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Tag: Neurodegeneration

  • Delirium linked to tripled dementia risk in older adults, Australian study finds

    Delirium linked to tripled dementia risk in older adults, Australian study finds

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    In a recent study published in BMJ, researchers explored the relationship between delirium and new-onset dementia among older adults with no dementia diagnosis at baseline.

    Study: Delirium and incident dementia in hospital patients in New South Wales, Australia: retrospective cohort study. Image Credit: LightField Studios/Shutterstock.comStudy: Delirium and incident dementia in hospital patients in New South Wales, Australia: retrospective cohort study. Image Credit: LightField Studios/Shutterstock.com

    Background

    Delirium is a syndrome marked by inattention and loss of awareness, frequently caused by acute events such as sickness or surgery. It is frequent in hospitals, particularly among individuals of advanced age with serious medical problems.

    Delirium is associated with adverse outcomes such as mortality, extended hospital admissions, and long-term cognitive deterioration.

    A comprehensive review and meta-analysis reported an association of delirium with new-onset dementia among individuals without dementia; however, these studies had small sample sizes and did not account for the significant risk of mortality in this vulnerable population. As the worldwide dementia burden grows, it is critical to identify delirium’s modifiable risk factor.

    About the study

    The present study investigated whether delirium is associated with new-onset dementia in older adults using state-level hospital data linked to the New South Wales (NSW) Centre for Health Record Linkage.

    The researchers conducted the study from July 2001 to March 2020, extracting data for 650,590 patients aged 65 years and older, excluding those with dementia at study initiation, as determined using the International Classification of Diseases, tenth revision (ICD-10) codes. They also excluded individuals with inconsistent data and those aged over 110 years.

    The researchers matched delirium patients 1:1 to healthy individuals using clinical (e.g., diagnoses and procedures) and personal (e.g., gender, birth date, nationality, and residence) characteristics and followed them for over five years.

    They considered the follow-up period as the duration between the index period (between January 2009 and December 2014) termination and that of the dataset.

    They performed Fine-Gray hazards and Cox proportional hazards and modeling to determine the associations between delirium with mortality and new-onset dementia. Study covariates included age, HFRS scores, primary diagnosis, episode duration, and intensive care unit admission duration.

    The team calculated hospital frailty risk scores (HFRS) and quantified the dose-response relationship between delirium and dementia incidence, stratifying data by sex.

    They also performed sensitivity analyses by extending the landmark period from a year to two and repeating analyses after eliminating individuals who died or received a dementia diagnosis within two years of their index episode.

    Results and discussion

    The researchers analyzed 55,211 pairs of delirium and non-delirium individuals (48% male, mean age of 83 years). Among the participants, 63,929 (58%) died, and 19,117 (17%) developed incident dementia in the follow-up period.

    Individuals with delirium showed a 39% increased risk of mortality [hazard ratio (HR), 1.4] and a three-fold higher risk for developing dementia (sub-distribution HR, 3.0) than non-delirium individuals.

    Among patients who experienced at least one delirium episode in the landmark period, each additional delirium episode related to a 10% increased death risk (HR, 1.1).

    The delirium-dementia association was more robust for males than females (sub-distribution HR, 3.2 vs. 2.9). Each additional delirium episode was related to a 20% higher new-onset dementia risk (sub-distribution HR, 1.2).

    Sensitivity analyses yielded similar results, indicating the robustness of the primary findings. The persistent connection between delirium presence and new-onset dementia years after the delirium episode (and remission of the triggering stresses) indicated that delirium is more than just an epiphenomenon or a sign of undiagnosed dementia or a fragile brain.

    Delirium and dementia have a dose-response association, which may lead to dementia through geriatric syndromes, medical consequences, and constraints. Delirium may potentially cause neuronal damage and neurodegeneration by disrupting biological systems.

    The relationship between systemic inflammatory indicators, delirium, and dementia is multifaceted and impacted by dementia pathogenesis. Neuroinflammation indicators such as amyloid-beta (Aβ) and tau proteins are associated with both disorders.

