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Tag: Frontotemporal Dementia

  • Human neuron model identifies potential therapeutic targets for Alzheimer’s disease

    Human neuron model identifies potential therapeutic targets for Alzheimer’s disease

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    Weill Cornell Medicine scientists have developed an innovative human neuron model that robustly simulates the spread of tau protein aggregates in the brain-;a process that drives cognitive decline in Alzheimer’s disease and frontotemporal dementia. This new model has led to the identification of novel therapeutic targets that could potentially block tau spread.

    The preclinical study, published April 5 in Cell, is a significant advancement in Alzheimer’s disease research.

    Currently no therapies can stop the spread of tau aggregates in the brains of patients with Alzheimer’s disease. Our human neuron model of tau spread overcomes the limitations of previous models and has unveiled potential targets for drug development that were previously unknown.”


    Dr. Li Gan, lead study author, director of the Helen and Robert Appel Alzheimer’s Disease Research Institute and the Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine

    Human pluripotent stem cells can develop into any cell of the body and can be coaxed to become neurons to model brain diseases in a lab dish. However, it had been nearly impossible to model tau propagation in these young neurons, as tau propagation requires decades in aging brains.

    Dr. Gan’s team used CRISPR technology to modify the genomes of human stem cells, prompting them to express forms of tau associated with diseased aging brains. “This model has been a game-changer, simulating tau spread in neurons within weeks-;a process that would typically take decades in the human brain,” Dr. Gan said.

    In their quest to halt tau propagation, Dr. Gan’s team employed CRISPRi screening to disable one thousand genes to ascertain their roles in tau spread. They discovered 500 genes that have a significant impact on tau abundance.

    “CRISPRi technology allowed us to use unbiased approaches to look for drug targets, not confined to what was previously reported by other scientists,” said one of the lead study authors Celeste Parra Bravo, a neuroscience doctoral candidate in the Weill Cornell Graduate School of Medical Sciences working in the Gan lab.

    One discovery includes the UFMylation cascade, a cellular process involving the attachment of a small protein named UFM1 to other proteins. This process’s connection to tau spread was previously unknown. Post-mortem studies of brains from patients with Alzheimer’s disease found that UFMylation is altered, and the team also found in preclinical models that inhibition of the enzyme required for UFMylation blocks tau propagation in neurons.

    “We are particularly encouraged by the confirmation that inhibiting UFMylation blocked tau spread in both human neurons and mouse models,” said paper co-author Dr. Shiaoching Gong, associate professor of research in neuroscience in the Appel Institute at Weill Cornell Medicine.

    Many Alzheimer’s disease treatments initially show promise in mouse models but do not succeed in clinical trials, Dr. Gan said. With the new human cell model, she is optimistic about the path ahead. “Our discoveries in human neurons open the door to developing new treatments that could truly make a difference for those suffering from this devastating disease.”

    Source:

    Journal reference:

    Bravo, C. P., et al. (2024) Human iPSC 4R tauopathy model uncovers modifiers of tau propagation. Cell. doi.org/10.1016/j.cell.2024.03.015.

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  • New treatments in sight for challenging neuropsychiatric symptoms in neurodegenerative diseases

    New treatments in sight for challenging neuropsychiatric symptoms in neurodegenerative diseases

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    In a recent study published in the journal JAMA Neurology, researchers reviewed the progress thus far in pharmacologically managing the various neuropsychiatric syndromes that manifest in neurodegenerative disorders and discussed the recent advances in understanding the pathobiology of neurodegenerative disorders that help improve clinical care and therapy.

    Study: Progress in Pharmacologic Management of Neuropsychiatric Syndromes in Neurodegenerative Disorders. Image Credit: PopTika / ShutterstockStudy: Progress in Pharmacologic Management of Neuropsychiatric Syndromes in Neurodegenerative Disorders. Image Credit: PopTika / Shutterstock

    Neurodegenerative disorders and neuropsychiatric syndromes

    Neurodegenerative disorders encompass a wide range of conditions, many of which are a factor of progressing age and manifest symptoms only in late middle age or old age. However, with the growing aging population in the world, the frequency of neurodegenerative disorders and associated conditions continues to increase. While Lewy body dementia, Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease are some of the more commonly heard neurodegenerative disorders, others include frontotemporal dementia, corticobasal syndrome, progressive supranuclear palsy, amyotrophic lateral sclerosis, chronic traumatic encephalopathy, traumatic encephalopathy syndrome, and multiple system atrophy.

