Tag: 4/4/24

Categories : NeurologyTags :

Wide-ranging Animal Studies Link pH Changes to Cognitive and Psychiatric Disorders

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A global collaborative research group has identified brain energy metabolism dysfunction leading to altered pH and lactate levels as common hallmarks in numerous animal models of neuropsychiatric and neurodegenerative disorders. These include models of intellectual disability, autism spectrum disorders, schizophrenia, bipolar disorder, depressive disorders, and Alzheimer’s disease. The findings were published in eLife.

The research group, comprising 131 researchers from 105 laboratories across seven countries, sheds light on altered energy metabolism as a key factor in various neuropsychiatric and neurodegenerative disorders. While considered controversial, an elevated lactate level and the resulting decrease in pH is now also proposed as a potential primary component of these diseases. Unlike previous assumptions associating these changes with external factors like medicationa, the research group’s previous findings suggest that they may be intrinsic to the disorders. This conclusion was drawn from five animal models of schizophrenia/developmental disorders, bipolar disorder, and autism, which are exempt from such confounding factorsb. However, research on brain pH and lactate levels in animal models of other neuropsychiatric and neurological disorders has been limited. Until now, it was unclear whether such changes in the brain were a common phenomenon. Additionally, the relationship between alterations in brain pH and lactate levels and specific behavioural abnormalities had not been clearly established.

This study, encompassing 109 strains/conditions of mice, rats, and chicks, including animal models related to neuropsychiatric conditions, reveals that changes in brain pH and lactate levels are a common feature in a diverse range of animal models of conditions, including schizophrenia/developmental disorders, bipolar disorder, autism, as well as models of depression, epilepsy, and Alzheimer’s disease. This study’s significant insights include:

I. Common Phenomenon Across Disorders: About 30% of the 109 types of animal models exhibited significant changes in brain pH and lactate levels, emphasising the widespread occurrence of energy metabolism changes in the brain across various neuropsychiatric conditions.

II. Environmental Factors as a Cause: Models simulating depression through psychological stress, and those induced to develop diabetes or colitis, which have a high comorbidity risk for depression, showed decreased brain pH and increased lactate levels. Various acquired environmental factors could contribute to these changes.

III. Cognitive Impairment Link: A comprehensive analysis integrating behavioural test data revealed a predominant association between increased brain lactate levels and impaired working memory, illuminating an aspect of cognitive dysfunction.

IV. Confirmation in Independent Cohort: These associations, particularly between higher brain lactate levels and poor working memory performance, were validated in an independent cohort of animal models, reinforcing the initial findings.

V. Autism Spectrum Complexity: Variable responses were noted in autism models, with some showing increased pH and decreased lactate levels, suggesting subpopulations within the autism spectrum with diverse metabolic patterns.

“This is the first and largest systematic study evaluating brain pH and lactate levels across a range of animal models for neuropsychiatric and neurodegenerative disorders. Our findings may lay the groundwork for new approaches to develop the transdiagnostic characterisation of different disorders involving cognitive impairment,” states Dr Hideo Hagihara, the study’s lead author.

Professor Tsuyoshi Miyakawa, the corresponding author, explains, “This research could be a stepping stone towards identifying shared therapeutic targets in various neuropsychiatric disorders. Future studies will centre on uncovering treatment strategies that are effective across diverse animal models with brain pH changes. This could significantly contribute to developing tailored treatments for patient subgroups characterized by specific alterations in brain energy metabolism.”

The exact mechanism behind the reduction in pH and the increase in lactate levels remains elusive. But the authors suggest that, since lactate production increases in response to neural hyperactivity to meet the energy demand, this might be the underlying reason.

Source: Fujita Health University

Categories : Neurodegenerative Diseases TransplantsTags :

Familial Alzheimer’s Disease Transferred via Bone Marrow Transplant in Mice Experiment

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Photo by Mari Lezhava on Unsplash

Familial Alzheimer’s disease can be transferred via bone marrow transplant, researchers show in the journal Stem Cell Reports. When the team transplanted bone marrow stem cells from mice carrying a hereditary version of Alzheimer’s disease into normal lab mice, the recipients developed Alzheimer’s disease – and at an accelerated rate.

