Publisher Health

Researchers have used fruit flies to decipher an unexplained connection between Alzheimer’s disease and a genetic variation, revealing that it causes neurons to die.
The findings from the WEHI-led team uncover a possible cause of neurodegeneration in the early stages of Alzheimer’s disease and open the door for the future development of new treatments for cognitive diseases.
At a glance A strong genetic link between Alzheimer’s disease and the mitochondrial TOMM40 gene has been noted for over a decade, but never explained. Using a well-established fruit fly model of neurodegenerative disease, researchers have gained new insight into this link and how it leads to the death of neurons. The research improves our understanding of the preclinical stages of cognitive diseases associated with ageing and pinpoints previously unexplored avenues for the development of new therapies.Over 55 million people worldwide are believed to be living with Alzheimer’s disease or other forms of dementia. In Australia, there are up to 487,500 people living with dementia. There is no known cure for the disease, but early intervention can help prevent disease progression.
The new research enhances our knowledge of how cell death and quality control pathways are involved in neurodegeneration and reveals potential targets for early intervention in cognitive conditions.
Gap in dementia research
A strong genetic link exists between increased levels of the mitochondrial TOMM40 gene and Alzheimer’s disease, but the mechanisms underlying this phenomenon are largely unknown.

This connection has been hard to untangle because this gene neighbours ‘The Alzheimer’s gene’ — ApoE4 — the strongest predictor of late onset Alzheimer’s disease.
But recent work has shown a genetic variation that causes over-production of TOMM40 can cause brain shrinkage, independent of the Alzheimer’s gene.
Lead researcher Dr Agalya Periasamy said the findings piqued the team’s curiosity, prompting them to investigate how too much TOMM40 causes the neurodegeneration underlying Alzheimer’s disease.
“If we can unpack this, we might be able to find a new way to intervene with the process to prevent neurons from dying,” Dr Periasamy said.
“Currently, we don’t have good treatments for Alzheimer’s and we urgently need new options.

“Our research offers a possible alternative avenue for development of much-needed therapeutic interventions for this devastating disease.”
Fruit fly model
The WEHI and Australian National University team used a common model of neurodegenerative disease, the fruit fly, to explore potential connections between elevated TOMM40 levels and Alzheimer’s.
The eyes of fruit flies contain cells called photoreceptors that are specialised neurons, making them ideal for research on neurodegeneration.
To investigate how an over-abundance of TOMM40 was linked to neurodegeneration, the team genetically engineered fruit flies to produce too much Tom40 protein, the protein produced by the TOMM40 gene, and observed the effect.
They found that enriching the protein caused marked cell death in the retina, with the amount of degeneration corresponding to the level of the protein.
After looking for the cause of the dying eye tissue, Dr Periasamy found evidence of a specific kind of cell death called apoptosis, typically involved in regular cell turnover and maintenance.
“We looked at the eyes of fly larvae under the microscope and found an increase in a protein that marks the activation of apoptosis, called ‘caspase-3’ in humans. This confirmed to us that apoptosis was the missing link we were looking for,” she said.
TOM protein complex and cell death
Tom40 is part of a larger protein complex called “TOM” that assembles on the mitochondria, where its main function is to import essential proteins.
The team investigated the impact of excessive Tom40 and found that TOM complex formation was sent into overdrive. This throws out the balance in the mitochondria and activates apoptosis.
“While the data show that the trigger for cell death is an overabundance of the TOM assembly, we found no evidence that protein import was involved in neurodegeneration,” said principal investigator Dr Jacqui Gulbis.
“Our findings identify a new entry point into cell quality control pathways that could be targeted to interrupt TOMM40-induced neurodegeneration.
“While this research is still in its early stages, it will be exciting to explore and tap into the relationship between TOMM40-linked apoptosis and Alzheimer’s disease to set the groundwork for the development of new therapies for cognitive conditions.”

A newly published study from York University sheds light on the biological underpinnings in sex differences in obesity-related disease, with researchers observing “striking” differences in the cells that build blood vessels in the fatty tissue of male versus female mice.
Men are more likely than women to develop conditions associated with obesity such as cardiovascular disease, insulin resistance and diabetes, says York Professor Tara Haas with the Faculty of Health’s School of Kinesiology and Health Science.
“People have used rodent models to study obesity, and the diseases that are associated with obesity — like diabetes — but they’ve typically always studied male rodents, because females are resistant to developing the same kinds of diseases,” says Haas, lead on the study. “We were really interested in exploring that difference because, to us, it spoke of something really fascinating happening in females that protects them.”
Haas and her team observed in an earlier study that when mice become obese, females grow a lot of new blood vessels to supply the expanding fat tissue with oxygen and nutrients, whereas males grow a lot less. In this latest study published in iScience, Haas and her co-authors, including York PhD student Alexandra Pislaru, Faculty of Health Assistant Professor Emilie Roudier, and former York post-doctorate student Martina Rudnicki, focused on differences in the endothelial cells that make up the building blocks of these blood vessels in fat tissue.
The team used software to help sift through thousands of genes to zero in on the ones that would be associated with blood vessel growth. They discovered that processes associated with the proliferation of new blood vessels were high in the female mice, whereas the males had a high level of processes associated with inflammation.
“It was very striking the extent of inflammation-associated processes that were prevalent in the males,” Haas recalls. “Other studies have shown that when endothelial cells have that kind of inflammatory response, they’re very dysfunctional, and they don’t respond to stimuli properly.”
Pislaru, who works in Haas’ lab and is a co-first author of the study, participated in this project as part of her dissertation.