    All neurodegenerative disorders are associated with neuropsychiatric syndromes, with neuropsychiatric syndromes being part of the diagnostic criteria for some of the neurodegenerative disorders. These neuropsychiatric syndromes can occur sequentially or simultaneously and play a major role in functional impairment and overall decline in quality of life, not to mention adding to caregiver distress.

    Non-pharmacological interventions such as psychosocial treatments have been extensively explored to ameliorate neuropsychiatric syndromes in cases of neurodegenerative disorders and to prevent relapse. These include exercise programs, environmental modifications, music, acupressure and massage therapy, activities such as art in combination with music, and animal-assisted interventions.

    However, in cases where psychosocial interventions are not successful in reducing the symptoms of neuropsychiatric syndromes or in cases where the patient might be a threat to themselves or others, pharmacological interventions are preferred. Although the development of pharmacological therapies to treat neuropsychiatric syndromes has been challenging, several medications have been approved for use by the United States (U.S.) Food and Drug Administration (FDA), specifically for patients with neurodegenerative disorders.

    In the present review, the researchers discussed in detail five of the major neuropsychiatric syndromes, their occurrence, symptoms, and options for pharmacological management of these syndromes.

    Depression

    Depression is one of the common symptoms of neurodegenerative disorders, with a high prevalence of major depressive disorders among patients with dementia. In patients with Alzheimer’s disease dementia, depression that is not diagnosed or treated in time often accelerates cognitive decline, suicide risk, and mortality risk. The incidence of depression in other neurodegenerative disorders such as Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies can often be close to 80%.

    Although the diagnosis of depression in patients with neurodegenerative disorders is challenging, selective serotonin reuptake inhibitors and selective serotonergic and noradrenergic reuptake inhibitors have been prescribed. For depression that is life-threatening or psychotic, electroconvulsive therapy has often been effective. However, studies have found that Alzheimer’s disease pathology involving a high brain amyloid burden can result in resistance to pharmacotherapy.

    Disinhibition

    Disinhibition has often been observed in patients with progressive supranuclear palsy, Huntington’s disease, and Alzheimer’s disease. It involves behavior that is considered inappropriate according to social norms, such as touching strangers, making sexually explicit jokes or remarks, improper sexual acts, speaking loudly, and oversharing personal details. It is most common in patients with the behavioral variant of frontotemporal dementia.

    Atypical antipsychotics, selective serotonin reuptake inhibitors, and antiepileptic or mood-stabilizing agents have often been used to treat disinhibition. However, none of these are specifically for treating disinhibition in patients with neurodegenerative disorders.

    Apathy

    Apathy in dementia patients is often linked to a two-fold increase in the risk of cognitive decline. It is believed to increase caregiver distress, decrease treatment responses, and elevate the risk of frailty. While no approved treatments exist for apathy in patients with neurodegenerative disorders, psychosocial interventions, noninvasive brain stimulation, and non-psychostimulant pharmacologic interventions have been explored.

    Psychosis

    Psychosis, which involves a wide range of delusions and hallucinations, has varied associations with different neurodegenerative disorders. Patients with dementia with Lewy bodies often experience misidentification, misrepresentation, visual hallucinations, and feelings of presence, while frontotemporal dementia patients often also experience paranoia. The antipsychotics that have been approved for patients with neurodegenerative disorders based on results from placebo-controlled, double-blind trials include Pimavanserin, Risperidone, and Aripiprazole.

    Agitation

    One of the most prevalent and disruptive neuropsychiatric syndromes in most neurodegenerative disorders is agitation, which involves kicking, shoving, shouting, hitting, and resisting care. It is associated with rapid progression of dementia and earlier mortality. Agitation also results in a higher probability of hospitalization and substantially negatively impacts the quality of life of the patients and their families.

