ADNI and private sector support is provided through the Foundation for NIH.

ADNI is led by principal investigator Michael Weiner from the University of California, San Francisco and the San Francisco VA Medical Center. Green will collaborate with Arthur Toga of the University of California, Los Angeles, and Andrew Saykin of Indiana University on the sequencing work.

The genome sequencing will be done at Illumina.

http://www.genomeweb.com//node/1099936?hq_e=el&hq_m=1303351&hq_l=3&hq_v=e1df6f3681

Read Full Post »

A plausible Low-cost Non-invasive Diagnostic Tool to Diagnose the Amyloid of Light Chain Composition

Posted in Alzheimer's Disease, Bone Disease and Musculoskeletal Disease, tagged , , , , , , , on June 28, 2012| 1 Comment »

Curated by: Dr. Venkat S. Karra, Ph.D.

In our recent article we mentioned about the amyloidosis, most importantly the most common form of amlyodosis – Primary Amyloidosis (AL).

Primary amyloidosis (AL) is an acquired plasma cell disorder in which a monoclonal immunoglobulin light chain is produced in the bone marrow and usually found in the blood or urine. AL amyloidosis occasionally occurs with multiple myeloma. The amyloid fibrils in this type of amyloidosis are made up of immunoglobulin light chain proteins (kappa or lambda).

Amyloidosis can only be diagnosed by a positive biopsy (i.e., an identification of the amyloid deposits in a piece of tissue). Initial biopsies are most commonly obtained from the abdominal fat.

If amyloid is suspected in other organs, however, a biopsy may be needed from these specific areas. If amyloid is present in a tissue biopsy, further tests can be done to determine the type of the amyloid.

The Amyloid Treatment & Research Program (ATRP) at Boston Medical Center (BMC) is an international referral center that treats amyloidosis with stem cell transplantation.

Last week researchers at Mayo Clinic have used urinary exosomes as a non-invasive diagnostic tool that will offer a snapshot of what is occurring in kidney tissue.

Urinary exosomes are rapidly becoming a powerful tool in the study of renal disease.

English: Urinary system

Already proteomics studies are looking into ways of using urinary exosome to diagnose genetic diseases and characterize disease biomarkers.

The urinary exosomes are excreted from every renal epithelial cells (from the glomerular podocytes to the urinary epithelial cells lining the urinary drainage system) provides us with an opportunity to study proteins once were either difficult or impossible to reach.

With this understanding the researchers undertook this study to evaluate the possible differences among urinary exosomes from patients with different plasma cells dyscrasias. This study suggests that urinary exosomes may be an excellent non-invasive tool for identifying patients with AL amyloidosis because high molecular weight light chain oligomers were found only in patients with AL.

The oligomeric light chain species captured in the urinary exosomes may represent the initial steps of amyloidogenesis. The potential of urinary exosomes in AL is tremendous and deserves further studies. When combined with mass spectrometry and other proteomics techniques, urinary exosomes represent tremendous potential to increase our understanding of amyloidogenesis.

Authors believe that this is the first report of the use of urinary exosome in the study of patients with plasma cell dyscrasias, specifically patients with AL amyloidosis.

References:

1. Amyloidosis: http://pharmaceuticalintelligence.com/2012/06/04/amyloidosis/

2. Alzheimers Disease: http://pharmaceuticalintelligence.com/category/alzheimers-disease-2/

3. Prospects for urinary proteomics: exosomes as a source of urinary biomarkers

4. Source article: Differences in Immunoglobulin Light Chain Species Found in Urinary Exosomes in Light Chain Amyloidosis (AL)

5.  Exosomal Fetuin-A identified by proteomics: a novel urinary biomarker for detecting acute kidney injury.

 6. Characterization of PKD protein-positive exosome-like vesicles.

7. Large-scale proteomics and phosphoproteomics of urinary exosomes.

8. Proteomic analysis of urinary exosomes from patients of early IgA nephropathy and thin basement membrane nephropathy.

Read Full Post »

New Bio-markers in Alzheimer’s & Stress Induced Changes in the Brains of Alzheimer’s Patients

Posted in Alzheimer's Disease, Etiology, Uncategorized, tagged , , , , , , , , on June 26, 2012| 5 Comments »

Curated by: Dr. Venkat S. Karra, Ph.D

Auguste Deter. Alois Alzheimer's patient in No...

