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Overview of Alzheimer’s Disease and Novel Treatments Targeting Beta-Amyloid Deposits

Posted in Alzheimer's Disease, Etiology, Neurodegenerative Diseases, Pharmacotherapy and Cell Activity, tagged Acetylcholinesterase, Alzheimer's Disease, Beta-Amyloid, FDA, neurodegenerative diseases on October 7, 2023| Leave a Comment »

Overview of Alzheimer’s Disease and Novel Treatments Targeting Beta-Amyloid Deposits

Reporter: Sharada Kittur, Research Assistant 1, Synthetic Biology in Drug Discovery

Alzheimer’s disease (AD) is a common type of dementia. People diagnosed with this disease suffer memory loss. Severe forms of the condition prevent the patients from responding to the environment. Alzheimer’s disease patients may also experience difficulty completing basic tasks, decreased or poor judgement as their executive function competence declines. Frequent changes in mood, personality, or behavior. AD is the 7th leading cause of death in the United States, and the 5th leading cause of death for adults aged 65 and over. Unlike cancer and heart disease, whose death rates are declining, the number of people struggling with Alzheimer’s disease is projected to increase in the coming years.

Currently, there are no cures for the disease. Many of the drugs on the market target only symptoms of the disease. The key mechanism of action (MOA) of AD drugs is inhibiting acetylcholinesterase. Acetylcholinesterase (AChE) is an enzyme that breaks down a neurotransmitter called acetylcholine (Ach), which is an important factor for memory functions. On average, Alzheimer’s disease patients have lower concentrations of acetylcholine. In order to treat this biomarker, scientists found molecules that can inhibit AChE, and reduce the breakdown of acetylcholine, thus improving the memory of patients with Alzheimer’s disease by enabling average levels of Ach. Some examples of AChE inhibitors currently on the market are

donepezil,
rivastigmine, and
galantamine.

One of the main causes of Alzheimer’s disease is believed to be the buildup of beta-amyloid plaques in the brain. Beta-amyloid is a toxic protein that is normally produced in small amounts in the brain. Then microglia, a type of macrophages in the nervous system, clear out the beta-amyloid deposits. In patients with Alzheimer’s disease, the microglia can’t clear away the beta-amyloid, and this obstructs neural function and attacks neurons. The cause of the microglia’s malfunction is still unknown, but it could be due to a gene called TREM2, that tells the microglia to clear the beta-amyloid proteins. When TREM2 doesn’t function properly, the microglia collects all of the beta-amyloid, but isn’t able to dispose of it. It then releases inflammatory chemicals, which increase the production of the amyloid precursor protein (APP). This also increases the production of β-secretase and γ-secretase, enzymes that form beta-amyloid by breaking down APP. This further exacerbates the problem.

On July 06, 2023, the Food and Drug Administration (FDA) fully approved Leqembi (lecanemab-irmb) to treat Alzheimer’s disease. Leqembi is a monoclonal antibody that specifically targets beta-amyloid proteins in the brain. It binds to the beta-amyloid proteins and clears them. This is very promising as in placebo-controlled clinical trials, it significantly decreased the beta-amyloid deposits in 18 months, and delayed cognitive decline by 5.3 months. It’s the first beta-amyloid targeting drug that was approved by the FDA as a Traditional Approval.

Leqembi is not a cure, however. It significantly slows down the mental function deterioration of the patients, but hasn’t been shown to fully maintain it at the current level over time. In addition, Leqembi has many side effects, such as headaches, and presents amyloid-related imaging abnormalities (ARIAs). ARIAs can cause swelling and bleeding in parts of the brain, but they should be temporary for most patients. Severe ARIAs only occur in a very small percentage of patients.

As researchers make progress in understanding the complex causes of Alzheimer’s disease, new treatments that are developed can help improve the lives of millions of people worldwide.

SOURCES:

“Alzheimer’s Association Welcomes U.S. FDA Traditional Approval of Leqembi: Full Details.” Alzheimer’s Disease and Dementia, Alzheimer’s Association, 6 July 2023, www.alz.org/news/2023/lecanemab-leqembi-traditional-fda-approval-full#:~:text=CHICAGO%2C%20July%206%2C%202023%20%E2%80%94,confirmation%20of%20elevated%20amyloid%20beta.

Smith, Tyler. “How Well Does Leqembi Work to Fight Alzheimer’s? First FDA-Approved Alzheimer’s Drug Offers Both Promise and Challenges.” UCHealth Today, 11 Aug. 2023, www.uchealth.org/today/how-well-does-leqembi-fight-alzheimers-first-fda-approved-alzheimers-drug/

Wang, Shaoxun, et al. “Is Beta-Amyloid Accumulation a Cause or Consequence of Alzheimer’s Disease?” Journal of Alzheimer’s Parkinsonism & Dementia, U.S. National Library of Medicine, 17 Nov. 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC5555607/

“What Happens to the Brain in Alzheimer’s Disease?” National Institute on Aging, U.S. Department of Health and Human Services, 16 May 2017, www.nia.nih.gov/health/what-happens-brain-alzheimers-disease#:~:text=In%20a%20person%20with%20Alzheimer’s,beta%2Damyloid%20and%20tau%20proteins.

“What Is Alzheimer’s Disease?” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 26 Oct. 2020, www.cdc.gov/aging/aginginfo/alzheimers.htm#:~:text=Alzheimer’s%20disease%20is%20the%20most,thought%2C%20memory%2C%20and%20language.

Alzheimer’s Disease: Novel Therapeutical Approaches — Articles of Note @PharmaceuticalIntelligence.com

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/04/05/alzheimers-disease-novel-therapeutical-approaches-articles-of-note-pharmaceuticalintelligence-com/

Role of infectious agent in Alzheimer’s Disease?

Alzheimer’s disease, snake venome, amyloid and transthyretin

Alzheimer’s Disease – tau art thou, or amyloid

Breakthrough Prize for Alzheimer’s Disease 2016

Tau and IGF1 in Alzheimer’s Disease

Amyloid and Alzheimer’s Disease

Important Lead in Alzheimer’s Disease Model

BWH Researchers: Genetic Variations can Influence Immune Cell Function: Risk Factors for Alzheimer’s Disease,DM, and MS later in life

BACE1 Inhibition role played in the underlying Pathology of Alzheimer’s Disease

Late Onset of Alzheimer’s Disease and One-carbon Metabolism

Alzheimer’s Disease Conundrum – Are We Near the End of the Puzzle?

Ustekinumab New Drug Therapy for Cognitive Decline resulting from Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease

New Alzheimer’s Protein – AICD

Developer of Alzheimer’s drug Exelon at Hebrew University’s School of Pharmacy: Israel Prize in Medicine awarded to Prof. Marta Weinstock-Rosin

TyrNovo’s Novel and Unique Compound, named NT219, selectively Inhibits the process of Aging and Neurodegenerative Diseases, without affecting Lifespan

@NIH – Discovery of Causal Gene Mutation Responsible for two Dissimilar Neurological diseases: Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)

Introduction to Nanotechnology and Alzheimer disease

Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

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

Brain Biobank

Removing Alzheimer plaques

Tracking protein expression

Schizophrenia genomics

Breakup of amyloid plaques

Mindful Discoveries

Beyond tau and amyloid

Serum Folate and Homocysteine, Mood Disorders, and Aging

Long Term Memory and Prions

Retromer in neurological disorders

Neurovascular pathways to neurodegeneration

Studying Alzheimer’s biomarkers in Down syndrome

Amyloid-Targeting Immunotherapy Targeting Neuropathologies with GSK33 Inhibitor

Brain Science

Sleep quality, amyloid and cognitive decline

microglia and brain maintenance

Notable Papers in Neurosciences

New Molecules to reduce Alzheimer’s and Dementia risk in Diabetic patients

The Alzheimer Scene around the Web

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

Keywords:

Alzheimer’s disease
microglia
gliosis
neurodegeneration
inflammation

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Novartis uses a ‘dimmer switch’ medication to fine-tune gene therapy candidates

Posted in Alzheimer's Disease, Biomarkers & Medical Diagnostics, Cerebrovascular and Neurodegenerative Diseases, CRISPR alternative for editing genes without cutting, CRISPR applied to Human Germ Line, CRISPR/Cas9 & Gene Editing, Etiology, Gene Therapy & Gene Editing Development, Genome Biology, Genomic Expression, Neurodegenerative Diseases, Open Access Journals, RNA Biology, Scientific Publishing, tagged Alternate splicing, Chronic renal disease, CRISPR-Cas9, gene therapy, Huntington's disease, Spinal muscular atrophy on August 7, 2021| Leave a Comment »

Novartis uses a ‘dimmer switch’ medication to fine-tune gene therapy candidates

Reporter: Amandeep Kaur, BSc., MSc.

Using viral vectors, lipid nanoparticles, and other technologies, significant progress has been achieved in refining the delivery of gene treatments. However, modifications to the cargo itself are still needed to increase safety and efficacy by better controlling gene expression.

To that end, researchers at Children’s Hospital of Philadelphia (CHOP) have created a “dimmer switch” system that employs Novartis’ investigational Huntington’s disease medicine branaplam (LMI070) as a regulator to fine-tune the quantity of proteins generated from a gene therapy.

The investigational medicine branaplam was shown to fine-tune the expression of an erythropoietin gene therapy in mice by scientists from Children’s Hospital of Philadelphia and Novartis. (Novartis)

According to a new study published in Nature, the X^on system altered quantities of erythropoietin—which is used to treat anaemia associated with chronic renal disease—delivered to mice using viral vectors. The method has previously been licenced by Novartis, the maker of the Zolgensma gene therapy for spinal muscular atrophy.

The X^on system depends on a process known as “alternative splicing,” in which RNA is spliced to include or exclude specific exons of a gene, allowing the gene to code for multiple proteins. The team used branaplam, a small-molecule RNA-splicing modulator, for this platform. The medication was created to improve SMN2 gene splicing in order to cure spinal muscular atrophy. Novartis shifted its research to try the medication against Huntington’s disease after a trial failure.

A gene therapy’s payload remains dormant until oral branaplam is given, according to X^on. The medicine activates the expression of the therapy’s functional gene by causing it to splice in the desired way. Scientists from CHOP and the Novartis Institutes for BioMedical Research put the dimmer switch to the exam in an Epo gene therapy carried through adeno-associated viral vectors. The usage of branaplam increased mice Epo levels in the blood and hematocrit levels (the proportion of red blood cells to whole blood) by 60% to 70%, according to the researchers. The researchers fed the rodents branaplam again as their hematocrit decreased to baseline levels. The therapy reinduced Epo to levels similar to those seen in the initial studies, according to the researchers.

The researchers also demonstrated that the X^on system could be used to regulate progranulin expression, which is utilised to treat PGRN-deficient frontotemporal dementia and neuronal ceroid lipofuscinosis. The scientists emphasised that gene therapy requires a small treatment window to be both safe and effective.