    Agitation is often treated with antipsychotics such as Risperidone, Aripiprazole, Quetiapine, and Brexpiprazole. Antidepressants such as Citalopram and the anticonvulsant Carbamazepine have also been used as pharmacological treatment options for agitation.

    Conclusions

    To summarize, the review examined the latest advances in the pharmacological management of neuropsychiatric syndromes associated with neurodegenerative disorders. The researchers provided a comprehensive summary of the symptoms of five major neuropsychiatric syndromes and the pharmacological options for their management.

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  • New fluid biomarker may one day detect ALS and FTD before symptoms appear

    New fluid biomarker may one day detect ALS and FTD before symptoms appear

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    Two progressively degenerative diseases, amyotrophic lateral sclerosis (ALS, commonly known as Lou Gehrig’s disease) and frontotemporal dementia (FTD, recently in the news with the diagnoses of actor Bruce Willis and talk show host Wendy Williams), are linked by more than the fact that they both damage nerve cells critical to normal functioning -; the former affecting nerves in the brain and spinal cord leading to loss of movement, the latter eroding the brain regions controlling personality, behavior and language.

    Research studies have repeatedly shown that in patients with ALS or FTD, the function of TAR DNA-binding protein 43, more commonly called TDP-43, becomes corrupted. When this happens, pieces of the genetic material called ribonucleic acid (RNA) can no longer be properly spliced together to form the coded instructions needed to direct the manufacture of other proteins required for healthy nerve growth and function. The RNA strands become riddled with erroneous code sequences called “cryptic exons” that instead affect proteins believed to be associated with increased risk for ALS and FTD development.

    Until now, it was unknown if this abnormality occurred early or late in the clinical courses of ALS and FTD. In a study in the February 2024 issue of the journal Nature Medicine (first posted online Jan. 25, 2024),Johns Hopkins Medicine researchers tell how they answered that long-pondered question.

    We developed a method for locating a specific cryptic exon-linked protein, hepatoma-derived growth factor-like 2 [HDGFL2], that is associated with the loss of TDP-43’s function. By doing so, we believe we’ve discovered a biomarker that could potentially be used to detect ALS and FTD in their earliest stages -; even before symptoms appear.”


    Philip Wong, Ph.D., senior study author, professor of pathology and neuroscience, Johns Hopkins University School of Medicine

    The hunt for the biomarker began with the researchers first identifying cryptic exon-linked proteins associated with TDP-43 function loss. Then, using fragments from those proteins known as cryptic peptides, they created monoclonal (laboratory-made) antibodies specific to each one. Placed into patient samples of blood or cerebrospinal fluid (the protective fluid that surrounds the brain and central nervous system), the monoclonal antibodies will seek and lock onto only the cryptic peptides for which they were designed, making those proteins detectable.

    “Of all the cryptic peptides for which we made monoclonal antibodies, the one that worked best was the one designed for the cryptic HDGFL2 protein,” says study lead author Katie Irwin, an M.D./Ph.D. student at the Johns Hopkins University School of Medicine. “We used that monoclonal antibody to develop an extremely sensitive detection test for the cryptic HDGFL2 protein in body fluids.”

    After validating their detection method in the lab, the researchers used it to test blood and cerebrospinal fluid samples from three different collections, encompassing people with the most common forms of familial (genetic) ALS and FTD linked to a mutation in the C9orf72 gene, sporadic (not defined as genetic) forms of ALS and FTD, and healthy controls. The collections also contained biofluid samples from patients with ALS and FTD prior to their diagnoses, meaning that the researchers could look for cryptic HDGFL2 at both presymptomatic and symptomatic stages of the diseases.

    “Our test found cryptic HDGFL2 in the presymptomatic stages of patients who were genetically predisposed to ALS and FTD, and were expected to go on to develop the diseases, giving the method credibility as a potential preclinical biomarker for predicting risk of ALS and FTD,” says Irwin. “And we discovered that the test also could detect elevated levels of cryptic HDGFL2 in fluids from people with sporadic disease cases where no family history of ALS or FTD was known.”

