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Archive for the ‘Alzheimer’s Disease’ Category

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.

According to a new study published in Nature, the Xon 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 Xon 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 Xon. 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 Xon 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 Xon-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. Xon 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/

Read Full Post »

Despite heated discussion over whether it works, the FDA has approved Aduhelm, bringing a new ray of hope to the Alzheimer’s patients.

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

On Monday, 7th June 2021, a controversial new Alzheimer’s Disease treatment was licensed in the United States for the first time in nearly 20 years, sparking calls for it to be made available worldwide despite conflicting evidence about its usefulness. The drug was designed for people with mild cognitive impairment, not severe dementia, and it was designed to delay the progression of Alzheimer’s disease rather than only alleviate symptoms.

Vhttps://youtu.be/atAhUI6OMnsII

The Controversies

The route to FDA clearance for Aducanumab has been bumpy – and contentious.

Though doctors, patients, and the organizations that assist them are in desperate need of therapies that can delay mental decline, scientists question the efficacy of the new medicine, Aducanumab or Aduhelm. In March 2019, two trials were halted because the medications looked to be ineffective. “The futility analysis revealed that the studies were most likely to fail,” said Isaacson of Weill Cornell Medicine and NewYork-Presbyterian. Biogen, the drug’s manufacturer revealed several months later that a fresh analysis with more participants found that individuals who got high doses of Aducanumab exhibited a reduction in clinical decline in one experiment. Patients treated with high-dose Aducanumab had 22% reduced clinical impairment in their cognitive health at 18 months, indicating that the advancement of their early Alzheimer’s disease was halted, according to FDA briefing documents from last year.

When the FDA’s members were split on the merits of the application in November, it was rejected. Three of its advisers went public, claiming that there was insufficient evidence that it worked in a scientific journal. They were concerned that if the medicine was approved, it might reduce the threshold for future approvals, owing to the scarcity of Alzheimer’s treatments.

Dr. Caleb Alexander, a drug safety and effectiveness expert at the Johns Hopkins Bloomberg School of Public Health, was one of the FDA advisers who was concerned that the data presented to the agency was a reanalysis after the experiment was stopped. It was “like the Texas sharpshooter fallacy,” he told the New York Times, “where the sharpshooter blows up a barn and then goes and paints a bullseye around the cluster of holes he loves.”

Some organizations, such as the non-profit Public Citizen’s Health Research Group, claimed that the FDA should not approve Aducanumab for the treatment of Alzheimer’s disease because there is insufficient proof of its efficacy.

The drug is a monoclonal antibody that inhibits the formation of amyloid protein plaques in the brain, which are thought to be the cause of Alzheimer’s disease. The majority of Alzheimer’s medications have attempted to erase these plaques.

Aducanumab appears to do this in some patients, but only when the disease is in its early stages. This means that people must be checked to see if they have the disease. Many persons with memory loss are hesitant to undergo testing because there is now no treatment available.

The few Alzheimer’s medications available appear to have limited effectiveness. When Aricept, also known as Donepezil, was approved more than 20 years ago, there was a major battle to get it. It was heralded as a breakthrough at the time – partly due to the lack of anything else. It has become obvious that it slows mental decline for a few months but makes little effect in the long run.

The findings of another trial for some patients backed up those conclusions.

Biogen submitted a Biologics License Application to the FDA in July 2020, requesting approval of the medicine.

The FDA’s decision has been awaited by Alzheimer’s disease researchers, clinicians, and patients since then.

Support for approval of the drug

Other groups, such as the Alzheimer’s Association, have supported the drug’s approval.

The Alzheimer’s Association‘s website stated on Friday, “This is a critical time, regardless of the FDA’s final judgment. We’ve never been this close to approving an Alzheimer’s drug that could affect the disease’s development rather than just the symptoms. We can keep working together to achieve our goal of a world free of Alzheimer’s disease and other dementias.”