In a statement, Beverly Davidson, Ph.D., the study’s senior author, said, “The dose of a medicine can define how high you want expression to be, and then the system can automatically ‘dim down’ at a pace corresponding to the half-life of the protein.”

“We may imagine scenarios in which a medication is used only once, such as to control the expression of foreign proteins required for gene editing, or only on a limited basis. Because the splicing modulators we examined are administered orally, compliance to control protein expression from viral vectors including X^on-based cassettes should be high.”

In gene-modifying medicines, scientists have tried a variety of approaches to alter gene expression. For example, methyl groups were utilised as a switch to turn on or off expression of genes in the gene-editing system CRISPR by a team of researchers from the Massachusetts Institute of Technology and the University of California, San Francisco.

Auxolytic, a biotech company founded by Stanford University academics, has described how knocking down a gene called UMPS could render T-cell therapies ineffective by depriving T cells of the nutrition uridine. X^on could also be tailored to work with cancer CAR-T cell therapy, according to the CHOP-Novartis researchers. The dimmer switch could help prevent cell depletion by halting CAR expression, according to the researchers. According to the researchers, such a tuneable switch could help CRISPR-based treatments by providing “a short burst” of production of CRISPR effector proteins to prevent undesirable off-target editing.

Source: https://www.fiercebiotech.com/research/novartis-fine-tunes-gene-therapy-a-huntington-s-disease-candidate-as-a-dimmer-switch?mkt_tok=Mjk0LU1RRi0wNTYAAAF-q1ives09mmSQhXDd_jhF0M11KBMt0K23Iru3ZMcZFf-vcFQwMMCxTOiWM-jHaEvtyGOM_ds_Cw6NuB9B0fr79a3Opgh32TjXaB-snz54d2xU_fw

Other Related Articles published in this Open Access Online Scientific Journal include the following:

Gene Therapy could be a Boon to Alzheimer’s disease (AD): A first-in-human clinical trial proposed

Reporter: Dr. Premalata Pati, Ph.D., Postdoc

https://pharmaceuticalintelligence.com/2021/03/22/gene-therapy-could-be-a-boon-to-alzheimers-disease-ad-a-first-in-human-clinical-trial-proposed/

Top Industrialization Challenges of Gene Therapy Manufacturing

Guest Authors: Dr. Mark Szczypka and Clive Glover

https://pharmaceuticalintelligence.com/2021/03/29/top-industrialization-challenges-of-gene-therapy-manufacturing/

Dysregulation of ncRNAs in association with Neurodegenerative Disorders

Curator: Amandeep Kaur

https://pharmaceuticalintelligence.com/2021/01/11/dysregulation-of-ncrnas-in-association-with-neurodegenerative-disorders/

Cancer treatment using CRISPR-based Genome Editing System

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2021/01/09/59906/

CRISPR-Cas9 and the Power of Butterfly Gene Editing

Reporter: Madison Davis

https://pharmaceuticalintelligence.com/2020/08/23/crispr-cas9-and-the-power-of-butterfly-gene-editing/

Gene Editing for Exon 51: Why CRISPR Snipping might be better than Exon Skipping for DMD

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/23/gene-editing-for-exon-51-why-crispr-snipping-might-be-better-than-exon-skipping-for-dmd/

Gene Editing: The Role of Oligonucleotide Chips

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/07/gene-editing-the-role-of-oligonucleotide-chips/

Cause of Alzheimer’s Discovered: protein SIRT6 role in DNA repair process – low levels enable DNA damage accumulation

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/06/15/cause-of-alzheimers-discovered-protein-sirt6-role-in-dna-repair-process-low-levels-enable-dna-damage-accumulation/

Delineating a Role for CRISPR-Cas9 in Pharmaceutical Targeting

Author & Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/08/30/delineating-a-role-for-crispr-cas9-in-pharmaceutical-targeting/

Brain Science

Larry H Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2015/11/03/brain-science/

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Inhibitory CD161 receptor recognized as a potential immunotherapy target in glioma-infiltrating T cells by single-cell analysis

Posted in Anticancer Resistance, “Antibody–enzyme conjugates”, Biochemical pathways, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Screening, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, CRISPR alternative for editing genes without cutting, Etiology, Gene Therapy & Gene Editing Development, Genomic Expression, Glioblastoma, Immunology, Immunotherapy, Innovation in Immunology Diagnostics, Metastasis Process, mRNA Therapeutics, NK Cell-Based Cancer Immunotherapy, tagged antibody-drug conjugate, cancer biology, CD161, gene expression, Glioblastoma, IDH-mutant gliomas, immune checkpoint, Immunotherapy, RNA sequencing, single-cell RNA-seq, T cells on February 20, 2021| Leave a Comment »

Inhibitory CD161 receptor recognized as a potential immunotherapy target in glioma-infiltrating T cells by single-cell analysis

Reporter: Dr. Premalata Pati, Ph.D., Postdoc

Brain tumors, especially the diffused Gliomas are of the most devastating forms of cancer and have so-far been resistant to immunotherapy. It is comprehended that T cells can penetrate the glioma cells, but it still remains unknown why infiltrating cells miscarry to mount a resistant reaction or stop the tumor development.

Gliomas are brain tumors that begin from neuroglial begetter cells. The conventional therapeutic methods including, surgery, chemotherapy, and radiotherapy, have accomplished restricted changes inside glioma patients. Immunotherapy, a compliance in cancer treatment, has introduced a promising strategy with the capacity to penetrate the blood-brain barrier. This has been recognized since the spearheading revelation of lymphatics within the central nervous system. Glioma is not generally carcinogenic. As observed in a number of cases, the tumor cells viably reproduce and assault the adjoining tissues, by and large, gliomas are malignant in nature and tend to metastasize. There are four grades in glioma, and each grade has distinctive cell features and different treatment strategies. Glioblastoma is a grade IV glioma, which is the crucial aggravated form. This infers that all glioblastomas are gliomas, however, not all gliomas are glioblastomas.

Decades of investigations on infiltrating gliomas still take off vital questions with respect to the etiology, cellular lineage, and function of various cell types inside glial malignancies. In spite of the available treatment options such as surgical resection, radiotherapy, and chemotherapy, the average survival rate for high-grade glioma patients remains 1–3 years (1).

A recent in vitro study performed by the researchers of Dana-Farber Cancer Institute, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard, USA, has recognized that CD161 is identified as a potential new target for immunotherapy of malignant brain tumors. The scientific team depicted their work in the Cell Journal, in a paper entitled, “Inhibitory CD161 receptor recognized in glioma-infiltrating T cells by single-cell analysis.” on 15th February 2021.

To further expand their research and findings, Dr. Kai Wucherpfennig, MD, PhD, Chief of the Center for Cancer Immunotherapy, at Dana-Farber stated that their research is additionally important in a number of other major human cancer types such as

melanoma,
lung,
colon, and
liver cancer.

Dr. Wucherpfennig has praised the other authors of the report Mario Suva, MD, PhD, of Massachusetts Common Clinic; Aviv Regev, PhD, of the Klarman Cell Observatory at Broad Institute of MIT and Harvard, and David Reardon, MD, clinical executive of the Center for Neuro-Oncology at Dana-Farber.

Hence, this new study elaborates the effectiveness of the potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes.

The Study-

**IMAGE SOURCE: Experimental Strategy (Mathewson ***et al***., 2021)**

The group utilized single-cell RNA sequencing (RNA-seq) to mull over gene expression and the clonal picture of tumor-infiltrating T cells. It involved the participation of 31 patients suffering from diffused gliomas and glioblastoma. Their work illustrated that the ligand molecule CLEC2D activates CD161, which is an immune cell surface receptor that restrains the development of cancer combating activity of immune T cells and tumor cells in the brain. The study reveals that the activation of CD161 weakens the T cell response against tumor cells.

Based on the study, the facts suggest that the analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 that codes for CD161 as a candidate inhibitory receptor. This was followed by the use of

CRISPR/Cas9 gene-editing technology to inactivate the KLRB1 gene in T cells and showed that CD161 inhibits the tumor cell-killing function of T cells. Accordingly,
genetic inactivation of KLRB1 or
antibody-mediated CD161 blockade

enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other forms of human cancers. The work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immune checkpoint targets.

Further, it has been identified that many cancer patients are being treated with immunotherapy drugs that disable their “immune checkpoints” and their molecular brakes are exploited by the cancer cells to suppress the body’s defensive response induced by T cells against tumors. Disabling these checkpoints lead the immune system to attack the cancer cells. One of the most frequently targeted checkpoints is PD-1. However, recent trials of drugs that target PD-1 in glioblastomas have failed to benefit the patients.

In the current study, the researchers found that fewer T cells from gliomas contained PD-1 than CD161. As a result, they said, “CD161 may represent an attractive target, as it is a cell surface molecule expressed by both CD8 and CD4 T cell subsets [the two types of T cells engaged in response against tumor cells] and a larger fraction of T cells express CD161 than the PD-1 protein.”

However, potential side effects of antibody-mediated blockade of the CLEC2D-CD161 pathway remain unknown and will need to be examined in a non-human primate model. The group hopes to use this finding in their future work by

utilizing their outline by expression of KLRB1 gene in tumor-infiltrating T cells in diffuse gliomas to make a remarkable contribution in therapeutics related to immunosuppression in brain tumors along with four other common human cancers ( Viz. melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma, and colorectal cancer) and how this may be manipulated for prevalent survival of the patients.

References

(1) Anders I. Persson, QiWen Fan, Joanna J. Phillips, William A. Weiss, 39 – Glioma, Editor(s): Sid Gilman, Neurobiology of Disease, Academic Press, 2007, Pages 433-444, ISBN 9780120885923, https://doi.org/10.1016/B978-012088592-3/50041-4.

Main Source

Mathewson ND, Ashenberg O, Tirosh I, Gritsch S, Perez EM, Marx S, et al. 2021. Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis. Cell.https://www.cell.com/cell/fulltext/S0092-8674(21)00065-9?elqTrackId=c3dd8ff1d51f4aea87edd0153b4f2dc7

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Contribution of Nervous System Functional Deterioration to late-life Mortality: The Role Neurofilament light chain (NfL) a Blood Biomarker for the Progression of Neurological Diseases and its Correlation to Age and Life Expectancy

Posted in Age and Life Expectancy, Alzheimer's Disease, Etiology, Innovations in Neurophysiology & Neuropsychology, Nervous System Function, tagged Age and Life Expectancy, Blood Biomarker for the Progression of Neurological Diseases, Neurofilament light chain (NfL) on February 19, 2021| Leave a Comment »

Contribution of Nervous System Functional Deterioration to late-life Mortality: The Role Neurofilament light chain (NfL) a Blood Biomarker for the Progression of Neurological Diseases and its Correlation to Age and Life Expectancy

Reporter: Aviva Lev-Ati, PhD, RN

A neuronal blood marker is associated with mortality in old age

Stephan A. Kaeser,

Benoit Lehallier,

Mikael Thinggaard,

Lisa M. Häsler,

Anja Apel,

Carina Bergmann,

Daniela Berdnik,

Bernard Jeune,

Kaare Christensen,

Sebastian Grönke,

Linda Partridge,

Tony Wyss-Coray,

Jonas Mengel-From &

Mathias Jucker

Nature Aging volume 1, pages218–225(2021)Cite this article

Abstract

Neurofilament light chain (NfL) has emerged as a promising blood biomarker for the progression of various neurological diseases. NfL is a structural protein of nerve cells, and elevated NfL levels in blood are thought to mirror damage to the nervous system. We find that plasma NfL levels increase in humans with age (n = 122; 21–107 years of age) and correlate with changes in other plasma proteins linked to neural pathways. In centenarians (n = 135), plasma NfL levels are associated with mortality equally or better than previously described multi-item scales of cognitive or physical functioning, and this observation was replicated in an independent cohort of nonagenarians (n = 180). Plasma NfL levels also increase in aging mice (n = 114; 2–30 months of age), and dietary restriction, a paradigm that extends lifespan in mice, attenuates the age-related increase in plasma NfL levels. These observations suggest a contribution of nervous system functional deterioration to late-life mortality.