    The apolipoprotein (APOE) genotype has been linked to delirium, indicating a role for genetic profiles associated with systemic inflammation. Understanding the pathophysiological processes of delirium dementia may lead to the development of innovative therapies to prevent or slow neurodegeneration.

    Conclusions

    The study findings showed that delirium presence was significantly associated with dementia incidence among older individuals with no prior dementia diagnosis. Patients with delirium but without baseline dementia had a three-fold increased risk of developing dementia.

    The findings indicate a causal link between the two disorders, necessitating the development of novel treatments. The study also emphasized the need to consider gender when examining the relationship between delirium and incident dementia. Delirium prevention and treatment can help lower the global dementia burden.

    Men had a greater chance of incident dementia related to delirium, implying a poorer reserve of neuropathology. However, the relationship between neuropathological load and clinical dementia is non-linear, and there may be gender disparities in neuropathology patterns.

    Men may have more severe delirium, and there may be underlying sex differences in the molecular underpinnings of delirium that cause brain destruction and hastened neurodegeneration. Future research should investigate these concepts to discover sex-specific intervention targets.

    Journal reference:

    • Emily H. Gordon, David D. Ward, Hao Xiong, Shlomo Berkovsky, and Ruth E. Hubbard. (2024) Delirium and incident dementia in hospital patients in New South Wales, Australia: retrospective cohort study, BMJ, doi: http://dx.doi.org/10.1136/bmj-2023-077634.

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  • Skin biopsy for α-synuclein detection proves effective

    Skin biopsy for α-synuclein detection proves effective

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    In a recent study published in JAMA, researchers evaluated the positivity rate of cutaneous phosphorylated alpha-synuclein protein (P-SYN) deposition among individuals with dementia with Lewy body presence (DLB), Parkinson’s disease (PD), pure autonomic failure (PAF), and multiple system atrophy (MSA).

    Study: Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies. Image Credit: BLACKDAY/Shutterstock.comStudy: Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies. Image Credit: BLACKDAY/Shutterstock.com

    Background

    Synucleinopathies are neurodegenerative illnesses that cause P-SYN accumulation in the peripheral and central nervous systems. They include PD, MSA, DLB, and PAF. These illnesses share clinical characteristics, including progressive impairment and neurodegeneration.

    Current pharmacology lacks disease-modifying medication for these illnesses, and many individuals diagnosed with synucleinopathies face diagnostic delays or misdiagnoses.

    A reliable biomarker for identifying synucleinopathies, such as immunohistochemistry of cutaneous phosphorylated α-synuclein, is urgently needed. This test might be sensitive and specific.

    About the study

    In the present prospective, multicenter, cross-sectional study, researchers investigated whether skin biopsy could detect P-SYN in PD, MSA, DLB, and PAF patients.

    The researchers enrolled clinically confirmed cases of DLB, PD, PAF, or MSA recruited from 19 community-based and 11 academic neurology practices between February 2021 and March 2023, aged between 40 and 99 years.

    Individuals without history or clinical features indicative of a synucleinopathy (such as constipation, hyposmia, dementia, rapid-eye movement [REM] sleep disorder, or mild cognitive impairments) or neurodegenerative disorders comprised the control group.

    The researchers excluded individuals with biopsy-associated risks and synucleinopathy-mimicking diseases. They also excluded those with missing data from questionnaires and clinical examinations. The study exposure was a cutaneous biopsy for P-SYN detection.

    The primary outcome was cutaneous P-SYN detection frequency among individuals with MSA, PD, PAF, or DLB and controls.

    The researchers obtained skin biopsy specimens from the posterior cervical area, 3.0 cm from the spinous process of C-7, and the distal aspects of the leg at a distance of 10 cm from the lateral malleolus, and the thigh 10 cm from the lateral knee.

    The team examined the participants using the Hoehn and Yahr scale, the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS), the Montreal Cognitive Assessment, and orthostatic blood pressure.

    The participants filled out questionnaires such as the 39-component Parkinson’s Disease Questionnaire, the European Quality of Life questionnaires (EQ-VAS and EQ-5D), the MSA Quality of Life assessment Questionnaire, the rapid eye movement (REM) sleep disorder questionnaire, and the Orthostatic Hypotension Questionnaire.