The study highlights the role of amyloid that originates outside of the brain in the development of Alzheimer’s disease, which changes the paradigm of Alzheimer’s from being a disease that is exclusively produced in the brain to a more systemic disease. Based on their findings, the researchers say that donors of blood, tissue, organ, and stem cells should be screened for Alzheimer’s disease to prevent its inadvertent transfer during blood product transfusions and cellular therapies.

“This supports the idea that Alzheimer’s is a systemic disease where amyloids that are expressed outside of the brain contribute to central nervous system pathology,” says senior author and immunologist Wilfred Jefferies, of the University of British Columbia. “As we continue to explore this mechanism, Alzheimer’s disease may be the tip of the iceberg and we need to have far better controls and screening of the donors used in blood, organ and tissue transplants as well as in the transfers of human derived stem cells or blood products.”

To test whether a peripheral source of amyloid could contribute to the development of Alzheimer’s in the brain, the researchers transplanted bone marrow containing stem cells from mice carrying a familial version of the disease — a variant of the human amyloid precursor protein (APP) gene, which, when cleaved, misfolded and aggregated, forms the amyloid plaques that are a hallmark of Alzheimer’s disease. They performed transplants into two different strains of recipient mice: APP-knockout mice that lacked an APP gene altogether, and mice that carried a normal APP gene.

In this model of heritable Alzheimer’s disease, mice usually begin developing plaques at 9 to 10 months of age, and behavioural signs of cognitive decline begin to appear at 11 to 12 months of age. Surprisingly, the transplant recipients began showing symptoms of cognitive decline much earlier – at 6 months post-transplant for the APP-knockout mice and at 9 months for the “normal” mice.

“The fact that we could see significant behavioural differences and cognitive decline in the APP-knockouts at 6 months was surprising but also intriguing because it just showed the appearance of the disease that was being accelerated after being transferred,” says first author Chaahat Singh of the University of British Columbia.

In mice, signs of cognitive decline present as an absence of normal fear and a loss of short and long-term memory. Both groups of recipient mice also showed clear molecular and cellular hallmarks of Alzheimer’s disease, including leaky blood-brain barriers and buildup of amyloid in the brain.

Observing the transfer of disease in APP-knockout mice that lacked an APP gene altogether, the team concluded that the mutated gene in the donor cells can cause the disease and observing that recipient animals that carried a normal APP gene are susceptible to the disease suggests that the disease can be transferred to health individuals.

Because the transplanted stem cells were hematopoietic cells, meaning that they could develop into blood and immune cells but not neurons, the researchers’ demonstration of amyloid in the brains of APP knockout mice shows definitively that Alzheimer’s disease can result from amyloid that is produced outside of the central nervous system.

Finally the source of the disease in mice is a human APP gene demonstrating the mutated human gene can transfer the disease in a different species.

In future studies, the researchers plan to test whether transplanting tissues from normal mice to mice with familial Alzheimer’s could mitigate the disease and to test whether the disease is also transferable via other types of transplants or transfusions and to expand the investigation of the transfer of disease between species.

“In this study, we examined bone marrow and stem cells transplantation. However, next it will be important to examine if inadvertent transmission of disease takes place during the application of other forms of cellular therapies, as well as to directly examine the transfer of disease from contaminated sources, independent from cellular mechanisms,” says Jefferies.

Source: Cell Press

Categories : Cardiovascular Disease Diet and NutritionTags :

Eggs are not the Cholesterol Menace They were Thought to be

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Photo by Annie Spratt on Unsplash

Many people hesitate to eat eggs amid concerns that they may raise cholesterol levels, with negative cardiovascular consequences. However, results from a prospective, controlled trial presented at the American College of Cardiology’s Annual Scientific Session show that over a four-month period cholesterol levels and other cardiovascular markers were similar among people who ate fortified eggs most days of the week compared with a non-egg eating control group.

A total of 140 patients with or at high risk for cardiovascular disease were enrolled in the PROSPERITY trial, which aimed to assess the effects of eating 12 or more fortified eggs a week versus a non-egg diet (consuming less than two eggs a week) on HDL- and LDL-cholesterol, as well as other key markers of cardiovascular health over a four-month study period.