SOURCE

https://www.nature.com/articles/s43587-021-00028-4

How long will a healthy older person live? A substance in blood may provide a clue

Bruce Goldman February 18, 2021

Levels of a substance in nonagenerians’ and centenarians’ blood accurately predict how much longer they’re going to live. The substance comes from the brain.

The findings, in a study published in Nature Aging, could prove useful in developing life-extending drugs. They also raise questions about the brain’s role in aging and longevity.

The study, conducted by Stanford investigators including neuroscientist Tony Wyss-Coray, PhD, in collaboration with researchers in Denmark and Germany, zeroed in on a substance whose technical name is neurofilament light chain (abbreviated NfL). A structural protein produced in the brain, NfL is found in trace amounts in cerebrospinal fluids and blood, where it’s an indicator of damage to long extensions of nerve cells called axons.

Axons convey signals from one nerve cell to the next and are critical to all brain function. You’d rather they remain intact.

Too much NfL (different from the NFL)

High NfL levels in the blood have previously been associated with Alzheimer’s disease, multiple sclerosis, Huntington’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease) and other neurological disorders. But the people monitored in the new study were generally pretty healthy for their age.

The researchers first looked at 122 people whose ages ranged from 21 to 107, and found increasing blood levels of NfL — as well as increasing variation among individuals — with increasing age.

Next, the scientists followed the fates of 135 people age 100 or over for a four-year period. Most of those centenarians were in good shape to begin with, as shown by their performance on standard tests of mental ability and by a measure of their capacity to meet the routine demands of daily living.

Not unexpectedly, those whose mental tests indicated impairment had more NfL in their blood than those with the sharpest minds did. And those with low levels were substantially likelier to live longer than those with high levels.

A look at people in their 90s confirmed the findings in the over-100 group. Blood NfL levels among 180 93-year-olds not only predicted the duration of these folks’ survival, but did so better than mental or daily-coping test scores did.

The investigators showed that mice’s blood NfL levels, too, increase with age. But cutting their caloric intake, beginning in young adulthood — already known to prolong the lives of mice and numerous other species — chopped the little creatures’ blood levels of this substance in half in old age. (This new finding doesn’t prove that lowering NfL blood levels causes increased longevity, but it’s consistent with it.)

Tie to life expectancy?

At a minimum, NfL appears to accurately flag mortality’s approach. That means it might be possible to monitor it as a surrogate marker for remaining life expectancy, much as blood cholesterol levels are used as proxies for cardiovascular health. If so, it could someday help drug developers assess life-extending interventions’ efficacy.

Clinical trials of interventions believed to enhance longevity have been impractical, because it would almost certainly take so long to get a statistically significant result that such trials would be hugely expensive — a major hang-up for pharmas considering investment in longevity drugs. But monitoring a proxy such as NfL could cut years off of such trials’ duration, perhaps encouraging drug developers to dive into the clinical arena with life-prolonging pharmacological candidates.

Possibly most intriguing of all: The new findings hint that maintaining a healthy brain in old age is the best route to a long life.

“It will be interesting to see how and why the brain might be so important in counting down our final years and months,” Wyss-Coray told me.

Photo by Pablo Bendandi

SOURCE

https://scopeblog.stanford.edu/2021/02/18/how-long-will-a-healthy-older-person-live-a-substance-in-blood-may-provide-a-clue/?utm_source=Stanford+Report&utm_campaign=2bba6009da-EMAIL_CAMPAIGN_2021_02_18_04_16&utm_medium=email&utm_term=0_29ce9f751e-2bba6009da-52267013

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Dysregulation of ncRNAs in association with Neurodegenerative Disorders

Posted in Alzheimer's Disease, Biomarkers & Medical Diagnostics, Cerebrovascular and Neurodegenerative Diseases, Etiology, Molecular Genetics & Pharmaceutical, mRNA, mRNA Therapeutics, Neurodegenerative Diseases, Neurological Diseases, RNA Biology, RNA interference (RNAi) therapeutic, tagged Alzheimers Disease, neurodegenerative disorders, Neurological Disorders, Non-coding RNA, Parkinsons disease, RNA Biology, RNA interference (RNAi) therapeutic on January 11, 2021| Leave a Comment »

Dysregulation of ncRNAs in association with Neurodegenerative Disorders

Curator: Amandeep Kaur

Research over the years has added evidences to the hypothesis of “RNA world” which explains the evolution of DNA and protein from a simple RNA molecule. Our understanding of RNA biology has dramatically changed over the last 50 years and rendered the scientists with the conclusion that apart from coding for protein synthesis, RNA also plays an important role in regulation of gene expression.

Figure: Overall Taxonomy of ncRNAs
https://www.nature.com/articles/s42256-019-0051-2

The universe of non-coding RNAs (ncRNAs) is transcending the margins of preconception and altered the traditional thought that the coding RNAs or messenger RNAs (mRNAs) are more prevalent in our cells. Research on the potential use of ncRNAs in therapeutic relevance increased greatly after the discovery of RNA interference (RNAi) and provided important insights into our further understanding of etiology of complex disorders.

Figure: Atomic Structure of Non-coding RNA
https://en.wikipedia.org/wiki/Non-coding_RNA

Latest research on neurodegenerative disorders has shown the perturbed expression of ncRNAs which provides the functional association between neurodegeneration and ncRNAs dysfunction. Due to the diversity of functions and abundance of ncRNAs, they are classified into Housekeeping RNAs and Regulatory ncRNAs.

The best known classes of ncRNAs are the microRNAs (miRNAs) which are extensively studied and are of research focus. miRNAs are present in both intronic and exonic regions of matured RNA (mRNA) and are crucial for development of CNS. The reduction of Dicer-1, a miRNA biogenesis-related protein affects neural development and the elimination of Dicer in specifically dopaminergic neurons causes progressive degeneration of these neuronal cells in striatum of mice.

A new class of regulatory ncRNAs, tRNAs-derived fragments (tRFs) is superabundantly present in brain cells. tRFs are considered as risk factors in conditions of neural degeneration because of accumulation with aging. tRFs have heterogenous functions with regulation of gene expression at multiple layers including regulation of mRNA processing and translation, inducing the activity of silencing of target genes, controlling cell growth and differentiation processes.

The existence of long non-coding RNAs (lncRNAs) was comfirmed by the ENCODE project. Numerous studies reported that approximately 40% of lncRNAs are involved in gene expression, imprinting and pluripotency regulation in the CNS. lncRNA H19 is of paramount significance in neural viability and contribute in epilepsy condition by activating glial cells. Other lncRNAs are highly bountiful in neurons including Evf2 and MALAT1 which play important function in regulating neural differentiation and synapse formation and development of dendritic cells respectively.

Recently, a review article in Nature mentioned about the complex mechanisms of ncRNAs contributing to neurodegenerative conditions. The ncRNA-mediated mechanisms of regulation are as follows:

Epigenetic regulation: Various lncRNAs such as BDNF-AS, TUG1, MEG3, NEAT1 and TUNA are differentially expressed in brain tissue and act as epigenetic regulators.
RNAi: RNA interference includes post-transcriptional repression by small-interfering RNAs (siRNAs) and binding of miRNAs to target genes. In a wide spectrum of neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Huntington’s disease, Amyotrophic lateral sclerosis, Fragile X syndrome, Frontotemporal dementia, and Spinocerebellar ataxia, have shown perturbed expression of miRNA.
Alternative splicing: Variation in splicing of transcripts of ncRNAs has shown adverse affects in neuropathology of degenerative diseases.
mRNA stability: The stability of mRNA may be affected by RNA-RNA duplex formation which leads to the degradation of sense mRNA or blocking the access to proteins involved in RNA turnover and modify the progression of neurodegenerative disorders.
Translational regulation: Numerous ncRNAs including BC200 directly control the translational process of transcripts of mRNAs and effect human brain of Alzheimer’s disease.
Molecular decoys: Non-coding RNAs (ncRNAs) dilute the expression of other RNAs by molecular trapping, also known as competing endogenous RNAs (ceRNAs) which hinder the normal functioning of RNAs. The ceRNAs proportion must be equivalent to the number of target miRNAs that can be sequestered by each ncRNAs in order to induce consequential de-repression of the target molecules.

Table: ncRNAs and related processes involved in neurodegenerative disorders
https://www.nature.com/articles/nrn.2017.90

The unknown functions of numerous annotated ncRNAs may explain the underlying complexity in neurodegenerative disorders. The profiling of ncRNAs of patients suffering from neurodevelopmental and neurodegenerative conditions are required to outline the changes in ncRNAs and their role in specific regions of brain and cells. Analysis of Large-scale gene expression and functional studies of ncRNAs may contribute to our understanding of these diseases and their remarkable connections. Therefore, targeting ncRNAs may provide effective therapeutic perspective for the treatment of neurodegenerative diseases.

References https://www.nature.com/scitable/topicpage/rna-functions-352/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035743/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695195/ https://link.springer.com/article/10.1007/s13670-012-0023-4 https://www.nature.com/articles/nrn.2017.90

New Explanations for Evolution of Alzheimer’s Disease (AD): The Association between Brain neuroanatomy, Brain Pathology and AD Biomarkers – Orientation and Attention are affected by the roles of Temporo-parietal junction (TPJ), Ventral attentional control network, Theory of mind, Inferior parietal cortex

Posted in Alzheimer's Disease, Etiology on February 27, 2020| Leave a Comment »

New Explanations for Evolution of Alzheimer’s Disease (AD): The Association between Brain neuroanatomy, Brain Pathology and AD Biomarkers – Orientation and Attention are affected by the roles of Temporo-parietal junction (TPJ), Ventral attentional control network, Theory of mind, Inferior parietal cortex

Reporter and Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 3/2/2020

Blood test method may predict Alzheimer’s protein deposits in brain

NIH-funded study reports advance in blood-based detection of ptau181, a biomarker of Alzheimer’s disease.

https://www.nih.gov/news-events/news-releases/blood-test-method-may-predict-alzheimers-protein-deposits-brain

On 2/27/2020 I attended an AFHU event with Prof. Shahar Arzi, MD, PhD as Speaker. The main argument was the Title of this curation: AD biomarkers of Amyloid and Tau deposits are found in the TPJ areas of the Brain where Attention, Theory of Mind and Empathy functions occur. Early detection of AD reveals symptoms of effects on Orientation and Attention. Application of Machine Learning (ML) on Brain imaging data allows for prediction of AD disease progression.