    Wong says that having a biomarker capable of detecting cryptic HDGFL2 in the biofluids of presymptomatic patients enables them to compare its findings to results using an established biomarker for ALS and FTD.

    “The current biomarker for ALS and FTD looks for structural components of central nervous system [brain and spinal cord] nerves called neurofilaments that are shed into the biofluids, but only after symptoms begin appearing,” explains Wong. “If we use it and our cryptic HDGFL2 biomarker to determine both presymptomatic and symptomatic ALS and FTD, we can map the course of these diseases and obtain greater insight into each of their stages.”

    Wong says that knowledge could help steer patients into clinical trials for new ALS and FTD therapies earlier and “at a time when it might truly make a difference.”

    Irwin says she and her colleagues are gathering biofluid samples from around the world from patients with FTD, genetic ALS and sporadic ALS.

    “We hope to support the effectiveness, reliability and sensitivity of our biomarker by testing it on thousands of patient samples, and once validated, encourage its use as a clinical tool,” she says. “We also plan to explore the use of our biomarker for determining the effectiveness of therapies in preclinical ALS and FTD by looking for reductions in cryptic HDGFL2 levels -; and restoration of TDP-43 function -; after treatment.”

    Along with Wong and Irwin, the members of the study team from Johns Hopkins Medicine are Kyra Bowden, Kerstin Braunstein, Koping Chang, Pei Jasin, Jonathan Ling, Abhay Moghekar, Esther Oh, Irika Sinha, Bryan Traynor and Juan Troncoso. Other team members are Dan Bartlett and Denitza Raitcheva from Biogen, James Berry and Mark Garret from Massachusetts General Hospital, and Timothy Miller from the Washington University School of Medicine in St. Louis.

    Funding for the study came from National Institutes of Health grants R01NS095969, UH3NS115608 and R33NS115161; the Robert Packard Center for ALS Research at Johns Hopkins; the Target ALS Foundation; ALS Finding a Cure; the ALS Association; U.S. Food and Drug Administration grant 1U01FD008129; the Alzheimer’s Association; the Institute for Data-Intensive Engineering and Science; the Intramural Research Program of NIH (National Institute on Aging/National Institute on Neurological Disorders and Stroke grant 1ZIAAG000933); and the Karen Toffler Charitable Trust.

    Ling and Wong are inventors on a provisional patent application submitted by The Johns Hopkins University that covers the use of TDP-43-associated cryptic exon-derived neoepitopes as biomarkers. Traynor holds patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. Bartlett is an employee and shareholder of Biogen. At the time of the study, Raitcheva was an employee and shareholder of Biogen.

    Source:

    Journal reference:

    Irwin, K. E., et al. (2024). A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD. Nature Medicine. doi.org/10.1038/s41591-023-02788-5.

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  • Groundbreaking study unveils new insights into neurodegenerative disorder symptoms

    Groundbreaking study unveils new insights into neurodegenerative disorder symptoms

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    In a recent study published in Nature Medicine, researchers developed a method for rapidly gathering and integrating clinical (CD) and neuropathological diagnoses (ND) data by examining medical record summaries from donors at the Netherlands Brain Bank (NBB) to detect disease trajectories.

    Study: Identification of clinical disease trajectories in neurodegenerative disorders with natural language processing. Image Credit: Natali _ Mis/Shutterstock.comStudy: Identification of clinical disease trajectories in neurodegenerative disorders with natural language processing. Image Credit: Natali _ Mis/Shutterstock.com

    Background

    Neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies, are a worldwide health issue due to their wide range of clinical symptoms and complicated comorbidities.

    Current research struggles to acquire complete clinical data, which limits statistical designs. Innovative data-driven strategies that use large autopsy cohorts are required to improve diagnosis.

    Brain banks give vital information on neurodegenerative illnesses, but drawbacks such as limited clinical data and binary case-control designs impede development.

    About the study

    In the present study, researchers created a computer pipeline to translate medical record summaries from Netherlands Brain Bank (NBB) donors into clinical illness trajectories, which included 84 neuropsychiatric symptoms and signs recognized using natural language processing.