    The researchers obtained disease symptom and duration data from participant medical records. The referral physician, who evaluated the individual, provided a clinical diagnosis.

    The participant history, examination scores, medical records, and ancillary test results were transmitted to two disease specialists for central review to validate the diagnosis of the particular synucleinopathy based on specified consensus and eligibility criteria for diagnoses or controls.

    Results

    Out of 428 patients (277 with synucleinopathy and 151 controls), 343 were included in the primary analysis [mean age, 70 years; 175 (51%) men]; 223 fulfilled the consensus criteria for synucleinopathy, and 120 met the criterion as controls following expert panel evaluation.

    Among those with synucleinopathy, 96 (28%) were diagnosed with Parkinson’s disease, 50 (15%) with Lewy body dementia, 55 (16%) with multiple system atrophy, and 22 (6.4%) with complete autonomic failure.

    The proportion of participants with P-SYN in their skin was 93% (n = 89) with Parkinson’s disease, 98% (n=54) with multiple system atrophy, 96% (n=48) with Lewy body dementia, and 100% (n=22) with complete autonomic failure; 3.30% (n=4) of controls had cutaneous phosphorylated-SYN deposition.

    P-SYN detection in the subepidermal plexus varied by synucleinopathy subtype, with MSA (49%, n=27) having a higher prevalence than Parkinson’s disease (3.1%, n=3), DLB (10%, n=5), or PAF (9.1%, n=2). There were no infections or significant problems.

    The length-dependent small fiber neuropathy varies amongst synucleinopathy subtypes. Neuropathy was most prevalent in DLB patients (78%, n=39), followed by those with Parkinson’s disease (63%, n = 60), PAF (46%, n=10), and MSA (22%, n=12).

    The overall P-SYN for all research participants corresponded with their exam results and surveys. P-SYN deposition by the study participants was associated with the period since MSA, PAF, and PD diagnosis.

    Conclusions

    The study findings showed that skin biopsy may identify phosphorylated alpha-synuclein among individuals with DLB, PD, PAF, and MSA. The findings demonstrated that cutaneous P-SYN in >92% of participants, with skin biopsies, was tolerated well with minor side effects.

    However, there were 21% of misdiagnosed cases. Accurate diagnosis is critical for patient and family counseling, starting symptomatic treatment, and conducting clinical studies of possible disease-modifying medications.

    Cognitive neurology experts recommend skin biopsy as a novel method for movement problems. The findings might speed up medication development for synucleinopathies by enhancing patient homogeneity in clinical trials.

    More studies are needed to confirm the findings and better understand the potential relevance of skin biopsy detection in clinical treatment.

    Journal reference:

    • Christopher H. Gibbons, MD, MMSc, et al., (2024) Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies, JAMA 2024, doi: 10.1001/jama.2024.0792.

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  • Study reveals neurological effects of reused frying oils

    Study reveals neurological effects of reused frying oils

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    A new study found higher levels of neurodegeneration in rats that consumed reused deep fried cooking oils and their offspring compared to rats on a normal diet. Deep frying, which involves completely submerging food in hot oil, is a common method of food preparation around the world.

    Results from the study also suggest that the increased neurodegeneration is tied to the oil’s effects on the bidirectional communication network between the liver, gut and brain. The liver–gut–brain axis plays a crucial role in regulating various physiological functions, and its dysregulation has been associated with neurological disorders.

    Kathiresan Shanmugam, an associate professor from Central University of Tamil Nadu in Thiruvarur, led the research team.

    “Deep-frying at high temperatures has been linked with several metabolic disorders, but there have been no long-term investigations on the influence of deep-fried oil consumption and its detrimental effects on health,” said Shanmugam, formerly at Madurai Kamaraj University, Madurai. “To our knowledge we are first to report long-term deep-fried oil supplementation increases neurodegeneration in the first-generation offspring.”

    Sugasini Dhavamani, a research collaborator from the University of Illinois at Chicago, will present the research at Discover BMB, the annual meeting of the American Society for Biochemistry and Molecular Biology, which will be held March 23–26 in San Antonio.