“We know that cardiovascular disease is, to some extent, mediated through risk factors like high blood pressure, high cholesterol and increased BMI and diabetes. Dietary patterns and habits can have a notable influence on these and there’s been a lot of conflicting information about whether or not eggs are safe to eat, especially for people who have or are at risk for heart disease,” said Nina Nouhravesh, MD, a research fellow at the Duke Clinical Research Institute in Durham, North Carolina, and the study’s lead author. “This is a small study, but it gives us reassurance that eating fortified eggs is OK with regard to lipid effects over four months, even among a more high-risk population.”

Eggs are a common and relatively inexpensive source of protein and dietary cholesterol. Nouhravesh and her team wanted to look specifically at fortified eggs as they contain less saturated fat and additional vitamins and minerals, such as iodine, vitamin D, selenium, vitamin B2, 5 and 12, and omega-3 fatty acids.

For this study, patients were randomly assigned to eat 12 fortified eggs a week (cooked in whatever manner they chose) or to eat fewer than two eggs of any kind (fortified or not) per week.  All patients were 50 years of age or older (the average age was 66 years), half were female and 27% were Black. All patients had experienced one prior cardiovascular event or had two cardiovascular risk factors, such as high blood pressure, high cholesterol, increased BMI or diabetes. The co-primary endpoint was LDL and HDL cholesterol at four months. Secondary endpoints included lipid, cardiometabolic and inflammatory biomarkers and levels of vitamin and minerals. 

Patients had in-person clinic visits at the start of the study and visits at one and four months to take vital signs and have bloodwork done. Phone check-ins occurred at two and three months and patients in the fortified egg group were asked about their weekly egg consumption. Those with low adherence were provided additional education materials.

Results showed a -0.64mg/dL and a -3.14mg/dL reduction in HDL-cholesterol and LDL cholesterol, respectively, in the fortified egg group. While these differences weren’t statistically significant, the researchers said the differences suggest that eating 12 fortified eggs each week had no adverse effect on blood cholesterol. In terms of secondary endpoints, researchers observed a numerical reduction in total cholesterol, LDL particle number, another lipid biomarker called apoB, high-sensitivity troponin (a marker of heart damage), and insulin resistance scores in the fortified egg group, while vitamin B increased.

“While this is a neutral study, we did not observe adverse effects on biomarkers of cardiovascular health and there were signals of potential benefits of eating fortified eggs that warrant further investigation in larger studies as they are more hypothesis generating here,” Nouhravesh said, explaining that subgroup analyses revealed numerical increases in HDL cholesterol and reductions in LDL cholesterol in patients 65 years or older and those with diabetes in the fortified egg group compared with those eating fewer than two eggs.

So why have eggs gotten a bad rap? Some of the confusion stems from the fact that egg yolks contain cholesterol. Experts said a more important consideration, especially in the context of these findings, might be what people are eating alongside their eggs, such as buttered toast, bacon and other processed meats, which are not heart healthy choices. As always, Nouhravesh said it’s a good idea for people with heart disease to talk with their doctor about a heart healthy diet.

This single-centre study is limited by its small size and reliance on patients’ self-reporting of their egg consumption and other dietary patterns. It was also an unblinded study, which means patients knew what study group they were in, which can influence their health behaviours.

The study was funded by Eggland’s Best.

Source: American College of Cardiology

Categories : GeneticsTags :

New Genetic Tool Predicts Unintentional Mutations from CRISPR Edits

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CRISPR-Cas9 is a customisable tool that lets scientists cut and insert small pieces of DNA at precise areas along a DNA strand. This lets scientists study our genes in a specific, targeted way. Credit: Ernesto del Aguila III, National Human Genome Research Institute, NIH

Since its breakthrough development more than a decade ago, CRISPR has revolutionised DNA editing across a broad range of fields, including new therapies for an array of disorders spanning cancers, blood conditions and diabetes. But in some cases, the DNA repair process leaves in unintentional, harmful edits. Now, University of California San Diego researchers have developed a new system to understand these repair outcomes and where they can go wrong. The system is described in Nature Communications.

In some designed treatments, patients are injected with CRISPR-treated cells or with packaged CRISPR components with a goal of repairing diseased cells with precision gene edits. Yet, while CRISPR has shown immense promise as a next-generation therapeutic tool, the technology’s edits are still imperfect. CRISPR-based gene therapies can cause unintended but harmful “bystander” edits to parts of the genome, at times leading to new cancers or other diseases.

Unravelling the complex biological dynamics behind both on- and off-target CRISPR edits is daunting, since intricate bodily tissues feature thousands of different cell types and CRISPR edits can depend on many different biological pathways.