The drug has gotten so much attention that the Knight Alzheimer Disease Research Center at Washington University in St. Louis issued a statement on Friday stating that even if it is approved, “it will still likely take several months for the medication to pass other regulatory steps and become available to patients.”

Biogen officials told KGO-TV on Monday that the medicine will be ready to ship in about two weeks and that they have identified more than 900 facilities across the United States that they feel will be medically and commercially suitable.

Officials stated the corporation will also provide financial support to qualifying patients so that their out-of-pocket payments are as low as possible. Biogen has also pledged not to raise the price for at least the next four years.

Most Medicare customers with supplemental plans, according to the firm, will have a limited or capped co-pay.

Case studies connected to the Drug Approval

Case 1

Ann Lange, one of several Chicago-area clinical trial volunteers who received the breakthrough Alzheimer’s treatment, said,

It really offers us so much hope for a long, healthy life.

Lange, 60, has Alzheimer’s disease, which she was diagnosed with five years ago. Her memory has improved as a result of the monthly infusions, she claims.

She said,

I’d forget what I’d done in the shower, so I’d scribble ‘shampoo, conditioner, face, body’ on the door. Otherwise, I’d lose track of what I’m doing “Lange remarked. “I’m not required to do that any longer.

Case 2

Jenny Knap, 69, has been receiving infusions of the Aducanumab medication for about a year as part of two six-month research trials. She told CNN that she had been receiving treatment for roughly six months before the trial was halted in 2019, and that she had recently resumed treatment.

Knap said,

I can’t say I noticed it on a daily basis, but I do think I’m doing a lot better in terms of checking for where my glasses are and stuff like that.

When Knap was diagnosed with mild cognitive impairment, a clinical precursor to Alzheimer’s disease, in 2015, the symptoms were slight but there.

Her glasses were frequently misplaced, and she would repeat herself, forgetting previous talks, according to her husband, Joe Knap.

Joe added,

We were aware that things were starting to fall between the cracks as these instances got more often

Jenny went to the Lou Ruvo Center for Brain Health at the Cleveland Clinic in Ohio for testing and obtained her diagnosis. Jenny found she was qualified to join in clinical trials for the Biogen medicine Aducanumab at the Cleveland Clinic a few years later, in early 2017. She volunteered and has been a part of the trial ever since.

It turns out that Jenny was in the placebo category for the first year and a half, Joe explained, meaning she didn’t get the treatment.

They didn’t realize she was in the placebo group until lately because the trial was blind. Joe stated she was given the medicine around August 2018 and continued until February 2019 as the trial progressed. The trial was halted by Biogen in March 2019, but it was restarted last October, when Jenny resumed getting infusions.

Jenny now receives Aducanumab infusions every four weeks at the Cleveland Clinic, which is roughly a half-hour drive from their house, with Joe by her side. Jenny added that, despite the fact that she has only recently begun therapy, she believes it is benefiting her, combined with a balanced diet and regular exercise (she runs four miles).

The hope of Aducanumab is to halt the progression of the disease rather than to improve cognition. We didn’t appreciate any significant reduction in her condition, Jenny’s doctor, Dr. Babak Tousi, who headed Aducanumab clinical studies at the Cleveland Clinic, wrote to CNN in an email.

This treatment is unlike anything we’ve ever received before. There has never been a drug that has slowed the growth of Alzheimer’s disease, he stated, Right now, existing medications like donepezil and memantine aid with symptoms but do not slow the disease’s progression.

Jenny claims that the medicine has had no significant negative effects on her.

There was signs of some very minor bleeding in the brain at one point, which was quite some time ago. It was at very low levels, in fact, Joe expressed concern about Jenny, but added that the physicians were unconcerned.

According to Tousi, with repeated therapy, “blood vessels may become leaky, allowing fluid and red blood cells to flow out to the surrounding area,” and “micro hemorrhages have been documented in 19.1% of trial participants who got” the maximal dose of therapy”.

Jenny and Joe’s attitude on the future has improved as a result of the infusions and keeping a healthy lifestyle, according to Joe. They were also delighted to take part in the trial, which they saw as an opportunity to make a positive influence in other people’s lives.