Nuerodegenertive disease – Alzheimer’s – is presumed to be caused by the accumulation of β-amyloid.

The diagnosis of Alzheimer’s disease focuses on

β-amyloid protein and

tau protein

Though much attention is on radiolabeled markers, imaging βamyloid is problematic because many cognitively normal elderly have large amounts of β-amyloid in their brain, and appear as “positives” in the imaging tests.

At the same time therapeutic approaches for Alzheimer’s disease have not been focused much on the process of producing a neurofibrillary tangle composed on tau protein.

Various brain sections showing tau protein

Various brain sections showing tau protein (Photo credit: WBUR)

Now the BUSM researchers identified a new group of proteins, termed RNA-binding proteins, which accumulate in the brains of patients with Alzheimer’s disease, and are present at much lower levels in subjects who are cognitively intact.

The researchers believe this work opens up novel approaches to diagnose and stage the likelihood of progression by quantifying the levels of these RNA-binding protein biomarkers that accumulate in the brains of Alzheimer patients.

The group found two different proteins, both of which show striking patterns of accumulation. “Proteins such as TIA-1 and TTP, accumulate in neurons that accumulate tau protein, and co-localize with neurofibrillary tangles. These proteins also bind to tau, and so might participate in the disease process,” explained senior author Benjamin Wolozin, MD, PhD, a professor in the departments of pharmacology and neurology at BUSM.

“A different RNA binding protein, G3BP, accumulates primarily in neurons that do not accumulate pathological tau protein.

This observation is striking because it shows that neurons lacking tau aggregates (and neurofibrillary tangles) are also affected by the disease process,” he added.

Wolozin’s group also pursued the observation that some of the RNA binding proteins bind to tau protein, and tested whether one of these proteins, TIA-1, might contribute to the disease process.

‘Stress’ induced aggregation of RNA-binding proteins

Previously, scientists like Tara Vanderweyde et. al., have demonstrated that TIA-1 spontaneously aggregates in response to stress as a normal part of the stress response. They examined the relationship between Stress Granules (SGs) and neuropathology in brain tissue from P301L Tau transgenic mice, as well as in cases of Alzheimer’s disease and FTDP-17.

Stress Granules (SGs) are ‘Stress’ induced aggregation of RNA-binding proteins.

The pattern of SG pathology differed dramatically based on the RNA-binding protein examined. SGs positive for T-cell intracellular antigen-1 (TIA-1) or tristetraprolin (TTP) initially did not co-localize with tau pathology, but then merge with tau inclusions as disease severity increases. In contrast, G3BP (ras GAP-binding protein) identifies a novel type of molecular pathology that shows increasing accumulation in neurons with increasing disease severity, but often is not associated with classic markers of tau pathology. TIA-1 and TTP both bind phospho-tau, and TIA-1 overexpression induces formation of inclusions containing phospho-tau. These data suggest that SG formation might stimulate tau pathophysiology.

Thus, study of RNA-binding proteins and SG biology highlights novel pathways interacting with the pathophysiology of AD.

With this understanding, Wolozin and his colleagues hypothesize that since TIA-1 binds tau, it might stimulate tau aggregation during the stress response. They introduced TIA-1 into neurons with tau protein, and subjected the neurons to stress. Consistent with their hypothesis, tau spontaneously aggregated in the presence of TIA-1, but not in the absence. Thus, the group has potentially identified an entirely novel mechanism to induce tau aggregates de novo.

In future work, the group hopes to use this novel finding to understand how neurofibrillary tangles for in Alzheimer’s disease and to screen for novel compounds that might inhibit the progression of Alzheimer’s disease.

They believe that it may open up novel approaches to diagnose and stage the progression likelihood of the disease in Alzheimer patients.