    Deep frying food not only adds calories; reusing the same oil for frying, a common practice in both homes and restaurants, removes many of the oil’s natural antioxidants and health benefits. Oil that is reused also can contain harmful components such as acrylamide, trans fat, peroxides and polar compounds.

    To explore the long-term effects of reused deep-fried frying oil, the researchers divided female rats into five groups that each received either standard chow alone or standard chow with 0.1 ml per day of unheated sesame oil, unheated sunflower oil, reheated sesame oil or reheated sunflower oil for 30 days. The reheated oils simulated reused frying oil.

    Compared with the other groups, the rats that consumed reheated sesame or sunflower oil showed increased oxidative stress and inflammation in the liver. These rats also showed significant damage in the colon that brought on changes in endotoxins and lipopolysaccharides -; toxins released from certain bacteria. “As a result, liver lipid metabolism was significantly altered, and the transport of the important brain omega-3 fatty acid DHA was decreased. This, in turn, resulted in neurodegeneration, which was seen in the brain histology of the rats consuming the reheated oil as well as their offspring.”

    Additional studies in which MSG was used to induce neurotoxicity in the offspring showed that the offspring that consumed the reheated oils were more likely to show neuronal damage than the control group receiving no oil or those that received unheated oil.

    Although more studies are needed, the researchers say that supplementation with omega-3 fatty acids and nutraceuticals such as curcumin and oryzanol might be helpful in reducing liver inflammation and neurodegeneration. They added that clinical studies in humans are needed to evaluate the adverse effects of eating fried foods, especially those made with oil that is used repeatedly.

    As a next step, the researchers would like to study the effects of deep-frying oil on neurodegenerative diseases such as Alzheimer’s and Parkinson’s as well as on anxiety, depression and neuroinflammation. They would also like to further explore the relationship between gut microbiota and the brain to identify potential new ways to prevent or treat neurodegeneration and neuroinflammation.

    Source:

    American Society for Biochemistry and Molecular Biology

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  • Aging linked to length of genes, study suggests

    Aging linked to length of genes, study suggests

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    Aging may be less about specific “aging genes” and more about how long a gene is. Many of the changes associated with aging could be occurring due to decreased expression of long genes, say researchers in an opinion piece publishing March 21 in the journal Trends in Genetics. A decline in the expression of long genes with age has been observed in a wide range of animals, from worms to humans, in various human cell and tissue types, and also in individuals with neurodegenerative disease. Mouse experiments show that the phenomenon can be mitigated via known anti-aging factors, including dietary restriction.

    “If you ask me, this is the main cause of systemic aging in the whole body,” says co-author and molecular biologist Jan Hoeijmakers of the Erasmus University Medical Center, Rotterdam; the University of Cologne; and Oncode Institute/Princess Maxima Institute, Utrecht.

    The authors span four research groups from Spain, the Netherlands, Germany, and the United States, with each group arriving at the same conclusions using different methods.

    Aging is associated with changes at the molecular, cellular, and organ level-;from altered protein production to sub-optimal cell metabolism to compromised tissue architecture. These changes are thought to originate from DNA damage resulting from cumulative exposure to harmful agents such as UV radiation or reactive oxygen species generated by our own metabolism.

    While a lot of research in aging has focused on specific genes that might accelerate or slow aging, investigations of exactly which genes are more susceptible to aging have revealed no clear pattern in terms of gene function. Instead, susceptibility seems to be linked to the genes’ lengths.

    “For a long time, the aging field has been focused on genes associated with aging, but our explanation is that it is much more random-;it’s a physical phenomenon related to the length of the genes and not to the specific genes involved or the function of those genes,” says co-author Ander Izeta of the Biogipuzkoa Health Research Institute and Donostia University Hospital, Spain.

    It essentially comes down to chance; long genes simply have more potential sites that could be damaged. The researchers compare it to a road trip-;the longer the trip, the more likely that something will go wrong. And because some cell types tend to express long genes more than others, these cells are more likely to accumulate DNA damage as they age. Cells that don’t (or very rarely) divide also seem to be more susceptible compared to rapidly replicating cells because long-lived cells have more time to accumulate DNA damage and must rely on DNA repair mechanisms to fix them, whereas rapidly dividing cells tend to be short-lived.