As an alternative or complementary Explanation we present “The multiplex model of the genetics of Alzheimer’s disease”

The multiplex model reflects the combination of some, or all, of these model components (genetic and environmental), in a tissue-specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell and synaptic loss observed in AD.

The Loss of Orientation and Attention are an outcome of Brain neuroanatomy, Brain Pathology and AD Biomarkers

Dr. Shahar Arzy got his MD and MSc in neuroscience at the Hebrew University and PhD in neuroscience from the Swiss institute of Technology at the University of Geneva. He specialized in Neurology at Hadassah with subspecialty in cognitive neurology and epilepsy at Geneva University Hospital.

He now directs the Neuropsychiatry Lab at the Hebrew University and runs the neuropsychiatry clinic (with Dr. R. Eitan) and the epilepsy center (with Dr. D. Ekstein) in Hadassah Medical Center.

Dr. Arzy is a senior lecturer at the faculty of medicine, The Edmond And Lily Safra Brain Center and the Cognitive Science Program at the Hebrew University of Jerusalem.

Research Interests: Computational Neuropsychiatry Lab: Our lab of Computational Neuropsychiatry aims to bridge the gap between clinical practice and research, neurology, psychiatry, physics and psychology in order to re-formulate our understanding of the human self and its pathologies. To this aim we use newly developed computational methods (machine-learning algorithms, classifiers, network-approach and spectral analysis) applied directly on patients’ data (3T/7T fMRI, intracranial brain recordings, EEG, ECT), particularly tailored to improve clinical management and scientific understanding of neuropsychiatric disorders. The Neuropsychiatry Lab is located within the Department of Neurology and has a close collaboration with the Departments of Psychiatry, Neuroradiology and Neurosurgery, in order to develop approaches to address specific medical needs of neuropsychiatric patients and clinicians. Our main interests involve cortex-related functional conditions including epilepsy, neurodegenerative diseases, conversive and dissociative disorders, amnesias, disorientation states and different cognitive disturbances and misperceptions. By combining direct clinical involvement and cutting-edge computational methods we are able to challenge the customary context of the human “self” and to reframe neuropsychiatry, and at the same time to develop effective patient-tailored clinical tools to diagnose, monitor and treat these disorders.

SOURCE

https://scholars.huji.ac.il/jbc/people/dr-shahar-arzy

Gad A. Marshall

Position(s):

Associate Medical Director of Clinical Trials, Center for Alzheimer’s Research and Treatment, Brigham and Women’s Hospital

Associate Professor of Neurology, Harvard Medical School

Affiliation(s):

Brigham and Women’s Hospital; Massachusetts General Hospital; Harvard Medical School

Telephone:

(617) 732-8085

Interests:

I have a long-standing interest in clinical-pathologic and imaging correlates in Alzheimer’s disease. Most recently, I have been using PET imaging to assess the relationship between apathy, executive function and instrumental activities of daily living, in vivo amyloid deposition (PiB PET) and synaptic integrity (FDG PET) in mild cognitive impairment and mild Alzheimer’s disease.

My other main research interest and involvement is in clinical trials for the treatment of Alzheimer’s disease.

More Information: Marshall Profile

Biography & Research:

During my medical education at the Boston University School of Medicine, medical internship/neurology residency at the University of Pittsburgh and dementia fellowship at the University of California, Los Angeles, I developed both my clinical and research interests in Alzheimer’s disease. Along the way, I have collaborated with multiple investigators who encouraged and nurtured my drive to better understand this devastating disorder and find effective treatments.

I currently work as a behavioral neurologist at the Brigham and Women’s Hospital and the Massachusetts General Hospital, focusing on clinical trials and neuroimaging biomarkers in Alzheimer’s disease and its precursor stages.

Selected Publications:

Marshall GA, Kaufer DI, Lopez OL, Rao GR, Hamilton RL, DeKosky ST. Right Proscubiculum Amyloid Plaque Density Correlates with Anosognosia in Alzheimer’s Disease. J Neurol Neurosurg Psychiatry 2004; 75: 1396-1400. [PMCID: 1738763].

Marshall GA, Hendrickson R, Kaufer DI, Ivanco LS, Bohnen NI. Cognitive Correlates of Brain MRI Subcortical Signal Hyperintensities in Non-Demented Elderly. Int J Geriatr Psychiatry 2006; 21: 32-35.

Marshall GA, Fairbanks LA, Tekin S, Vinters HV, Cummings JL. Neuropathologic Correlates of Activities of Daily Living in Alzheimer’s Disease. Alzheimer Dis Assoc Disord 2006; 20: 56-59.

Marshall GA, Fairbanks LA, Tekin S, Vinters HV, Cummings JL. Neuropathologic Correlates of Apathy in Alzheimer’s Disease. Dement Geriatr Cogn Disord 2006; 21: 144-147.

Marshall GA, Shchelchkov E, Kaufer DI, Ivanco LS, Bohnen NI. White Matter Hyperintensities and Cortical Acetylcholinesterase Activity in Parkinsonian Dementia. Act Neurol Scand 2006; 113: 87-91.

Marshall GA, Monserratt L, Harwood D, Mandelkern M, Cummings JL, Sultzer DL. Positron Emission Tomography Metabolic Correlates of Apathy in Alzheimer’s Disease. Arch Neurol 2007; 64: 1015-1020.

Sperling RA, Laviolette PS, OíKeefe K, OíBrien J, Rentz DM, Pihlajamaki M, Marshall G, Hyman BT, Selkoe DJ, Hedden T, Buckner RL, Becker JA, Johnson KA. Amyloid Deposition is associated with Impaired Default Network Function in Older Persons Without Dementia. Neuron 2009; 63: 178-188. [PMCID: 2738994].

Becker JA, Hedden T, Carmasin J, Maye J, Rentz DM, Putcha D, Fischl B, Greve D, Marshall GA, Salloway S, Marks D, Buckner RL, Sperling RA, Johnson KA. Amyloid-Beta Associated Cortical Thinning in Clinically Normal Elderly. Ann Neurol 2011; 69: 1032-1042. [PMCID: 3117980].

Marshall GA, Rentz DM, Frey MT, Locascio JJ, Johnson KA, Sperling RA, Alzheimerís Disease Neuroimaging Initiative. Executive Function and Instrumental Activities of Daily Living in Mild Cognitive Impairment and Alzheimerís Disease. Alzheimers Dementia 2011; 7: 300-308. [PMCID: 3096844].

Marshall GA, Olson LE, Frey MT, Maye J, Becker JA, Rentz DM, Sperling RA, Johnson KA, Alzheimerís Disease Neuroimaging Initiative. Instrumental Activities of Daily Living Impairment is associated with Increased Amyloid Burden. Dement Geriatr Cogn Disord 2011; 31: 443-450. [PMCID: 3150869].

More publications may be accessed at www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed

SOURCE

https://www.madrc.org/members/10908

Perception and Multisensory Integration in Neurological Patients Using fMRI

https://clinicaltrials.gov/ct2/show/NCT01469858

02/11/2017

Soc-Cog Colloq – Shahar Arzi

14:00

Wechsler Orientation and its role in Alzheimer’s disease: Mental-orientation is the cognitive function that manages the relationship between the individual and the environment in time (events), space (places) and person (people), as based on a distinct brain system. Observing the clinical similarities between mental-orientation domains and characteristics of Alzheimer’s disease (AD), as well as the striking neuroanatomical overlap between the orientation system and amyloid deposition and brain atrophy in AD, we hypothesized that disturbance of mental-orientation is a core-disorder in AD. In the presentation I will first present the ideas behind mental-orientation as well as its underlying brain system and its relation to the default mode network. I will present the current clinical understanding of Alzheimer’s disease and caveats it poses, and will supply behavioral and neuroimaging data supporting the central role of mental-orientation in the Alzheimer’s disease spectrum. I will conclude with reviewing current efforts in the unified research of space and time and its implication to Alzheimer’s disease.

https://psychology.huji.ac.il/event/soc-cog-colloq-shahar-arzi

Professor Ben Hur Tamir spoke to the Hebrew speaking group on the fascinating topic concerning ‘memory. As Director of the Brain Health and Neurology Department in Hadassah, his field is neurobiology. He told the audience that Dementia, and indeed Alzheimer’s is an illness that causes a loss of brain function due to sections of the brain being eaten away. In addition, depression or fear affect mental function. Once a patient is ready to admit to this, often memory improves. Alzheimer’s disease is not genetic, and it usually appears later in life. However one gene has been identified, and some genes carry risks. The illness can be triggered by other conditions such as blood pressure levels, Parkinsons, diabetes.

There are various tests that show whether a patient has the illness, as well as MRI scans, and there are medications that can remove antibodies, but by the time the antibodies are discovered it is too late to be effective.

Early detection of dementia or Alzheimer’s is the current key to thinking logically. Professor Ben Hur told us of research on a tribe in South America that showed that early hints of the disease show some 15 years before western testing can confirm its existence. The sooner the illness is found, symptoms can be attacked. Professor Shachar Arzi has developed a test that can be turned into an APP, and Professor Ruth Gabizon is working on oxidisation damage because weak anti-oxidants do not reach the brain.

He briefly suggested the use of Omega 3, Vitamin B and exercise to help protect against development of these illnesses.

SOURCE

https://www.hadassah-israel.org/index.php?option=com_content&view=article&id=122:mediscope-2018&catid=8:news&lang=en&Itemid=384

Alzheimer’s disease patients activate attention networks in a short-term memory task

https://doi.org/10.1016/j.nicl.2019.101892

Highlights

• Patients with early AD succeeded in performing an fMRI short-term memory task.

• Dorsal attention network activation did not differ between patients and controls.

• Dorsal and ventral attention networks remained connected in high load task in AD.

• DAN was necessary for the task, but not sufficient to reach normal performance.