There was this apprehension of what was ahead before we went into the clinical trial, Joe recalled. “The medical aspect of the infusion gives us reason to be optimistic. However, doing the activity on a daily basis provides us with immediate benefits.”

The drug’s final commercialization announcement

Aducanumab, which will be marketed as Aduhelm, is a monthly intravenous infusion that is designed to halt cognitive decline in patients with mild memory and thinking issues. It is the first FDA-approved medication for Alzheimer’s disease that targets the disease process rather than just the symptoms.

The manufacturer, Biogen, stated Monday afternoon that the annual list price will be $56,000. In addition, diagnostic tests and brain imaging will very certainly cost tens of thousands of dollars.

The FDA approved approval for the medicine to be used but ordered Biogen to conduct a new clinical trial, recognizing that prior trials of the medicine had offered insufficient evidence to indicate effectiveness.

Biogen Inc said on Tuesday that it expects to start shipping Aduhelm, a newly licensed Alzheimer’s medicine, in approximately two weeks and that it has prepared over 900 healthcare facilities for the intravenous infusion treatment.

Other Relevant Articles

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/

Alzheimer’s Disease – tau art thou, or amyloid

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/02/15/alzheimers-disease-tau-art-thou-or-amyloid/

Connecting the Immune Response to Amyloid-β Aggregation in Alzheimer’s Disease via IFITM3

Reporter : Irina Robu, PhD

https://pharmaceuticalintelligence.com/2020/10/13/connecting-the-immune-response-to-amyloid-%ce%b2-aggregation-in-alzheimers-disease-via-ifitm3/

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

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/02/27/ustekinumab-new-drug-therapy-for-cognitive-decline-resulting-from-neuroinflammatory-cytokine-signaling-and-alzheimers-disease/

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

https://pharmaceuticalintelligence.com/2018/08/13/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/

Recent progress in neurodegenerative diseases and gliomas

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/05/28/recent-progress-in-neurodegenerative-diseases-and-gliomas/

Read Full Post »

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

A recent research work performed by the Researchers at the University of California San Diego School of Medicine has shared their first-in-human Phase I clinical trial to assess the safety and viability of gene therapy to deliver a key protein into the brains of persons with Alzheimer’s Disease (AD) or Mild Cognitive Impairment (MCI), a condition that often precedes full-blown dementia.  

Mark Tuszynski, M.D., Ph.D., Professor of Neuroscience and Director of the Translational Neuroscience Institute at UC San Diego and team predicted that Gene therapy could be a boon to potential treatments for the disorders like AD and MCI.

The study provides an insight into the genetic source of these mental diseases.

The roots of mental disorders have remained an enigma for so many years. Alzheimer’s disease (AD) is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks. AD is a neurodegenerative condition. A buildup of plaques and tangles in the brain, along with cell death, causes memory loss and cognitive decline. In most people with the disease, those with the late-onset type – symptoms first appear in their mid-60s. Alzheimer’s disease is the mostly appearing type of dementia in patients.

Drawing comparing a normal aged brain (left) and the brain of a person with Alzheimer’s (right).
Image Source: https://en.wikipedia.org/wiki/Alzheimer%27s_disease

What the study impart?

Despite decades of effort and billions of dollars of research investment, there are just mere two symptomatic treatments for AD. There is no cure or approved way to slow or stop the progression of the neurological disorder that afflicts more than 5 million Americans and is the sixth leading cause of death in the United States.

Prof. Tuszynski said gene therapy has been tested on multiple diseases and conditions, represents a different approach to a disease that requires new ways of thinking about the disease and new attempts at treatments.

The research team found that delivering the BDNF to the part of the brain that is affected earliest in Alzheimer’s disease; the entorhinal cortex and hippocampus – was able to protect from ongoing cell degeneration by reversing the loss of connections. “These trials were observed in aged rats, amyloid mice, and aged monkeys.”