Postdoctoral Scholar Zhiqian Li, Professor Ethan Bier and their colleagues developed a sequence analyser to help track on- and off-target mutational edits and the ways they are inherited from one generation to the next. Based on a concept proposed by former UC San Diego researcher David Kosman, the Integrated Classifier Pipeline (ICP) tool can reveal specific categories of mutations resulting from CRISPR editing.

Developed in flies and mosquitoes, the ICP provides a “fingerprint” of how genetic material is being inherited, which allows scientists to follow the source of mutational edits and related risks emerging from potentially problematic edits.

“The ICP system can cleanly establish whether a given individual insect has inherited specific genetic components of the CRISPR machinery from either their mothers or fathers since maternal versus paternal transmission result in totally different fingerprints,” said Bier, a professor in the UC San Diego School of Biological Sciences.

The ICP can help untangle complex biological issues that arise in determining the mechanisms behind CRISPR. While developed in insects, ICP carries vast potential for human applications.

“There are many parallel applications of ICP for analysing and following CRISPR editing outcomes in humans following gene therapy or during tumour progression,” said study first author Li. “This transformative flexible analysis platform has many possible impactful uses to ensure safe application of cutting-edge next-generation health technologies.”

ICP also offers help in tracking inheritance across generations in gene drive systems, which are new technologies designed to spread CRISPR edits in applications such as stopping the transmission of malaria and protecting agricultural crops against pest destruction. For example, researchers could select a single mosquito from the field where a gene-drive test is being conducted and use ICP analysis to determine whether that individual had inherited the genetic construct from its mother or its father, and whether it had inherited a defective element lacking the defining visible markers of that genetic element.

“The CRISPR editing system can be more than 90 percent accurate,” said Bier, “but since it edits over and over again it will eventually make a mistake. The bottom line is that the ICP system can give you a very high-resolution picture of what can go wrong.”

Source: University of California – San Diego

Categories : Mental HealthTags :

Working outside the Typical 9–5 in Younger Adulthood may be Linked with Worse Health Decades Later

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Employees with volatile work schedules early in their career had worse sleep and more depressive symptoms at age 50

Photo by Tim Gouw on Unsplash

The hours you work earlier in life may be associated with worse health years later, according to a study published April 3, 2024 in the open-access journal PLOS ONE by Wen-Jui Han from New York University, US.

Studies have consistently shown that nonstandard work schedules – working outside the traditional nine-to-five workday – can negatively impact physical and mental health as well as social and family life. The current study uses a life-course approach to provide a longer-term perspective on how work schedule patterns throughout a person’s working life impact their health in middle age.

Han used data from The National Longitudinal Survey of Youth-1979 (NLSY79), which includes data on more than 7000 people in the US over 30 years, to see whether employment patterns in younger adulthood were associated with sleep, physical health, and mental health at age 50.

Han found that around a quarter of participants (26%) worked stable standard hours, with a further third (35%) working mostly standard hours. Seventeen percent initially worked standard hours in their 20s, later transitioning into volatile working patterns – a combination of evening, night, and variable hours. Twelve percent initially worked standard hours and then switched to variable hours. A final ten percent were mostly not working over this period.

Compared to individuals who mostly worked during traditional daytime hours throughout their working career, those whose careers featured more volatile work schedules slept less, had lower sleep quality, and were more likely to report depressive symptoms at age 50. The most striking results were seen in those who had stable work hours in their 20s and then transitioned to more volatile work hours in their 30s. This effect size was significant and similar to that of being educated only to below high school level.

Han also found racial and gender-related trends. For example, Black Americans were more likely to have volatile work schedules associated with poorer health, highlighting how some groups may disproportionately shoulder the adverse consequences of such employment patterns.

Han suggests that volatile work schedules are associated with poor sleep, physical fatigue, and emotional exhaustion, which may make us vulnerable to an unhealthy life. The study also suggests that positive and negative impacts of work schedules on health can accumulate over one’s lifetime while highlighting how employment patterns can contribute to health inequities.

Han adds: “Work that is supposed to bring resources to help us sustain a decent life has now become a vulnerability to a healthy life due to the increasing precarity in our work arrangements in this increasingly unequal society. People with vulnerable social positions (eg, females, Blacks, low-education) disproportionately shoulder these health consequences.”