Abstract

Network functioning during cognitive tasks is of major interest in Alzheimer’s disease (AD). Cognitive functioning in AD includes variable performance in short-term memory (STM). In most studies, the verbal STM functioning in AD patients has been interpreted within the phonological loop subsystem of Baddeley’s working memory model. An alternative account considers that domain-general attentional processes explain the involvement of frontoparietal networks in verbal STM beside the functioning of modality-specific subsystems. In this study, we assessed the functional integrity of the dorsal attention network (involved in task-related attention) and the ventral attention network (involved in stimulus-driven attention) by varying attentional control demands in a STM task. Thirty-five AD patients and twenty controls in the seventies performed an fMRI STM task. Variation in load (five versus two items) allowed the dorsal (DAN) and ventral attention networks (VAN) to be studied. ANOVA revealed that performance decreased with increased load in both groups. AD patients performed slightly worse than controls, but accuracy remained above 70% in all patients. Statistical analysis of fMRI brain images revealed DAN activation for high load in both groups. There was no between-group difference or common activation for low compared to high load conditions. Psychophysiological interaction showed a negative relationship between the DAN and the VAN for high versus low load conditions in patients. In conclusion, the DAN remained activated and connected to the VAN in mild AD patients who succeeded in performing an fMRI verbal STM task. DAN was necessary for the task, but not sufficient to reach normal performance. Slightly lower performance in early AD patients compared to controls might be related to maintained bottom-up attention to distractors, to decrease in executive functions, to impaired phonological processing or to reduced capacity in serial order processing.

Re-evaluating the role of TPJ in attentional control: Contextual updating?☆

https://doi.org/10.1016/j.neubiorev.2013.08.010

https://www.sciencedirect.com/science/article/pii/S0149763413002005#fig0010

Abstract

The right temporo-parietal junction (TPJ) is widely considered as part of a network that reorients attention to task-relevant, but currently unattended stimuli (Corbetta and Shulman, 2002). Despite the prevalence of this theory in cognitive neuroscience, there is little direct evidence for the principal hypothesis that TPJ sends an early reorientation signal that “circuit breaks” attentional processing in regions of the dorsal attentional network (e.g., the frontal eye fields) or is completely right lateralized during attentional processing. In this review, we examine both functional neuroimaging work on TPJ in the attentional literature as well as anatomical findings. We first critically evaluate the idea that TPJ reorients attention and is right lateralized; we then suggest that TPJ signals might rather reflect post-perceptual processes involved in contextual updating and adjustments of top-down expectations; and then finally discuss how these ideas relate to the electrophysiological (P300) literature, and to TPJ findings in other cognitive and social domains. We conclude that while much work is needed to define the computational functions of regions encapsulated as TPJ, there is now substantial evidence that it is not specialized for stimulus-driven attentional reorienting.

image description

Fig. 1. Peak voxel coordinates for attention, theory of mind, and empathy. Coordinates were derived from the meta-analysis by Decety and Lamm, 2007a, Decety and Lamm, 2007b. Additional data points from more recent studies have also been added to the visualization (see Table 1 for references of studies included). Images of the peak voxel coordinates in MNI space were created using GingerALE (www.brainmap.org) and are depicted on the MRIcroN (http://www.mccauslandcenter.sc.edu/mricro/mricron/) template brain.

Fig. 2. Illustration of the anatomical location of the parietal cortex from the Automatic Anatomical Labeling (AAL) atlas (Tzourio-Mazoyer et al., 2002) (A) and the cytoarchitectonic parietal maps of the Juelich atlas (Eickhoff et al., 2005) (B). The maps are depicted on the flattened brain surface of the PALS atlas as implemented in Caret 5.65 (Van Essen, 2005). SPL: superior parietal lobe, IPL: inferior parietal lobe, AG: angular gyrus, SMG: supramarginal gyrus, STG: superior temporal gyrus, MTG: middle temporal gyrus.

Neuroscience & Biobehavioral Reviews

Volume 37, Issue 10, Part 2, December 2013, Pages 2608-2620

Review

The role of the right temporoparietal junction in attention and social interaction as revealed by ALE meta-analysis

S. C. Krall, C. Rottschy, E. Oberwelland, D. Bzdok, P. T. Fox, S. B. Eickhoff, G. R. Fink, and K. Konrad

Abstract

The right temporoparietal junction (rTPJ) is frequently associated with different capacities that to shift attention to unexpected stimuli (reorienting of attention) and to understand others’ (false) mental state [theory of mind (ToM), typically represented by false belief tasks]. Competing hypotheses either suggest the rTPJ representing a unitary region involved in separate cognitive functions or consisting of subregions subserving distinct processes. We conducted activation likelihood estimation (ALE) meta-analyses to test these hypotheses. A conjunction analysis across ALE meta-analyses delineating regions consistently recruited by reorienting of attention and false belief studies revealed the anterior rTPJ, suggesting an overarching role of this specific region. Moreover, the anatomical difference analysis unravelled the posterior rTPJ as higher converging in false belief compared with reorienting of attention tasks. This supports the concept of an exclusive role of the posterior rTPJ in the social domain. These results were complemented by meta-analytic connectivity mapping (MACM) and resting-state functional connectivity (RSFC) analysis to investigate whole-brain connectivity patterns in task-constrained and task-free brain states. This allowed for detailing the functional separation of the anterior and posterior rTPJ. The combination of MACM and RSFC mapping showed that the posterior rTPJ has connectivity patterns with typical ToM regions, whereas the anterior part of rTPJ co-activates with the attentional network. Taken together, our data suggest that rTPJ contains two functionally fractionated subregions: while posterior rTPJ seems exclusively involved in the social domain, anterior rTPJ is involved in both, attention and ToM, conceivably indicating an attentional shifting role of this region.

SOURCE

Brain Struct Funct. 2015 Mar; 220(2): 587–604.

Published online 2014 Jun 11. doi: 10.1007/s00429-014-0803-z

PMCID: PMC4791048

NIHMSID: NIHMS764322

PMID: 24915964

Published: 28 February 2020

The multiplex model of the genetics of Alzheimer’s disease

Nature Neuroscience (2020)Cite this article

Abstract

Genes play a strong role in Alzheimer’s disease (AD), with late-onset AD showing heritability of 58–79% and early-onset AD showing over 90%. Genetic association provides a robust platform to build our understanding of the etiology of this complex disease. Over 50 loci are now implicated for AD, suggesting that AD is a disease of multiple components, as supported by pathway analyses (immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau processing). Over 50% of late-onset AD heritability has been captured, allowing researchers to calculate the accumulation of AD genetic risk through polygenic risk scores. A polygenic risk score predicts disease with up to 90% accuracy and is an exciting tool in our research armory that could allow selection of those with high polygenic risk scores for clinical trials and precision medicine. It could also allow cellular modelling of the combined risk. Here we propose the multiplex model as a new perspective from which to understand AD. The multiplex model reflects the combination of some, or all, of these model components (genetic and environmental), in a tissue-specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell and synaptic loss observed in AD.

Hadassah International Symposium in Neurology

Seventieth Anniversary of the Department of Neurology and in Honor of Oded Abramsky

Magid Auditorium

Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem

June 3-5, 2007

The Department of Neurology at Hadassah University Hospital, is pleased to celebrate the 70th anniversary of its founding. The celebration will take place in Jerusalem, June 3-5, 2007.  The department was founded by the late Lipman Halpern who emigrated from Berlin to Jerusalem; He served as chairman until 1969, followed by Shaul Feldman who served until 1988 and Oded Abramsky who served until the end of  2005. The 70th anniversary is an historic event for Hadassah Medical Organization and the Hebrew University Hadassah Medical School. This occasion provides an opportunity to reflect on how the department came into being, to acknowledge the people who brought the department to this point, and the continuing role the department of neurology plays in patient care, research, education and community service. To honor seventy years of activities and achievements, the department is hosting an international forum of world-renowned neurologists. The event will honor the conclusion of Oded Abramsky’s term as chairman and the assumption of this role by Tamir Ben-Hur.

The scientific symposium includes overview presentations in various fields of clinical neurosciences by invited neurologists and Nobel Prize Laureates as well as presentations by members of the department of neurology.

We warmly welcome you to the symposium in Jerusalem.

Scientific Program

Sunday  June 3, 2007

09:00 – 09:45  Opening Session

Chairpersons:   Michael Sela (Weizmann Inst.)

Shaul Feldman (Hadassah)

           Oded Abramsky (Hadassah)

Welcome:        Tamir Ben-Hur  Chairman, Department of Neurology, Hadassah

Greetings:        Shlomo Mor-Yosef  Director General, Hadassah Medical Organization

                       Menachem Magidor  President, Hebrew University of Jerusalem

                       Ruth Arnon  Vice President, Israel Academy of Sciences

           Yoram Blachar  Chairman, Israel Medical Association

                       Avinoam Reches  Chairman, Israel Neurological Association

           Johan Aarli  President, World Federation of Neurology

09:45 – 11:15    Second Session

Neurodegeneration and protein degradation in disease

Chairpersons:  Burton Zweiman (Univ. Pennsylvania)

                       Douglas L. Arnold (McGill Univ.)

                       Bella Gross (Technion, Nahariya Hosp.)

09:45 – 10:05  Stanley B. Prusiner  Nobel Prize Laureate (UCSF)

                       Overview: Prion diseases

10:05 – 10:25   Aaron Ciechanover  Nobel Prize Laureate (Technion, Haifa)

     Ubiquitin-mediated protein degradation:

                       From basic mechanisms to  the patient bed

10:25 – 10:45   Roger Rosenberg (Univ. Texas)
Neurodegenerative diseases: New strategies in research and therapy

10:45 – 11:00    Scott A. Small (Columbia Univ.)

Alzheimer’s disease and aging

11:00 – 11:15    Howard L. Weiner (Harvard Univ.)

        Immunological treatments in neurodegenerative diseases

11:15 – 11:40    Coffee Break

11:40 – 13:05    Third Session

Paraneoplastic and Infectious diseases

Chairpersons:   Jack Antel (McGill Univ.)

                         Howard L. Lipton (Univ. Illinois Chicago)

                         Roni Milo (Ben-Gurion Univ., Barzilai Hosp.)

11:40 – 12:00    Jerome B. Posner (Memorial Sloan-Kettering)

                         Overview: Paraneoplastic syndromes

12:00 – 12:20    Richard T. Johnson (Johns Hopkins Univ.)

                        Overview: Neurovirology: State of the art

12:20 – 12:35    Donald H. Gilden (Univ. Colorado)

                        Antigen identification in MS

12:35 – 12:50    Peter G.E. Kennedy (Glasgow Univ.)

                       Neuropathogenesis of human trypanosomiasis (sleeping sickness)

12:50 – 13:05    Francisco Gonzalez-Scarano  (Univ. Pennsylvania)

NeuroAIDS

13:05 – 13:55    Lunch Break

13:55 – 15:25    Fourth Session

Epilepsy, vascular and extrapyramidal disorders

Chairpersons:    Robert B. Daroff (Case Western Reserve Univ.)

                        Stephen Davis (Melbourne Univ.)

           Rivka Inzelberg (Tel Aviv Univ., Meir Hosp.)

13:55 – 14:15    Frederick Andermann (McGill Univ.)

                        Overview: Epilepsy: State of the art

14:15 – 14:30    Timothy A. Pedley (Columbia Univ.)

Understanding epileptogenesis: A beginning

14:30 – 14:50    Louis R. Caplan (Harvard Univ.)