    Because neural cells are known to express particularly long genes and are also slow or non-dividing, they are especially susceptible to the phenomenon, and the researchers highlight the link between aging and neurodegeneration. Many of the genes involved in preventing protein aggregation in Alzheimer’s disease are exceptionally long, and pediatric cancer patients, who are cured by DNA-damaging chemotherapy, later suffer from premature aging and neurodegeneration.

    The authors speculate that damage to long genes could explain most of the features of aging because it is associated with known aging accelerants and because it can be mitigated with known anti-aging therapies, such as dietary restriction (which has been shown to limit DNA damage).

    Many different things that are known to affect aging seem to lead to this length-dependent regulation, for example, different types of irradiation, smoking, alcohol, diet, and oxidative stress.”


    Thomas Stoeger, Co-Author of Northwestern University

    However, although the association between the decline in long-gene expression and aging is strong, causative evidence remains to be demonstrated.

    “Of course, you never know which came first, the egg or the chicken, but we can see a strong relationship between this phenomenon and many of the well-known hallmarks of aging,” says Izeta.

    In future studies, the researchers plan to further investigate the phenomenon’s mechanism and evolutionary implications and to explore its relationship with neurodegeneration.

    This research was supported by the Max Planck Society, the Netherlands Organization for Scientific Research, the European Research Council, and the NIH.

    Source:

    Journal reference:

    Soheili-Nezhad, S., et al. (2024) Time is ticking faster for long genes in aging. Trends in Genetics. doi.org/10.1016/j.tig.2024.01.009.

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  • Boosting curcumin’s absorption and effectiveness for disease prevention and therapy

    Boosting curcumin’s absorption and effectiveness for disease prevention and therapy

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    In a recent review published in the journal Antioxidants, researchers explored the potential of nano-formulations to boost the bioavailability and bioactivity of curcumin and its metabolites to amplify their antioxidant properties and disease-preventing effects potentially.

    Study: Enhancing the Bioavailability and Bioactivity of Curcumin for Disease Prevention and Treatment. Image Credit: tarapong srichaiyos/Shutterstock.comStudy: Enhancing the Bioavailability and Bioactivity of Curcumin for Disease Prevention and Treatment. Image Credit: tarapong srichaiyos/Shutterstock.com

    Background

    The roots of turmeric, containing the bioactive compound curcumin, have a long history of use in traditional medicine. Curcumin exhibits therapeutic potential in various diseases, including cancer, inflammation, and neurodegeneration.

    However, its low bioavailability and rapid conversion to metabolites pose challenges. Curcuminoids, including curcumin, dimethoxycurcumin, and bisdemethoxycurcumin, display cellular regulatory effects with varying potencies.

    Various nano-formulations have been developed to address curcumin’s bioavailability limitations, aiming to enhance its stability and uptake.

    They include nano-emulsions, micelles, exosomes, phospholipid complexes, liposomes, biopolymer nanoparticles, and nanostructured lipid carriers.

    Researchers in the present review explore the effects of curcumin and its metabolites and nano-formulations’ potential to amplify their disease-preventing actions.

    Bioavailability of curcumin and curcuminoids

    Curcumin undergoes significant metabolism in the liver and intestine, with limited distribution to other organs. Intraperitoneal administration demonstrates higher bioavailability than oral intake, which is particularly prevalent in animal studies.

    Curcumin’s bioavailability varies significantly, with plasma concentrations ranging from nanomolar to microgram levels. Factors like dose, duration, and mode of administration influence bioavailability across species.

    Despite its poor water solubility, oral administration of curcumin in rats and humans revealed high concentrations and persistence in the gastrointestinal tract and colorectal tissue, demonstrating stability in the acidity of the stomach.

    In cell culture, curcumin shows greater stability in the presence of serum- or blood-enriched media than in serum-free media. Cell-based studies highlight the importance of administration routes in optimizing curcumin levels.

    Increasing the bioavailability of curcumin with nano-formulations

    Diverse nano-formulations aim to enhance curcumin’s bioactivity, leveraging improved solubility, stability, absorption routes, and co-administration strategies.