Source & Related articles

Curated by: Dr. Venkat S. Karra, Ph.D

Read Full Post »

‘B’exarotene to become double ‘B’lock-buster – What are the chances?

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical R&D Investment, Uncategorized, tagged , , , , , on June 7, 2012| Leave a Comment »

A recent study by researchers at Case Western Reserve University is likely to promise a new life to Alzheimer’s victims and their loved ones.

Alzheimer’s disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). Oral administration of the retinoid X receptors (RXRs) agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function.

Thus, researchers hope and believe that, RXR activation stimulates physiological Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits in humans as well.

Bexarotene has been approved for the treatment of cancer by the U.S. Food and Drug Administration for more than a decade. It has a good safety and side-effect profile, which researchers hope will help speed the transition to clinical trials of the drug.

source

Reported by: Dr. V. S. Karra, Ph.D

Read Full Post »

How to deal with the most common form of inherited amyloidoses?

Posted in Alzheimer's Disease, Biological Networks, Gene Regulation and Evolution, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Etiology, Genome Biology, International Global Work in Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacotherapy of Cardiovascular Disease, Uncategorized, tagged , , , , , , , on June 5, 2012| 9 Comments »

In our recent article on “Amyloidosis” we discussed about its causes and forms. One such form is familial amyloidosis (ATTR) a most common form of inherited amyloidoses.

Transthyretin protein structure

Transthyretin protein structure (Photo credit: Wikipedia)

ATTR is caused by a mutation in the transthyretin (TTR) gene that produces abnormal transthyretin protein which deposits as amyloid fibrils.

Symptoms of disease are usually:

Neuropathy (numbness and tingling in the arms and legs, dizziness upon standing, and alternating constipation and diarrhea), and

Cardiomyopathy and occur in mid to late life.

The standard treatment is liver transplantation since the transthyretin protein which causes familial amyloidosis is made in the liver, replacing this organ removes the source of mutant protein production. A new liver will make only normal transthyretin.

It is known that the transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by above mentioned progressive neuropathy and/or cardiomyopathy. The early onset TTR amyloidoses are caused by inherited TTR mutations that weaken the tetramers’ ability to stick together, producing monomers which are  more likely to aggregate into amyloids and other aggregate structures.

Transthyretin (TTR) is a tetrameric protein involved in the transport of thyroxine and the vitamin A–retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation.

Scientists from The Scripps Research Institute and Pfizer Inc. have published a new study showing how this type of amyloidosis can be inhibited. A new drug called tafamidis (Vyndaqel®)) has been developed to treat this deadly nerve disease caused by transthyretin (TTR) amyloid fibril formation, or the accumulation of abnormal assemblies of the TTR protein. Researchers have designed tafamidis to grab either of those thyroxine-binding sites, in a way that bridges the seam and helps keep the tetramer from coming apart.

Tafamidis binds to the natural, functional TTR structure (mutant and wild type), in a way that prevents it from deviating from this natural, functional form into the amyloid state. TTR’s natural, functional form is a “tetramer”made from four copies of the protein. Amyloidosis occurs when these tetramers come apart and the individual TTR proteins (“monomers”) undergo shape changes enabling them to misassemble into dysfunctional amyloid aggregates. Included in the TTR aggregate distribution are amyloid fibrils—protein stacks made from millions of TTR monomers—although researchers suspect that smaller, shorter-lived pre-amyloid aggregates do more direct damage to nerve cells and nerve fibers.

Tafamidis  treats ATTR by reducing the rate of amyloid formation, and clinical trials have shown that it delays the typical progression of nerve destruction in polyneuropathy patients.

This drug is approved for use in Europe and currently under review by the US Food and Drug Administration (FDA), and it is the first medication approved by a major regulatory agency to treat an amyloid disease, a class of conditions that include Alzheimer’s.

 Source:

http://www.scripps.edu/newsandviews/e_20120604/tafamidis.html

http://www.pnas.org/content/suppl/2012/05/29/1121005109.DCSupplemental/sapp.pdf

Curated by: Dr. Venkat S. Karra, Ph.D.