                        Overview: Cerebrovascular diseases: State of the art

14:50 – 15:05    Vladimir Hachinsky  (London Univ., Ontario)

Vascular dementia

15:05 –  15:30Stanley Fahn (Columbia Univ.)

                        Overview: Parkinson’s disease and other extrapyramidal disorders

15:30 – 15:55    Coffee Break

15:55 – 17:15    Fifth Session

Neuromuscular disorders

Chairpersons:    Klaus V. Toyka (Univ. Wurzburg)

                        Aksel Siva (Istanbul Univ.)

David Yarnitsky (Technion, Rambam Hosp.)

15:55 – 16:20    George Karpati (McGill Univ.)

                        Overview:  Muscle diseases: State of the art

16:20 – 16:40    John Newsom-Davis (Oxford Univ.)

Neuromuscular junction disorders

16:40 – 17:00    Gerard Said (Bicetre Univ.)

                        Overview: Peripheral neuropathy:  State of the art

17:00 – 17:15    Robert P. Lisak (Wayne State Univ.)

Schwannopathies

Monday  June 4, 2007

09:00 – 10:10    Sixth Session

Sandy and Peter Collins Lectures on MS

Chairpersons:   Ioannis Milonas (Aristotle Univ.)

                         Tomas Olsson  (Karolinska Inst.)

                                    Ariel Miller (Technion, Carmel Hosp.)

09:00 – 09:20    Reinhard Hohlfeld (Munich Univ.)

                      Immunology of multiple sclerosis

09:20 – 09:40    Hans Lassmann  (Univ. Vienna)

Pathology of multiple sclerosis

09:40 – 09:55   Hans-Peter Hartung (Heinrich-Heine Univ.)

Current therapies in multiple sclerosis

09:55 – 10:10   Lawrence Steinman (Stanford Univ.)

Future therapies in multiple sclerosis

10:10 – 10:30   Coffee Break

10:30 – 11:40    Seventh Session

Stem cells and  Neurology

Chairpersons:   Leslie P. Weiner ( Univ. South Carolina)

                        Krzysztof Selmaj (Lodz Univ.)

Joab Chapman (Tel Aviv Univ., Sheba Hosp.)

10:30 – 10:50    Evan Y. Snyder (Burnham Inst., La Jolla)

Overview: stem cells therapy

10:50 – 11:10     Ian D. Duncan (Univ.  Wisconsin)

                         Remyelination in the CNS

11:10 – 11:25     Douglas Kerr (Johns Hopkins Univ.)

             Cell therapy for neurogenerative diseases

11:25 – 11:40     Jeff W.M. Bulte (Johns Hopkins Univ.)

Molecular neuroimaging of cell therapy

11:40 – 12:50    Eight Session

            Agnes Ginges Lectures in Neurogenetics

Chairpersons:   Steve P. Ringel (Univ. Colorado)

                       Anna  Czlonkowska (Inst. Psychiatry-Neurology, Warsaw)

                       Boaz Weller (Technion, Bnai Zion Hosp.)

11:40 – 12:00    Stefano Di Donato (Carlo Besta Inst., Milano)

                        Overview: Neurogenetics:  State of the art

12:00 – 12:20    Salvatore DiMauro (Columbia Univ.)

Mitochondrial diseases

12:20 – 12:35    Stefan M. Pulst (UCLA)

Ion channels dysfunction in genetic spinocerebellar syndromes

12:35 – 12:50    Alastair D.S. Compston (Cambridge Univ.)

Genetics of MS and other demyelinating disorders

12:50 – 13:40    Lunch Break

13:40 – 16:35     Ninth Session

Department of Neurology, Hadassah: Research highlights

Chairpersons:   Yair Birnbaum (Director,  Hadassah Univ. Hosp., Ein Kerem)

Milton Alter (Temple Univ.)

                        Itzhak Wirguin (Ben-Gurion Univ.)

13:40 – 13: 55   Tamir Ben-Hur

                        Stem cell therapy in neurological diseases

13:55 – 14:10    Dimitrios Karussis

                        Neuroprotection in MS

14:10 – 14:25    Talma Brenner

            Pregnancy, alphafetoprotein, EAE and MS

14:25 – 14:40    Ruth Gabizon

                        When prions meet other pathological insults

14:40 – 14:55    Hanna Rosenmann

                        Novel animal models of Alzheimer’s disease and tauopathy

14:55 – 15:05    Tali Siegal

Longitudinal assessment of genetic and epigenetic markers  in progressive oligodendroglial tumors

15:05 – 15:15    Ronen R. Leker

                        Manipulation of endogenous neural stem cells in stroke

15:15 – 15:25    Netta Levin

      Plasticity in the human visual cortex: fMRI studies

15:25 – 15:35    Dana Ekstein

                        The role of zinc in epileptogenesis

15:35 – 15:45    Shahar Arzi

Remembering the future, predicting the past:

                        An electrophysiological study of mental time travel

15:45 – 16:05    Coffee break

16:05 – 16:20    Zohar Argov

One gene is not enough: Lessons from hereditary neuromuscular disorders identified at Hadassah

16:20 – 16:35    Alex Lossos

        Adult genetic neurometabolic diseases: Hadassah’s experience

16:35 – 17:45Closing Session

Vision of future Neurology

Chairpersons:   Ehud Razin (Dean, Hebrew University Hadassah Medical School)

                        Shlomo Rotshenker (Chairman, Israel Neuroscience Society)

                        Eldad Melamed (Tel Aviv Univ., Beilinson Hosp.)

Greetings:         Ehud Olmert  Israel Prime Minister

                        Avi Israeli  Director General, Israel Ministry of Health

16:50 – 17:05    Natan M. Bornstein(Tel Aviv Univ., Ichilov Hosp.)

Neurology in Israel

17:05 – 17:25    Donald H. Silberberg (Univ. Pennsylvania)

Neurology in developing countries

17:25 – 17:45    Lewis P. Rowland (Columbia Univ.)

                        Prospects for neurology in the 21st century

Tuesday  June 5, 2007

Seventieth Meeting of the HebrewUniversity Board of Governors

13:30

Dedication of :

“The Stanley B. PrusinerMedicalInformationCenter“

Hebrew University Hadassah Medical School

Judah Magnes Square, Ein Kerem, Jerusalem

SOURCE

https://www.e-med.co.il/emed/new/usersite/content.asp?CatID=22&ContentID=113928

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Read Full Post »

Brain Health – Evidence that Lifestyle Habits can improve Brain Health – APOe4 gene in women appears to more often convert mild cognitive impairment to Alzheimer’s

Posted in Alzheimer's Disease, Etiology on February 10, 2020| Leave a Comment »

Brain Health – Evidence that Lifestyle Habits can improve Brain Health – APOe4 gene in women appears to more often convert mild cognitive impairment to Alzheimer’s

Reporter: Aviva Lev-Ari, PhD, RN

Brain health is determined by how the organ is functioning; how much

blood flow
nutrients and
oxygen it is getting; and
how it is cleaning and filtering things like harmful proteins – high amyloid burden is decreasing in importance by climbing steps during excercise – proteins that increase the risk for Alzheimer’s can start to deposit in the brain 15-20 years before the onset of symptoms

Factors in boosting brain health

Exercise increases blood flow to the brain and increases the size of the anterior hippocampus, leading to improvements in spatial memory vs reduction in size and atrophy. Healthy lifestyle habits can reduce or negate risk — even in the presence of genetic predisposition
Diet – Mediterranean, heart-healthy diet can minimize adverse effects on memory and decrease the incidence of Alzheimer’s and dementia. It boost memory and cognition.
Exercise and diet increase release of endorphins which can stimulate cognitive functioning and mood improvements
Brain Derived Nerve Growth Factor (BDNF) — which can help memory, focus and attention — may increase as a result of physical activity.
Sleep and Mood are interconnected

Genetic Factors affecting Brain Health

ApoE4 gene carriers have an increased risk.
One copy of the gene can increase risk by 2-4 times the risk of the general population, and
Two copies of the gene may increase risk up to 10 times that of the general population. But that is risk, not cause.

Age

People over age 65, 1-2% have Alzheimer’s disease.
Above 85 years old, the prevalence is 30-50%.

Sex

Women have a higher risk of Alzheimer’s than do men.
Could this just be because women live longer than men?
Women may have more physiological risks than men.
For example, the APOe4 gene in women appears to more often convert mild cognitive impairment to Alzheimer’s.

Variability by Ethnicity and Race

Alzheimer’s disease within specific ethnic groups and races – has different disease profiles, more studies with diversity are needed.

Highest risk for developing Alzheimer’s and other neurodegenerative diseases

Genetic predisposition,
Low education,
High age and
Vascular risk factors

Minimizing Risk and induce Slower Progression – We can’t change age and we can’t change genetics. The modifiable risk factors are:

exercise,
sleep,
diet, and
cognitive stimulation

SOURCE

https://hip.stanford.edu/calendar-news/news/boosting-brain-health/

Read Full Post »

Higher soluble platelet-derived Growth Factor Receptor-beta – a significant Predictor of Cognitive impairment even after controlling for Amyloid-beta or Tau in multiple types of Dementia

Posted in Alzheimer's Disease, Etiology, Innovations in Neurophysiology & Neuropsychology, tagged blood–brain barrier (BBB) breakdown, brain capillary damage, cerebrospinal fluid biomarker, Neuroimaging, neuropathology, neurovascular dysfunction, regional BBB permeability, tau, vasculotoxic effects of amyloid-β (Aβ) on January 15, 2019| Leave a Comment »

Higher soluble platelet-derived Growth Factor Receptor-beta – a significant Predictor of Cognitive impairment even after controlling for Amyloid-beta or Tau in multiple types of Dementia

Reporter: Aviva Lev-Ari, PhD, RN

Researchers studied brain capillary damage [blood–brain barrier (BBB) breakdown] using

a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell pericyte, soluble platelet-derived growth factor receptor-β
regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging (MRI)
Results: early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer’s Aβ and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aβ and tau.

Nature Medicine – Original reference

Source Reference: Nation D, et al “Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction” Nature Medicine 2019; DOI: https://doi.org/10.1038/s41591-018-0297-y.

Letter | Published: 14 January 2019

Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction

Daniel A. Nation,

Melanie D. Sweeney,

Axel Montagne,

Abhay P. Sagare,

Lina M. D’Orazio,

Maricarmen Pachicano,

Farshid Sepehrband,

Amy R. Nelson,

David P. Buennagel,

Michael G. Harrington,

Tammie L. S. Benzinger,

Anne M. Fagan,

John M. Ringman,

Lon S. Schneider,

John C. Morris,

Helena C. Chui,

Meng Law,

Arthur W. Toga &

Berislav V. Zlokovic

Nature Medicine (2019) | Download Citation

Abstract

Multiple Types of Dementia:

vascular dementia,
vascular cognitive impairment,
Parkinson’s disease,
Lewy body dementia,
frontotemporal dementia, or
other disorders that might account for cognitive impairment.