The protein, called Brain-Derived Neurotrophic Factor or BDNF, a family of growth factors found in the Brain and Central Nervous System that support the survival of existing neurons and promote growth and differentiation of new neurons and synapses. BDNF is especially important in brain regions susceptible to degeneration in AD. It is normally produced throughout life in the entorhinal cortex, an important memory center in the brain and one of the first places where the effects of AD typically appear in the form of short-term memory loss. Persons with AD have diminished levels of BDNF.

However, BDNF is a large molecule and cannot pass through the Blood-Brain Barrier. As a solution, researchers will use gene therapy in which a harmless Adeno-Associated Virus (AAV2) is modified to carry the BDNF gene and injected directly into targeted regions of the brain, where researchers hope it will prompt the production of therapeutic BDNF in nearby cells.

Precautions were taken precisely in injecting the patient to avoid exposure to surrounding degenerating neurons since freely circulating BDNF can cause adverse effects, such as seizures or epileptic conditions.

The recent research and study speculate a safe and feasible assessment of the AAV2-BDNF pathway in humans. A previous gene therapy trial from 2001 to 2012 using AAV2 and a different protein called Nerve Growth Factor (NGF) was carried out by Prof. Tuszynski and team where they observed immense growth, axonal sprouting, and activation of functional markers in the brains of participants.

He also shared that “The BDNF gene therapy trial in AD represents an advancement over the earlier NGF trial, BDNF is a more potent growth factor than NGF for neural circuits that degenerate in AD. Besides, new methods for delivering BDNF will more effectively deliver and distribute it into the entorhinal cortex and hippocampus.”

The research team hopes that the three-year-long trial will recruit 12 participants with either diagnosed AD or MCI to receive AAV2-BDNF treatment, with another 12 persons serving as comparative controls over that period.

The researchers have plans to build on recent successes of gene therapy in other diseases, including a breakthrough success in the treatment of congenital weakness in infants (spinal muscular atrophy) and blindness (Leber Hereditary Optic Neuropathy, a form of retinitis pigmentosa).”

Main Source

https://www.universityofcalifornia.edu/news/could-gene-therapy-halt-progression-alzheimers-disease-first-human-clinical-trial-will-seek?utm_source=fiat-lux

Related Articles

https://pharmaceuticalintelligence.com/2016/04/21/alzheimers-disease-and-dm/
https://pharmaceuticalintelligence.com/2016/03/21/role-of-infectious-agent-in-alzheimers-disease/
https://pharmaceuticalintelligence.com/2016/02/15/alzheimers-disease-tau-art-thou-or-amyloid/

Read Full Post »

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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Other related articles published in this Open Access Online Scientific Journal include the following:

 

Single Cell Sequencing:

Part 4.1 in Genomics Volume 2

Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology 

On Amazon.com since 12/28/2019

https://www.amazon.com/dp/B08385KF87

 

4.1.3   Single-cell Genomics: Directions in Computational and Systems Biology – Contributions of Prof. Aviv Regev @Broad Institute of MIT and Harvard, Cochair, the Human Cell Atlas Organizing Committee with Sarah Teichmann of the Wellcome Trust Sanger Institute

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/09/03/single-cell-genomics-directions-in-computational-and-systems-biology-contributions-of-ms-aviv-regev-phd-broad-institute-of-mit-and-harvard-cochair-the-human-cell-atlas-organizing-committee-wit/

 

4.1.4   Cellular Genetics

https://www.sanger.ac.uk/science/programmes/cellular-genetics

 

4.1.5   Cellular Genomics

https://www.garvan.org.au/research/cellular-genomics

 

4.1.6   SINGLE CELL GENOMICS 2019 – sometimes the sum of the parts is greater than the whole, September 24-26, 2019, Djurönäset, Stockholm, Sweden http://www.weizmann.ac.il/conferences/SCG2019/single-cell-genomics-2019

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2019/05/29/single-cell-genomics-2019-september-24-26-2019-djuronaset-stockholm-sweden/