    They scanned NBB donor files, defined and predicted clinical features in the recorded history, translated predicted symptoms and signs into clinical illness trajectories, and applied them for downstream analysis.

    The researchers developed a novel cross-disorder clinical classification system including 90 neuropsychiatric symptoms and signs related to brain illnesses and general well-being. One scorer evaluated 18,917 phrases from a randomly selected group of 293 contributors to build a dataset for refining, validating, and testing various Natural Language Processing (NLP) models.

    The researchers optimized five model designs [support vector machine (SVM), bag of words (BOW), T5, PubMedBERT, and Bio_ClinicalBERT] and chose the best one based on microprecision.

    The team developed the clinical illness trajectories, including several neuropsychiatric symptoms and signs, duration, and more donors than previously published. They then ran an enrichment assessment to investigate whether the estimated clinical features were more prevalent in each disease than expected.

    To assess the diagnostic accuracy of this brain autopsy cohort, the researchers cleaned and matched CD descriptions to the human disease ontology and compared the generated clinical diagnosis labels to the neurodegenerative diagnoses.

    The researchers incorporated machine-learning algorithms into healthcare practices to consistently predict neuropathological diagnoses from clinical illness trajectories.

    They included 3,042 donors who provided 199,901 words of clinical history data and were diagnosed with different neuropathologically characterized brain illnesses.

    The team chose symptoms and signs based on their medical-scientific importance, existence in the clinical history, and definition clarity.

    The team used a gated recurrent unit (GRU-D) to assess the accuracy of forecasting ND from clinical illness trajectories, emphasizing the apolipoprotein E4 genotype associated with early AD and severe neurodegeneration.

    The team used clinical illness trajectories to conduct temporal profiling of specific neuropsychiatric signs and symptoms across various disorders.

    They also performed a survival analysis to determine whether there were differences in the overall survival rate after the first observation of a sign or symptom between donors with different neuropathological diagnoses.

    Results

    The researchers identified indications and symptoms that differ between often misdiagnosed illnesses and clinical subgroups of diverse brain disorders, indicating that neuronal substructures are affected differently.

    The inter-annotator agreement for model reliability was high, with 269 signs and symptoms considerably enriched in particular diagnoses, 148 of which were pre-defined to be of diagnostic value.

    All neuropsychiatric features showed significant enrichment in one or more brain conditions, indicating they were related to a subcategory of diseases.

    As predicted, dementia and memory impairment were much more prevalent in dementias such as AD, frontotemporal dementia (FTD), vascular dementia (VD), dementia with Lewy bodies (DLB), and pervasive development disorders (PDDs), a finding not observed in Parkinson’s disease without dementia.

    Likewise, multiple sclerosis (MS) demonstrated significant enrichment for mobility impairment, muscle weakness, and fatigue, consistent with the debilitating disease of the central nervous system.

    Progressive supranuclear palsy (PSP), multiple system atrophy (MSA), PD, MS, PDD, and ATAXIA showed increased enrichment for reduced mobility.

    In contrast, MND, VD, PSP, MS, and MSA showed higher enrichment for muscle weakness, indicating that the approach may identify a distinct set of disease-specific symptoms.

    The researchers found specific indications and symptoms increased in specific subtypes of dementia, such as paranoia and façade behavior in Alzheimer’s disease and hearing issues and muscular weakness in vascular dementia.

    Eighty-four percent of neuropathologically identified Alzheimer’s disease donors and 83% of neuropathologically defined FTD donors were clinically diagnosed with Alzheimer’s disease or frontotemporal dementia, respectively.

    MSA was commonly clinically diagnosed as Parkinson’s disease, whereas vascular dementia and PSP were classified clinically as several different conditions, indicating that NBB brain donors frequently receive a misdiagnosis.

    Conclusion

    The study findings highlighted NLP usage to identify the clinical trajectories of neurodegenerative diseases. The findings indicate that many brain illnesses have largely overlapping symptoms, which might indicate disturbed neuronal substructures.

    The findings can help epidemiologists, molecular biologists, and computational researchers investigate the clinical symptoms of neurodegenerative disorders and build prediction models to identify new data-driven clinical subgroups for diseases such as dementia, Parkinson’s disease, and multiple sclerosis.