Read Full Post »

Amyloidosis

Posted in Bone Disease and Musculoskeletal Disease, Cell Biology, Signaling & Cell Circuits, Genome Biology, Infectious Disease & New Antibiotic Targets, International Global Work in Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Uncategorized, tagged , , , , , , , , , , , , on June 4, 2012| 4 Comments »

β-amyloid fibrils.

β-amyloid fibrils. (Photo credit: Wikipedia)

Extracellular deposition of insoluble fibrillar proteins in tissues and organs lead to a condition known as amyloidosis which is thought to be caused by misfolding of proteins. There are several types of amyloidosis, but the unifying feature of the amyloidoses is that the deposits share a common ß-pleated sheet structural conformation that confers unique staining properties.

There are several types of amyloidosis and the most common form is the primary amyloidosis (AL) for amyloid of light chain composition. Symptoms can occur in any organ of the body and the organs most often involved include the heart, kidneys, nervous system, and gastrointestinal tract.

Amyloid deposits in these organs can cause

shortness of breath,

fatigue,

edema (swelling of ankles and legs),

dizziness upon standing,

a feeling of fullness in the stomach (especially after eating),

diarrhea,

weight loss,

enlarged tongue,

numbness of the legs and arms,

protein in the urine (proteinurea) and

enlarged liver (hepatomegaly).

Primary amyloidosis (AL) is an acquired plasma cell disorder in which a monoclonal immunoglobulin light chain is produced in the bone marrow and usually found in the blood or urine. AL amyloidosis occasionally occurs with multiple myeloma. The amyloid fibrils in this type of amyloidosis are made up of immunoglobulin light chain proteins (kappa or lambda).

Amyloidosis caused by infection or inflammation is known as Secondary Amyloidosis (also known as AA amyloidosis) in which elevation of an acute phase protein, SAA, a portion of which (AA protein) deposits as amyloid fibrils. AA amyloidosis usually begins as disease in the kidneys, but other organs can be affected, and may cause protein in the urine, edema, and fatigue.

Medical or surgical treatment of the underlying chronic infection or inflammatory disease can slow down or stop the progression of this type of amyloid where as in case of AL chemotherapy is the standard practice.

Other forms of amyloidosis are familial amyloidosis (ATTR) a most common form of inherited amyloidoses caused by a mutation in the transthyretin (TTR) gene that produces abnormal transthyretin protein which deposits as amyloid fibrils. Symptoms of disease are usually neuropathy (numbness and tingling in the arms and legs, dizziness upon standing, and diarrhea) and cardiomyopathy and occur in mid to late life. The standard treatment is liver transplantation since the transthyretin protein which causes familial amyloidosis is made in the liver, replacing this organ removes the source of mutant protein production. A new liver will make only normal transthyretin. Each family has its own pattern of organ involvement and associated symptoms and the mode of transmission is autosomal dominant.

Other rare forms of inherited amyloidosis include apolipoprotein A-I (AApoAI), apolipoprotein A-II (AApoAII) gelsolin (AGel), fibrinogen (AFib), and lysozyme (ALys).

Beta-2 microglobulin amyloidosis is caused by chronic renal failure and often occurs in patients who are on dialysis for many years. Amyloid deposits are made of the beta-2 microglobulin protein that accumulated in tissues, particularly around joints, when it cannot be excreted by the kidney because of renal failure.

There are many types of localized amyloidoses. The most common and best known is Alzheimer’s disease.

Localized amyloid deposits in the airway (trachea or bronchus), eye, or urinary bladder are made up of light chain proteins, similar to those in AL amyloidosis. However, in localized amyloidosis the abnormal plasma cells producing the amyloid light chains are in the tissues, not in the bone marrow. Other localized types of amyloidosis are associated with hormone proteins, aging, or specific areas of the body, and have not been found to develop into systemic amyloidosis

Diagnosis of this disease is sometimes difficult as many of the sysmptoms are general and can occur in other diseases. Symptoms in each patient depend on the type of amyloidosis and on the type of involved organ systems.