    These formulations show promising outcomes in preclinical studies, with increased bioavailability, cellular uptake, blood-brain barrier permeability, and tissue distribution.

    Nano-formulations present potential therapeutic applications across various diseases, including cardiovascular, liver, lung, neurodegenerative, cancer, metabolic, and gastrointestinal diseases.

    Despite safety concerns associated with higher curcumin levels, most formulations demonstrate tolerability in clinical trials, emphasizing their potential to address diseases with inflammatory, oxidative stress, or aging components.

    Antimicrobial action

    Curcumin’s antimicrobial efficacy is prominent in topical and oral applications, hindered systemically by higher minimal inhibitory concentrations.

    Nano-formulations enhance antimicrobial potential, while curcumin-microbiota interaction supports intestinal health and reduces inflammation.

    Regulatory effects of curcumin and its nano-formulations

    Nanotechnology-based systems, including micelles, liposomes, and nano-emulsions, enhance curcumin’s oral bioavailability, exhibiting improved absorption and stability.

    Piperine, a natural agent co-administered with curcumin, significantly increases its oral bioavailability, demonstrating promise for enhancing the therapeutic potential of curcumin.

    Combinations of curcumin with nano-formulations or bioactive compounds like quercetin, piperine, salsalate, and vitamin B6 show additive effects, providing effective strategies to augment curcumin’s bioactivity and combat various conditions, including colitis and tumorigenesis.

    Curcumin exhibits therapeutic potential for liver diseases, demonstrating anti-inflammatory, antioxidant, and anti-fibrotic effects.

    Nano-formulations of curcumin show increased efficacy in treating conditions like non-alcoholic fatty liver disease (NAFLD), promoting lipid metabolism, and reducing inflammation.

    Studies also explore curcumin’s impact on adipose tissue, revealing its potential to inhibit adipocyte formation and ameliorate hepatic steatosis. Furthermore, under caloric restriction, curcumin supplementation, alone or with piperine, enhances fat loss and reduces inflammation in obese mice.

    Curcumin’s nano-formulations promise to improve outcomes in myocardial infarction, ischemia, and hypertension.

    Clinical trials suggest positive effects of curcumin on body weight, body fat, and metabolic markers in overweight/obese individuals, as well as in the prevention of cardiovascular diseases. Further research in clinical settings is warranted to optimize curcumin’s anti-inflammatory effects in human chronic inflammation.

    Formulations like galactomannan complexes and natural nanoparticles address Curcumin’s limited brain uptake owing to the blood-brain barrier. They have shown neuroprotective effects on brain injury and ischemia.

    In Alzheimer’s disease, curcumin is found to inhibit amyloid-Aβ production and may influence tau protein aggregation, as seen in preclinical studies. However, clinical trial results on the cognitive benefits of curcumin nano-formulations vary, warranting further investigation into factors like treatment duration, formulation, and dosage.

    Potential safe concentration range and toxicity of curcumin

    Curcumin is proven to be safe and non-toxic in in vitro, animal, and human studies. No toxicity was observed in humans, even at high doses of up to 8 g daily for three months.

    Curcumin nanoparticles also demonstrate safety in breast cancer models, and curcumin exhibits cardioprotective effects against chemotherapy-induced toxicity in both in vitro and in vivo studies, highlighting its versatile and well-tolerated nature.

    Conclusion

    In conclusion, advances in nanoscience have addressed curcumin’s solubility issues, leading to nano-formulations with enhanced dispersion and therapeutic advantages.

    Pre-clinical evidence consistently supports improved bioavailability and bioactivity, necessitating future human trials for optimized dosages and exploring combination therapies.

    Comprehensive studies on the bio-interactions of curcumin with cellular structures are crucial to understanding the mechanisms behind the selective uptake of curcumin nanoparticles.

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  • Dysregulated cellular stress management becomes a source of stress

    Dysregulated cellular stress management becomes a source of stress

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    • RESEARCH BRIEFINGS

    Stress responses protect cells from harmful conditions, but once the stress has resolved, these responses must be actively turned off to avoid cell damage that might lead to the development of neurodegenerative disease.