 

4.1.7   Norwich Single-Cell Symposium 2019, Earlham Institute, single-cell genomics technologies and their application in microbial, plant, animal and human health and disease, October 16-17, 2019, 10AM-5PM

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2019/06/04/norwich-single-cell-symposium-2019-earlham-institute-single-cell-genomics-technologies-and-their-application-in-microbial-plant-animal-and-human-health-and-disease-october-16-17-2019-10am-5pm/

 

4.1.8   Newly Found Functions of B Cell

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

https://pharmaceuticalintelligence.com/2019/05/23/newly-found-functions-of-b-cell/

 

4.1.9 RESEARCH HIGHLIGHTS: HUMAN CELL ATLAS

https://www.broadinstitute.org/research-highlights-human-cell-atlas

 

CRISPR – 200 articles in the Journal

 

Chapter 21 in Genomics Volume 1

Genomics Orientations for Personalized Medicine. On Amazon.com since 11/23/2015

http://www.amazon.com/dp/B018DHBUO6

 

Glioblastoma – 150 articles in the Journal

Most recent

 

Immunotherapy may help in glioblastoma survival

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

https://pharmaceuticalintelligence.com/2019/03/16/immunotherapy-may-help-in-glioblastoma-survival/

 

New Treatment in Development for Glioblastoma: Hopes for Sen. John McCain

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/07/25/new-treatment-in-development-for-glioblastoma-hopes-for-sen-john-mccain/

 

Funding Oncorus’s Immunotherapy Platform: Next-generation Oncolytic Herpes Simplex Virus (oHSV) for Brain Cancer, Glioblastoma Multiforme (GBM)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/28/funding-oncoruss-immunotherapy-platform-next-generation-oncolytic-herpes-simplex-virus-ohsv-for-brain-cancer-glioblastoma-multiforme-gbm/

 

Glioma, Glioblastoma and Neurooncology

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/10/19/glioma-glioblastoma-and-neurooncology/

 

Positron Emission Tomography (PET) and Near-Infrared Fluorescence Imaging:  Noninvasive Imaging of Cancer Stem Cells (CSCs)  monitoring of AC133+ glioblastoma in subcutaneous and intracerebral xenograft tumors

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/29/positron-emission-tomography-pet-and-near-infrared-fluorescence-imaging-noninvasive-imaging-of-cancer-stem-cells-cscs-monitoring-of-ac133-glioblastoma-in-subcutaneous-and-intracerebral-xenogra/

 

Gamma Linolenic Acid (GLA) as a Therapeutic tool in the Management of Glioblastoma

Eric Fine* (1), Mike Briggs* (1,2), Raphael Nir# (1,2,3)

https://pharmaceuticalintelligence.com/2013/07/15/gamma-linolenic-acid-gla-as-a-therapeutic-tool-in-the-management-of-glioblastoma/

 

 

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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

 

Reporter: Aviva Lev-Ati, PhD, RN

 

A neuronal blood marker is associated with mortality in old age

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

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

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

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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
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

 

Other related articles were published in this Open Access Online Scientific Journal, including the following:

RNA in synthetic biology

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/03/26/rna-in-synthetic-biology/

mRNA Data Survival Analysis

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

https://pharmaceuticalintelligence.com/2016/06/18/mrna-data-survival-analysis/

Recent progress in neurodegenerative diseases and gliomas

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/05/28/recent-progress-in-neurodegenerative-diseases-and-gliomas/

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

Reporter and writer: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/02/19/genomic-promise-for-neurodegenerative-diseases-dementias-autism-spectrum-schizophrenia-and-serious-depression/

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Connecting the Immune Response to Amyloid-β Aggregation in Alzheimer’s Disease via IFITM3

Reporter : Irina Robu, PhD

Alzheimer’s disease is a complex condition and it begins with slow aggregation of amyloid-β deposits over the course of years. This produces a mild cognitive impairment and a state of chronic inflammation enough to trigger harmful aggregation of the altered tau protein. Clearing amyloid-β from the brain hasn’t produced telling benefits to patients suggesting that it is not the key process in the development of the condition.