Amyloidosis can only be diagnosed by a positive biopsy (i.e., an identification of the amyloid deposits in a piece of tissue). Initial biopsies are most commonly obtained from the abdominal fat. image from BMCIf amyloid is suspected in other organs, however, a biopsy may be needed from these specific areas. Tissue biopsies must be stained properly with Congo red, a dye which will color the amyloid if it is present and cause it to have a unique appearance when viewed under a special microscope. If amyloid is present in a tissue biopsy, further tests can be done to determine the type of the amyloid.

The Amyloid Treatment & Research Program (ATRP) at Boston Medical Center (BMC) is an international referral center that treats amyloidosis with stem cell transplantation. The Program offers a multi-disciplinary approach to diagnosis and treatment of this multi-organ disorder. Amyloid doctors specializing in cardiology, pulmonary, nephrology, gastroenterology, neurology, and other systems participate in patient evaluation and care.

The ATRP at BMC studies the systemic types of amyloidoses defined under amyloid types. Other forms of amyloidosis include Alzheimer’s and other neurodegenerative diseases, prion diseases, serpinopathies, some of the cystic fibroses, and others.

They have developed Amyloid Light Chain Database, called ALBase, with the support of an NHLBI P01 award, HL68705. ALBase is a curated database and collection of analytical and graphical tools designed to facilitate the analysis of amyloidogenic immunoglobulin (Ig) light chains (LC) occurring in patients with AL amyloidosis. ALBase is designed to compile and analyze Ig LC sequences from patients with AL amyloidosis, to compare their predicted protein sequence and structure to non-amyloidogenic LC sequences from patients with multiple myeloma or health controls. The hypothesis underlying this is that the primary sequence of the LC is likely to be a major determinant of secondary structure and of propensity to unfold, oligomerize, and form fibrils.

“ALBase is available to the scientific community for research purposes. Please reference the site if you make use of it.”

Two patients of Dr. David Seldin are diagnosed with systemic amyloidosis and they shared their experiences from diagnosis to treatment and recovery (You can listen to an audio of this broadcast by clicking here: Rare Disease Feature (WAER 88.3 FM)).

Both patients credit their physicians for investigating abnormal tests and nonspecific symptoms, and for referring them to amyloid specialists early in the disease course.

http://www.bu.edu/amyloid/david-c-seldin-m-d-ph-d/

http://www.bu.edu/amyloid/2012/03/08/npr-interview/

http://www.bmc.org/amyloid.htm#2012gala

Curated by: Dr. Venkat S. Karra, Ph.D

Read Full Post »

Insight into how cholesterol promotes amyloidogenesis

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Personalized and Precision Medicine & Genomic Research, Pharmacotherapy of Cardiovascular Disease, tagged , , , , , , , on June 1, 2012| 2 Comments »

Enzymes act on the APP (Amyloid precursor prot...

Enzymes act on the APP (Amyloid precursor protein) and cut it into fragments of protein, one of which is called beta-amyloid and its crucial in the formation of senile plaques in Alzheimer (Photo credit: Wikipedia)

C99 is the transmembrane carboxyl-terminal domain of the amyloid precursor protein that is cleaved by γ-secretase to release  the amyloid-β polypeptides, which are associated with Alzheimer’s disease. Nuclear magnetic resonance and electron paramagnetic resonance spectroscopy show that the extracellular amino terminus of C99 includes a surface-embedded “N-helix” followed by a short “N-loop” connecting to the transmembrane domain (TMD). The TMD is a flexibly curved α helix, making it well suited for processive cleavage by γ-secretase. Titration of C99 reveals a binding site for cholesterol, providing mechanistic insight into how cholesterol promotes amyloidogenesis. Membrane-buried GXXXG motifs (G, Gly; X, any amino acid), which have an established role in oligomerization, were also shown to play a key role in cholesterol binding. The structure and cholesterol binding properties of C99 may aid in the design of Alzheimer’s therapeutics.

Source

Reported by: Dr. V. S. Karra, Ph.D

Read Full Post »

« Newer Posts