In a subset of 73 patients who had gadolinium-based contrast MRI, soluble platelet-derived growth factor receptor-beta was positively correlated with blood-brain barrier breakdown, limited to the hippocampus and medial temporal lobe structures.

“These brain regions show the earliest pathology in Alzheimer’s disease and are associated with memory deficits,” observed Gwenn Smith, PhD, of Johns Hopkins School of Medicine, who was not part of the research. “These promising results support further investigation of CSF and MRI measures of blood-brain barrier breakdown as an early pathological event associated with the development of Alzheimer’s disease,” she told MedPage Today.

The findings represent only one point in time, the researchers cautioned. Future studies will look at how soon cognitive decline occurs after blood vessel damage starts.

Nature Medicine – Original Reference

Source Reference: Nation D, et al “Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction” Nature Medicine 2019; DOI: https://doi.org/10.1038/s41591-018-0297-y.

SOURCE

https://www.medpagetoday.com/neurology/dementia/77414?xid=nl_mpt_DHE_2019-01-15&eun=g99985d0r&pos=&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily%20Headlines%202019-01-15&utm_term=NL_Daily_DHE_Active

Comments:

January 15, 2019

— W.E. Feeman, Jr, MD

Small vessel vascular disease can be due to the usual atherothrombotic disease (ATD) risk facotrs: dyslipidemia, cigarette smoking, and hypertension, with some contribution by the very high blood sugar levels of uncontrolled diabetes. It all fits together.

Read Full Post »

Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults

Posted in Alzheimer's Disease, Etiology, Pharmacotherapy and Cell Activity, RNA Biology, RNA interference (RNAi) therapeutic, tagged autonomic symptoms, hATTR amyloidosis, hereditary transthyretin-mediated (hATTR) amyloidosis, neuropathy impairment, polyneuropathy, RNA interference (RNAi) therapeutic on August 13, 2018| Leave a Comment »

Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults

Reporter: Aviva Lev-Ari, PhD, RN

Aug 10,2018

− First and Only FDA-approved Treatment Available in the United States for this Indication –

− ONPATTRO Shown to Improve Polyneuropathy Relative to Placebo, with Reversal of Neuropathy Impairment Compared to Baseline in Majority of Patients –

− Improvement in Specified Measures of Quality of Life and Disease Burden Demonstrated Across Diverse, Global Patient Population –

− Alnylam to Host Conference Call Today at 3:00 p.m. ET. −

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Aug. 10, 2018– Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that the United States Food and Drug Administration (FDA) approved ONPATTRO™ (patisiran) lipid complex injection, a first-of-its-kind RNA interference (RNAi) therapeutic, for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. ONPATTRO is the first and only FDA-approved treatment for this indication. hATTR amyloidosis is a rare, inherited, rapidly progressive and life-threatening disease with a constellation of manifestations. In addition to polyneuropathy, hATTR amyloidosis can lead to other significant disabilities including decreased ambulation with the loss of the ability to walk unaided, a reduced quality of life, and a decline in cardiac functioning. In the largest controlled study of hATTR amyloidosis, ONPATTRO was shown to improve polyneuropathy – with reversal of neuropathy impairment in a majority of patients – and to improve a composite quality of life measure, reduce autonomic symptoms, and improve activities of daily living.

ONPATTRO was reviewed by the FDA under Priority Review and had previously been granted Breakthrough Therapy and Orphan Drug Designations. On July 27, patisiran received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) for the treatment of hereditary transthyretin-mediated amyloidosis in adults with stage 1 or stage 2 polyneuropathy under accelerated assessment by the European Medicines Agency. The recommended Summary of Product Characteristics (SmPC) for the European Union (EU) includes data on secondary and exploratory endpoints. Expected in September, the European Commission will review the CHMP recommendation to make a final decision on marketing authorization, applicable to all 28 EU member states, plus Iceland, Liechtenstein and Norway. Regulatory filings in other markets, including Japan, are planned beginning in mid-2018.

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20180810005398/en/

INTELLECTUAL PROPERTY

Alnylam protects its Intellectual Property (IP) with fundamental, chemistry, delivery, and target patents and patent applications covering the development and commercialization of RNAi therapeutics as well as that afforded by the various trademark, copyright, and trade secret laws.

Alnylam’s patent estate includes a large number of issued patents and pending patent applications in the world’s major pharmaceutical markets—United States, European Union, and Japan, along with other countries throughout the world. This broad portfolio covers, for example, oligonucleotides, including synthetic RNA molecules, both modified and unmodified, optimized for a variety of delivery modalities, such as lipid- and conjugate-based systems, their synthesis and use, including use as therapeutics, diagnostics, and research reagents. We believe these patents and pending applications place Alnylam in the strongest possible position to not only build our company over the long term and accelerate our efforts to bring life-saving drugs to patients in need, but to enable other companies for advancement of RNAi therapeutics with licenses to our IP estate and associated know-how. This belief has been validated by the progress of Alnylam to date with multiple programs in pre-clinical and clinical development and with well over 30 distinct agreements entered into with leading pharmaceutical, biotechnology, and research reagent companies.

Alnylam has an extensive array of registered trademarks in the United States, European Union, Japan and other countries throughout the world as well as various copyrighted works. In addition to patent protection, Alnylam further safeguards its IP through the use of trade secret protection afforded by the relevant state and federal trade secret laws.

SOURCE

http://www.alnylam.com/our-science/intellectual-property/

Post : Patisiran

URL : http://newdrugapprovals.org/2018/08/13/patisiran/

Posted : August 13, 2018 at 9:51 am

Author : DR ANTHONY MELVIN CRASTO Ph.D

Tags : 50FKX8CB2Y, 6024128, ALN-18328, ALN-TTR02, Alnylam

Pharmaceuticals, BREAKTHROUGH THERAPY, FAST TRACK, FDA 2018,

GENZ-438027, Onpattro, Orphan Drug Designation, patisiran, Priority

review, SAR-438037

Categories : 0rphan drug status, Breakthrough Therapy Designation,

FAST TRACK FDA, FDA 2018, Priority review

https://upload.wikimedia.org/wikipedia/commons/thumb/b/ba/Patisiran.png/60

0px-Patisiran.png

Patisiran

Sense strand:

https://integrity.thomson-pharma.com/integrity/img//en/vspacer_en.gif

GUAACCAAGAGUAUUCCAUdTdT

https://integrity.thomson-pharma.com/integrity/img//en/vspacer_en.gif

Anti-sense strand:

https://integrity.thomson-pharma.com/integrity/img//en/vspacer_en.gif

AUGGAAUACUCUUGGUUACdTdT

RNA, (A-U-G-G-A-A-Um-A-C-U-C-U-U-G-G-U-Um-A-C-dT-dT), complex with RNA

(G-Um-A-A-Cm-Cm-A-A-G-A-G-Um-A-Um-Um-Cm-Cm-A-Um-dT-dT) (1:1),

ALN-18328, 6024128 , ALN-TTR02 , GENZ-438027 , SAR-438037 ,

50FKX8CB2Y (UNII code)

for RNA, (A-U-G-G-A-A-Um-A-C-U-C-U-U-G-G-U-Um-A-C-dT-dT), complex

with RNA(G-Um-A-A-Cm-Cm-A-A-G-A-G-Um-A-Um-Um-Cm-Cm-A-Um-dT-dT) (1:1)

Nucleic Acid Sequence

Sequence Length: 42, 21, 2112 a 7 c 7 g 4 t 12 umultistranded (2);

modified

CAS 1420706-45-1

Treatment of Amyloidosis,

SEE…..https://endpts.com/gung-ho-alnylam-lands-historic-fda-ok-on-patisi

ran-revving-up-the-first-global-rollout-for-an-rnai-breakthrough/

Lipid-nanoparticle-encapsulated double-stranded siRNA targeting a 3

untranslated region of mutant and wild-type transthyretin mRNA

Patisiran (trade name Onpattro®) is a medication for the treatment of

polyneuropathy ( https://en.wikipedia.org/wiki/Polyneuropathy ) in

people with hereditary transthyretin-mediated amyloidosis (

https://en.wikipedia.org/wiki/Hereditary_transthyretin-mediated_amyloidosi

) . It is the first small interfering RNA (

https://en.wikipedia.org/wiki/Small_interfering_RNA ) -based drug

approved by the FDA ( https://en.wikipedia.org/wiki/FDA ) . Through

this mechanism, it is a gene silencing (

https://en.wikipedia.org/wiki/Gene_silencing ) drug that interferes

with the production of an abnormal form of transthyretin (

https://en.wikipedia.org/wiki/Transthyretin ) .

https://upload.wikimedia.org/wikipedia/commons/thumb/b/ba/Patisiran.png/60

0px-Patisiran.png

( https://en.wikipedia.org/wiki/File:Patisiran.png )

Chemical structure of Patisiran.

During its development, patisiran was granted orphan drug status (

https://en.wikipedia.org/wiki/Orphan_drug_status ) , fast track

designation ( https://en.wikipedia.org/wiki/Fast_track_designation ) ,

priority review ( https://en.wikipedia.org/wiki/Priority_review ) and

breakthrough therapy designation (

https://en.wikipedia.org/wiki/Breakthrough_therapy_designation ) due

to its novel mechanism and the rarity of the condition it is designed

to treat.[1] ( https://en.wikipedia.org/wiki/Patisiran#cite_note-1 )

[2] ( https://en.wikipedia.org/wiki/Patisiran#cite_note-2 ) It was

approved by the FDA in August 2018 and is expected to cost around

$345,000 to $450,000 per year.[3] (

https://en.wikipedia.org/wiki/Patisiran#cite_note-3 )

Patisiran was granted orphan drug designation in the U.S. and Japan

for the treatment of familial amyloid polyneuropathy. Fast track

designation was also granted in the U.S. for this indication. In the

E.U., orphan drug designation was assigned to the compound for the

treatment of transthyretin-mediated amyloidosis (initially for the

treatment of familial amyloid polyneuropathy)

Hereditary transthyretin-mediated amyloidosis (

https://en.wikipedia.org/wiki/Hereditary_transthyretin-mediated_amyloidosi

) is a fatal rare disease (

https://en.wikipedia.org/wiki/Rare_disease ) that is estimated to

affect 50,000 people worldwide. Patisiran is the first drug approved

by the FDA to treat this condition.[4] (

https://en.wikipedia.org/wiki/Patisiran#cite_note-4 )

Patisiran is a second-generation siRNA therapy targeting mutant

transthyretin (TTR) developed by Alnylam for the treatment of familial

amyloid polyneuropathy. The product is delivered by means of Arbutus

Biopharma’s (formerly Tekmira Pharmaceuticals) lipid nanoparticle

technology

https://endpts.com/wp-content/uploads/2018/08/GettyImages-902989426.jpg

“A lot of people think it’s winter out there for RNAi. But I think

it’s springtime.” — Alnylam CEO John Maraganore, NYT, February 7,

2011.