Recent research indicates that beta-amyloid has antiviral and antimicrobial properties, indicating a possible link between the immune response against infections and development of Alzheimer’s disease. Scientists have discovered evidence that protein interferon-induced transmembrane protein 3 (IFITM3) is involved in immune response to pathogens and play a key role in the accumulation of beta amyloid in plaques. IFITM3 is able to alter the activity of gamma-secretase enzyme, which breaks down the precursor proteins into fragments of beta-amyloid that make up plaques. 

Yet it was determined that the production of IFITM3 starts in reply to activation of the immune system by invading viruses and bacteria. Indeed, researchers found that the level of IFITM3 in human brain samples correlated with levels of certain viral infections as well as with gamma-secretase activity and beta-amyloid production. Age is the number one risk factor for Alzheimer’s and the levels of both inflammatory markers and IFITM3 increased with advancing age in mice.

Innate immunity is also correlated with Alzheimer’s disease1, but the influence of immune activation on the production of amyloid beta is unknown. They were able to identify IFITM3 as γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-β.

According to the current research, inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-β. The expression of IFITM3 is increased with ageing and in mouse models that express Alzheimer’s disease genes. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer’s disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer’s disease. These conclusions disclose a mechanism in which γ-secretase is controlled by neuroinflammation via IFITM3 and the risk of Alzheimer’s disease is thus amplified

SOURCE

https://www.nature.com/articles/s41586-020-2681-2

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Medical Device Technology for Alzheimer’s Diseases

Reporter: Danielle Smolyar

 

Alzheimer’s disease is said to be caused by a large number of proteins that are overproduced around a brain cell. Alzheimer’s is an irreversible disease that overtime decreases a person’s memory and the ability to perform tasks. With this disease, it is hard to function day to day life because it is hard to take on simple daily tasks or activities. It is a powerful and advanced disease that has not yet been found a cure. There have been many trials and scientists and researchers are still trying to figure out and find a cure for this disease because so many people, unfortunately, suffer from it.

This acute disease has no cure yet.  In an article titled, World Alzheimer’s Month: Exploring the latest research and devices for early detection, According to the Alzheimer’s Association,

“an estimated 5.3 million Americans are currently living with Alzheimer’s disease. By 2025, that number is expected to increase to more than seven million. Doctors diagnose dementia in around 10 million people every year, and 60–70% of these new diagnoses detect Alzheimer’s disease.”

The reality of the disease is tragic and the fact that the numbers keep growing calls for more urgency to find a cure and help innocent people fight off this disease. With society’s new technological and medical advancements, researchers have been working on finding a cure or developing a medical device to help people with Alzheimer’s. The article also states, ”Dr. Thom Wilcockson, from the UK’s Loughborough University, found that

eye-tracking technology could help identify mild cognitive impairment (MCI) in patients who might go on to develop Alzheimer’s disease in the future.”

With this technology and how advanced our society is, technology could eventually find a cure. With this device, it can help and make a considerable change in the number of people who develop Alzheimer’s. This new tool could help people prepare for the sickness or prevent future conditions from getting worse. Ultimately, if we have this technology, it can teach the world and educate the world on this condition and how we can take strides into preventing it from happening.

Dr. Thom Wilcosckon stated that looking for MCI can be a benchmark or sign for doctors to look for early development of Alzheimer’s:

Dr. Wilcockson and the research team worked with 42 patients with a diagnosis of aMCI, 47 with a diagnosis of naMCI, 68 people with dementia caused due to Alzheimer’s disease, and 92 healthy controls as part of their study. During the study, the participants were instructed to complete antisaccade tasks that are simple computer test where participants are told to look away from a distractor stimulus. The researchers found that they were able to differentiate between the two forms of MCI by looking at the eye-tracking results.