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  • Neural cell culture model sheds light on the intricate mechanisms underlying neurodegeneration

    Neural cell culture model sheds light on the intricate mechanisms underlying neurodegeneration

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    Scientists at the University of Zurich have developed an innovative neural cell culture model, shedding light on the intricate mechanisms underlying neurodegeneration. Their research pinpointed a misbehaving protein as a promising therapeutic target in the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

    Neurodegenerative diseases cause some of the neurons in our brains to die, resulting in different symptoms depending on the brain region affected. In amyotrophic lateral sclerosis (ALS), neurons in the motor cortex and spinal cord degenerate, leading to paralysis. In frontotemporal dementia (FTD), on the other hand, neurons located in the parts of the brain involved in cognition, language and personality are affected.

    Both ALS and FTD are relentlessly progressive diseases and effective treatments are still lacking. As the population ages, the prevalence of age-related neurodegenerative diseases such as ALS and FTD is expected to increase.

    Despite the identification of the aberrant accumulation of a protein called TDP-43 in neurons in the central nervous system as a common factor in the vast majority of ALS and about half of FTD patients, the underlying cellular mechanisms driving neurodegeneration remain largely unknown.

    Flexible, durable, reproducible: ideal cell culture model for ALS and FTD research

    In their study, first author Marian Hruska-Plochan and corresponding author Magdalini Polymenidou of the Department of Quantitative Biomedicine at the University of Zurich developed a novel neural cell culture model that replicates the aberrant behavior of TDP-43 in neurons. Using this model, they discovered a toxic increase in the protein NPTX2, suggesting it as a potential therapeutic target for ALS and FTD.

    To mimic neurodegeneration, Marian Hruska-Plochan developed a new cell culture model called “iNets,” derived from human induced pluripotent stem cells. These cells, originated from skin cells and reprogrammed to a very early, undifferentiated stage in the laboratory, serve as a source for developing many different, desired cell types. iNets are a network of interconnected neurons and their supporting cells growing in multiple layers in a dish.

    The cultures lasted exceptionally long – up to a year – and were easily reproduced. +

    The robustness of aging iNets allows us to perform experiments that would not have been possible otherwise. And the flexibility of the model makes it suitable for a wide range of experimental methodologies.”


    Marian Hruska-Plochan, First Author

    As a case in point, the iNets cell cultures provided the ideal model to investigate the progression from TDP-43 dysfunction to neurodegeneration.

    How protein dysfunction leads to neurodegeneration

    Employing the iNets model, the researchers identified a toxic accumulation of NPTX2, a protein normally secreted by neurons through synapses, as the missing link between TDP-43 misbehavior and neuronal death. To validate their hypothesis, they examined brain tissue from deceased ALS and FTD patients and indeed found that, also in patients, NPTX2 accumulated in cells containing abnormal TDP-43. This means that the iNets culture model accurately predicted ALS and FTD patient pathology.

    In additional experiments in the iNets model, the researchers tested whether NPTX2 could be a target for drug design to treat ALS and FTD. The team engineered a setup in which they lowered the levels of NPTX2 while neurons were suffering from TDP-43 misbehavior. They found that keeping NPTX2 levels low counteracted neurodegeneration in the iNets neurons. Therefore, drugs that reduce the amount of the protein NPTX2 have potential as a therapeutic strategy to halt neurodegeneration in ALS and FTD patients.

    Magdalini Polymenidou sees great promise in this discovery: “We still have a long way to go before we can bring this to the patients, but the discovery of NPTX2 gives us a clear shot of developing a therapeutic that acts at the core of the disease,” she said. “In conjunction with two additional targets recently identified by other research teams, it is conceivable that anti-NPTX2 agents could emerge as a key component of combination therapies for ALS and FTD in the future,” she added.

    Source:

    Journal reference:

    Hruska-Plochan, M., et al. (2024). A model of human neural networks reveals NPTX2 pathology in ALS and FTLD. Nature. doi.org/10.1038/s41586-024-07042-7.

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