Patisiran — designed to silence messenger RNA and block the production

of TTR protein before it is made — is number 6 on Clarivate’s list of

blockbusters (

https://endpts.com/12-blockbusters-the-surging-list-of-1b-plus-drugs-rolli

ng-out-on-the-market-this-year-might-surprise-you/

) set to launch this year, with a 2022 sales forecast of $1.22

billion. Some of the peak sales estimates range significantly higher

as analysts crunch the numbers on a disease that afflicts only about

30,000 people worldwide.

PATENT

WO 2016033326

https://patents.google.com/patent/WO2016033326A2

Transthyretin (TTR) is a tetrameric protein produced primarily in the

liver.

Mutations in the TTR gene destabilize the protein tetramer, leading to

misfolding of monomers and aggregation into TTR amyloid fibrils

(ATTR). Tissue deposition results in systemic ATTR amyloidosis

(Coutinho et al, Forty years of experience with type I amyloid

neuropathy. Review of 483 cases. In: Glenner et al, Amyloid and

Amyloidosis, Amsterdam: Excerpta Media, 1980 pg. 88-93; Hou et al.,

Transthyretin and familial amyloidotic polyneuropathy. Recent progress

in understanding the molecular mechanism of

neurodegeneration. FEBS J 2007, 274: 1637-1650; Westermark et al,

Fibril in senile systemic amyloidosis is derived from normal

transthyretin. Proc Natl Acad Sci USA 1990, 87: 2843-2845). Over 100

reported TTR mutations exhibit a spectrum of disease symptoms.

[0004] TTR amyloidosis manifests in various forms. When the peripheral

nervous system is affected more prominently, the disease is termed

familial amyloidotic

polyneuropathy (FAP). When the heart is primarily involved but the

nervous system is not, the disease is called familial amyloidotic

cardiomyopathy (FAC). A third major type of TTR amyloidosis is called

leptomeningeal/CNS (Central Nervous System) amyloidosis.

[0005] The most common mutations associated with familial amyloid

polyneuropathy (FAP) and ATTR-associated cardiomyopathy, respectively, are Val30Met

(Coelho et al, Tafamidis for transthyretin familial amyloid

polyneuropathy: a randomized, controlled trial. Neurology 2012, 79:

785-792) and Vall22Ile (Connors et al, Cardiac amyloidosis in African

Americans: comparison of clinical and laboratory features of

transthyretin VI 221 amyloidosis and immunoglobulin light chain

amyloidosis. Am Heart J 2009, 158: 607-614). [0006] Current treatment

options for FAP focus on stabilizing or decreasing the amount of

circulating amyloidogenic protein. Orthotopic liver transplantation

reduces mutant TTR levels (Holmgren et al, Biochemical effect of liver

transplantation in two Swedish patients with familial amyloidotic

polyneuropathy (FAP-met30). Clin Genet 1991, 40: 242-246), with

improved survival reported in patients with early-stage FAP, although

deposition of wild-type TTR may continue (Yazaki et al, Progressive

wild-type transthyretin deposition after liver transplantation

preferentially occurs into myocardium in FAP patients. Am J Transplant

2007, 7:235-242; Adams et al, Rapid progression of familial amyloid

polyneuropathy: a multinational natural history study Neurology 2015

Aug 25; 85(8) 675-82; Yamashita et al, Long-term survival after liver

transplantation in patients with familial amyloid polyneuropathy.

Neurology 2012, 78: 637-643; Okamoto et al., Liver

transplantation for familial amyloidotic polyneuropathy: impact on

Swedish patients’ survival. Liver Transpl 2009, 15: 1229-1235; Stangou

et al, Progressive cardiac amyloidosis following liver transplantation

for familial amyloid polyneuropathy: implications for amyloid

fibrillogenesis. Transplantation 1998, 66:229-233; Fosby et al, Liver

transplantation in the Nordic countries – An intention to treat and

post-transplant analysis from The Nordic Liver Transplant Registry

1982-2013. Scand J Gastroenterol. 2015 Jun; 50(6):797-808.

Transplantation, in press).

[0007] Tafamidis and diflunisal stabilize circulating TTR tetramers,

which can slow the rate of disease progression (Berk et al,

Repurposing diflunisal for familial amyloid polyneuropathy: a

randomized clinical trial. JAMA 2013, 310: 2658-2667; Coelho et al.,

2012; Coelho et al, Long-term effects of tafamidis for the treatment

of transthyretin familial amyloid polyneuropathy. J Neurol 2013, 260:

2802-2814; Lozeron et al, Effect on disability and safety of Tafamidis

in late onset of Met30 transthyretin familial amyloid polyneuropathy.

Eur J Neurol 2013, 20: 1539-1545). However, symptoms continue to

worsen on treatment in a large proportion of patients, highlighting

the need for new, disease-modifying treatment options for FAP.

[0008] Description of dsRNA targeting TTR can be found in, for example,

International patent application no. PCT/US2009/061381 (WO2010/048228) and

International patent application no. PCT/US2010/05531 1 (WO201

1/056883).

Summary

[0009] Described herein are methods for reducing or arresting an increase

in a Neuropathy Impairment Score (NIS) or a modified NIS (mNIS+7) in a

human subject by administering an effective amount of a transthyretin

(TTR)-inhibiting composition, wherein the effective amount reduces a

concentration of TTR protein in serum of the human subject to below 50

μg/ml or by at least 80%. Also described herein are methods for

adjusting a dosage of a TTR- inhibiting composition for treatment of

increasing NIS or Familial Amyloidotic Polyneuropathy (FAP) by

administering the TTR- inhibiting composition to a subject having the

increasing NIS or FAP, and determining a level of TTR protein in the

subject having the increasing NIS or FAP. In some embodiments, the

amount of the TTR- inhibiting composition subsequently administered to

the subject is increased if the level of TTR protein is greater than

50 μg/ml, and the amount of the TTR- inhibiting composition

subsequently administered to the subject is decreased if the level of

TTR protein is below 50 μg/ml. Also described herein are formulated

versions of a TTR inhibiting siRNA.

http://www.alnylam.com/wp-content/uploads/2017/03/Acting_Upstream_of_Today

_s_Medicines.jpg

PATENT

WO 2016203402

PAPERS

Annals of Medicine (Abingdon, United Kingdom) (2015), 47(8), 625-638.

Pharmaceutical Research (2017), 34(7), 1339-1363

Annual Review of Pharmacology and Toxicology (2017), 57, 81-105

CLIP

https://www.thepharmaletter.com/media/image/alnylam-large.jpg

Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic,

ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of

Hereditary Transthyretin-Mediated Amyloidosis in Adults

Aug 10,2018

− First and Only FDA-approved Treatment Available in the United States

for this Indication –

− ONPATTRO Shown to Improve Polyneuropathy Relative to Placebo, with

Reversal of Neuropathy Impairment Compared to Baseline in Majority of

Patients –

− Improvement in Specified Measures of Quality of Life and Disease

Burden Demonstrated Across Diverse, Global Patient Population –

SOURCE

http://investors.alnylam.com/news-releases/news-release-details/alnylam-announces-first-ever-fda-approval-rnai-therapeutic?elqTrackId=5b9b83df05514e548f022d8324583ba1&elq=e50414057f3841798651d20561bbe4db&elqaid=22818&elqat=1&elqCampaignId=10597

https://endpts.com/gung-ho-alnylam-lands-historic-fda-ok-on-patisir an-revving-up-the-first-global-rollout-for-an-rnai-breakthrough/

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Curation of selected topics and articles on Role of G-Protein Coupled Receptors in Chronic Disease as supplemental information for #TUBiol3373

Posted in Alzheimer's Disease, Autoimmune Inflammatory DIseases, Biological Networks, Biological Networks, Gene Regulation and Evolution, Bone Disease and Musculoskeletal Disease, Ca2+ triggered activation, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Cell Biology, Signaling & Cell Circuits, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Crohn's disease, Curation, Etiology, Frontiers in Cardiology and Cardiovascular Disorders, interventional oncology, Obesity, Pharmacotherapy and Cell Activity, tagged #TUBiol3373, Alzheimer Disease, Amyloid aggregates, cardiovascular and lung disease, Cardiovascular and Metabolic Diseases, chronic diseases, Chronic Obstructive Lung Disease (COPD), G Protein coupling, G-protein coupled receptors (GPCR), ovarian cancer on May 2, 2018| Leave a Comment »

Curation of selected topics and articles on Role of G-Protein Coupled Receptors in Chronic Disease as supplemental information for #TUBiol3373

Curator: Stephen J. Williams, PhD

Below is a series of posts and articles related to the role of G protein coupled receptors (GPCR) in various chronic diseases. This is only a cursory collection and by no means represents the complete extensive literature on pathogenesis related to G protein function or alteration thereof. However it is important to note that, although we think of G protein signaling as rather short lived, quick, their chronic activation may lead to progression of various disease. As to whether disease onset, via GPCR, is a result of sustained signal, loss of desensitization mechanisms, or alterations of transduction systems is an area to be investigated.

From:

Molecular Pathogenesis of Progressive Lung Diseases

Author: Larry H. Bernstein, MD, FCAP

Chronic Obstructive Lung Disease (COPD)

Inflammatory and infectious factors are present in diseased airways that interact with G-protein coupled receptors (GPCRs), such as purinergic receptors and bradykinin (BK) receptors, to stimulate phospholipase C [PLC]. This is followed by the activation of inositol 1,4,5-trisphosphate (IP3)-dependent activation of IP3 channel receptors in the ER, which results in channel opening and release of stored Ca²⁺ into the cytoplasm. When ER Ca2+ stores are depleted a pathway for Ca²⁺ influx across the plasma membrane is activated. This has been referred to as “capacitative Ca²⁺ entry”, and “store-operated calcium entry” (3). In the next step PLC mediated Ca²⁺ i is mobilized as a result of GPCR activation by inflammatory mediators, which triggers cytokine production by Ca²⁺ i-dependent activation of the transcription factor nuclear factor kB (NF-kB) in airway epithelia.

In Alzheimer’s Disease

Important Lead in Alzheimer’s Disease Model

Larry H. Bernstein, MD, FCAP, Curator discusses findings from a research team at University of California at San Diego (UCSD) which the neuropeptide hormone corticotropin-releasing factor (CRF) as having an important role in the etiology of Alzheimer’s Disease (AD). CRF activates the CRF receptor (a G stimulatory receptor). It was found inhibition of the CRF receptor prevented cognitive impairment in a mouse model of AD. Furthermore researchers at the Flanders Interuniversity Institute for Biotechnology found the loss of a protein called G protein-coupled receptor 3 (GPR3) may lower the amyloid plaque aggregation, resulting in improved cognitive function. Additionally inhibition of several G-protein coupled receptors alter amyloid precursor processing, providing a further mechanism of the role of GPCR in AD (see references in The role of G protein-coupled receptors in the pathology of Alzheimer’s disease by Amantha Thathiah and Bart De Strooper Nature Reviews Feb 2011; 12: 73-87 and read post).