This modern technique of being able to pinpoint a specific aspect that would differentiate patients and their sicknesses from one another can cause a massive shift in the Alzheimer’s world. One step at a time, doctors, scientists, and researches are learning more about Alzheimers and are inching closer to hopefully finding a cure in the near future.

SOURCES:

World Alzheimer’s Month: Exploring latest research and devices for early detection

World Alzheimer’s Month: Exploring latest research and devices for early detection

 

https://www.nhs.uk/conditions/alzheimers-disease/causes/

https://www.nsmedicaldevices.com/news/world-alzheimers-month-medical-devices/

 

Other related articles published on this Open Access Online Scientific Journal include the following:

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/

 

More …

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

Read Full Post »

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

 

 

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 HospitalMassachusetts General HospitalHarvard 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 InformationMarshall 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.

 

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

 

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://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, 2007aDecety 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.

Review

 

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

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

PMCID: PMC4791048
NIHMSID: NIHMS764322
PMID: 24915964
  • The multiplex model of the genetics of Alzheimer’s disease

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

 

REFERENCE for the Genetics of Alzheimer’s Disease

  1. Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706 (1991).
  2. Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–760 (1995).
  3. Rogaev, E. I. et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376, 775–778 (1995).
  4. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).
  5. Ricciarelli, R. & Fedele, E. The amyloid cascade hypothesis in Alzheimer’s disease: it’s time to change our mind. Curr. Neuropharmacol. 15, 926–935 (2017).
  6. Doody, R. S., Farlow, M. & Aisen, P. S., Alzheimer’s Disease Cooperative Study Data Analysis and Publication Committee. Phase 3 trials of solanezumab and bapineuzumab for Alzheimer’s disease. N. Engl. J. Med. 370, 1460 (2014).
  7. Honig, L. S. et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N. Engl. J. Med. 378, 321–330 (2018).
  8. Galimberti, D. & Scarpini, E. Disease-modifying treatments for Alzheimer’s disease. Ther. Adv. Neurol. Disord. 4, 203–216 (2011).
  9. Yiannopoulou, K. G. & Papageorgiou, S. G. Current and future treatments for Alzheimer’s disease. Ther. Adv. Neurol. Disord. 6, 19–33 (2013).
  10. Jagust, W. Imaging the evolution and pathophysiology of Alzheimer disease. Nat. Rev. Neurosci. 19, 687–700 (2018).
  11. Rajan, K. B., Wilson, R. S., Weuve, J., Barnes, L. L. & Evans, D. A. Cognitive impairment 18 years before clinical diagnosis of Alzheimer disease dementia. Neurology 85, 898–904 (2015).
  12. Rosenblum, W. I. Why Alzheimer trials fail: removing soluble oligomeric beta amyloid is essential, inconsistent, and difficult. Neurobiol. Aging 35, 969–974 (2014).
  13. Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168–174 (2006).
  14. Wingo, T. S., Lah, J. J., Levey, A. I. & Cutler, D. J. Autosomal recessive causes likely in early-onset Alzheimer disease. Arch. Neurol. 69, 59–64 (2012).
  15. Saunders, A. M. et al. Apolipoprotein E epsilon 4 allele distributions in late-onset Alzheimer’s disease and in other amyloid-forming diseases. Lancet 342, 710–711 (1993).
  16. Strittmatter, W. J. et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 1977–1981 (1993).
  17. Corder, E. H. et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat. Genet. 7, 180–184 (1994).
  18. Liao, F., Yoon, H. & Kim, J. Apolipoprotein E metabolism and functions in brain and its role in Alzheimer’s disease. Curr. Opin. Lipidol. 28, 60–67 (2017).
  19. Deane, R. et al. ApoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J. Clin. Invest. 118, 4002–4013 (2008).
  20. Verghese, P. B., Castellano, J. M. & Holtzman, D. M. Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol. 10, 241–252 (2011).
  21. Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat. Genet. 41, 1088–1093 (2009).
  22. Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 41, 1094–1099 (2009).

 

 

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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/

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