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  • New scSNV-seq technique unveils genetic drivers of diseases like cancer and Alzheimer’s

    New scSNV-seq technique unveils genetic drivers of diseases like cancer and Alzheimer’s

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    Scientists have developed a new screening tool to uncover how genetic changes affect gene activity and can lead to diseases such as cancer, autoimmunity, neurodegeneration and cardiovascular disease. This new tool enables the investigation of thousands of DNA mutations identified by genetic studies in one experiment, guiding the development of advanced diagnostics and treatments.

    The technique, called scSNV-seq, enables researchers to rapidly assess the impact of thousands of genetic changes in cells that have never been screened before, directly connecting these changes to how those same cells operate. This provides a comprehensive view from which researchers can pinpoint the mutations that contribute to disease. This will offer crucial insights for developing targeted therapies.

    In the new study, published in Genome Biology, researchers from the Wellcome Sanger Institute and their collaborators at Open Targets and EMBL’s European Bioinformatics Institute (EMBL-EBI) applied scSNV-seq to the blood cancer gene, JAK1. The technique accurately assessed the impact of JAK1 mutations, revealing for the first time that certain mutations caused a “halfway house” phenotype cycling between different states. This is not possible under previous approaches.

    The technique is designed to demonstrate versatility across cell types, including hard-to-culture primary cells like T cells and stem-cell derived neurons, as well as various editing methods such as base editing and prime editing. Applied on a large scale, scSNV-seq could transform understanding of the genetic changes driving cancer and decoding genetic risk for Alzheimer’s, arthritis, diabetes and other complex diseases.

    Advances in human genetics combined with the increasing affordability of DNA sequencing technologies have unveiled hundreds of thousands of disease-related genetic variants that are increasing at a staggering rate. Yet, tools to interpret them lag behind, sometimes relying on tedious manual processes.

    When using advanced gene-editing tools to introduce defined genetic mutations, using current screening methods, it is difficult to distinguish between cells where the editing did not work and those where it successfully introduced a harmless change without affecting the cell’s behaviour.

    Researchers from the Wellcome Sanger Institute and their collaborators set out to address this with a new screening technique, scSNV-seq, which directly couples the specific genetic information in the genotype of a cell to its gene activity. The team tested the effectiveness of scSNV-seq by altering specific DNA bases within the JAK1 gene, which is linked to inflammation and cancer, to study their effects on cell behavior.

    They demonstrated scSNV-seq could accurately categorise different types of genetic changes into three categories: benign, causing loss of function, and altering function. They showed certain mutations caused an intermediate phenotype cycling between different states – an observation not possible under existing approaches.

    Dr Sarah Cooper, first author of the study at the Wellcome Sanger Institute, said: “In an era where the rate of genetic variant discovery outpaces our ability to interpret their effects, scSNV-seq fills a major gap for studying challenging cells like T cells and neurons. We are already using it to shed light on the impact of Alzheimer’s and Parkinson’s risk variants on brain cells.”

    Our technique is able to directly connect effects of mutations to how a cell behaves, revealing downstream impacts that previous technologies alone cannot deliver. The technique speeds up the identification of causal genetic mutations, which will allow better diagnosis and deepens our molecular understanding of diseases, paving the way for more targeted and effective treatments.”

    Dr Andrew Bassett, Senior Study Author, Wellcome Sanger Institute

    Source:

    The Wellcome Sanger Institute

    Journal reference:

    Cooper, S.E., et al. (2024) scSNV-seq: high-throughput phenotyping of single nucleotide variants by coupled single-cell genotyping and transcriptomics. Genome Biology. doi.org/10.1186/s13059-024-03169-y.

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  • Non-neuronal brain cells modulate behaviour

    Non-neuronal brain cells modulate behaviour

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  • Synchronized neuronal activity drives waste fluid flow

    Synchronized neuronal activity drives waste fluid flow

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    Nature, Published online: 28 February 2024; doi:10.1038/d41586-024-00422-z

    Active neurons can stimulate the clearance of their own metabolic waste by driving changes to ion gradients in the surrounding fluid and by promoting the pulsation of nearby blood vessels.

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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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