“It is exciting to observe the continuing resilience that female endothelial cells display even when stressed by a long-term high-fat diet,” Pislaru says. “The findings from our study can help researchers to get a better understanding of why obesity manifests differently in men and women.”
The researchers also examined the behaviour of the endothelial cells when they were taken out of the body and studied in petri dishes.
“Even when we take them out of the body where they don’t have the circulating sex hormones or other kinds of factors, male and female endothelial cells still behave very differently from each other,” Haas explains.
Female endothelial cells replicated faster, while male endothelial cells displayed greater sensitivity to an inflammatory stimulus. By comparing with previously published data sets, the researchers found endothelial cells from aged male mice also displayed a more inflammatory profile compared to female cells.
“You can’t make the assumption that both sexes are going to respond to the same series of events the same way,” says Haas. “This isn’t just an obesity related issue — I think it’s a much broader conceptual problem that also encompasses healthy aging. One implication of our findings is that there will be situations where the treatment that is ideal for men is not going to be ideal for women and vice-versa.”
The study was funded by a grant through the Canadian Institutes of Health Research, as well as the Natural Science and Engineering Research Council of Canada and York’s Faculty of Health.
While humans and mice have different genes that may be turned up or down, Haas believes the general findings would likely apply and is interested studying the same cells in humans in future research.
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A MedUni Vienna research team has discovered a highly potent biomarker for clinical response to CAR-T cell therapy, describing the prerequisites for optimal use of this novel therapy for lymphoma treatment. The current findings are an essential step forward towards optimizing this promising therapy. The results of the study were recently published in the top journal Frontiers in Immunology.
Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma (non-Hodgkin’s lymphoma). The 5-year survival rates are now between 55% and 64%. However, patients who have an early relapse of the disease or who do not respond to combined antibody chemotherapy have an even worse prognosis.
In recent years, a new, very effective form of therapy has emerged for those affected: CAR-T cells. For this therapy, the body’s own lymphocytes are taken, equipped with chimeric T cell receptors (CAR = chimeric antigen receptor) specific for the lymphatic cancer cells, expanded and then returned to the patient. The T cells are turned into killer cells due to the expression of the chimeric T cell receptors and, in the best case, eliminate the lymphatic cancer cells in the patient’s body forever. Even though this therapy can be very effective when there is a response of CAR-T cells to the lymphoma cells and enables long-term survival; unfortunately, it does not work for all patients.
In their clinical research, the scientists began at the point of origin for CAR-T cell production: the nature of the patient’s own T lymphocytes (T cells). In the process, they discovered that patients with lymphoma often have a deficiency of T lymphocytes (T cell lymphopenia). Since lymphopenia is often accompanied by an increase in “exhausted” T cells, this study started to measure the number of these cells. Indeed, exhausted T cells were found to be significantly increased in a subset of patients. Such exhausted T cells are usually only found in patients suffering from chronic inflammation.
With these observations, the research teams led by Nina Worel (Transfusion Medicine) and Ulrich Jäger (Haematology), in collaboration with Winfried Pickl’s team (Institute of Immunology), created the basis for dividing groups of patients into those with a high and those with a low probability of responding to CAR-T cell therapy.
“Our study shows how important the nature of the T cells is for CAR-T cell production and that exhausted T cells, which can be found in a considerable proportion of patients, pose a problem for subsequent CAR-T cell therapy,” says study leader Winfried Pickl. “Our observations of the mode of action of the differently exhausted T cells, which were used as starting material for the production of CAR-T cells, show that the degree of differentiation does not have a negative influence on the direct killing of cancer cells by CAR-T cells, but it does have a negative influence on the leukemia cell-dependent growth and the factor production of the CAR-T cells. This suggests that exhausted CD27negCD28neg-CAR-T cells may not be able to persist for longer periods of time in patients, which may limit their long-term efficacy.”
The selection of T cells could provide a decisive advantage
In summary, Pickl states: “The low frequency of differentiated (exhausted) CD3posCD27negCD28neg-T cells at the time of leukapheresis represents a new blood biomarker that can be used even before the start of CAR-T cell production and infusion and predicts the response to treatment with CAR-T cells in patients. Removal of such cells from the leukapheresis product prior to the initiation of CAR-T cell production could significantly improve the success of therapy even in patients with an unfavourable initial situation.”
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Smallpox was once one of humanity’s most devastating diseases, but its origin is shrouded in mystery. For years, scientific estimates of when the smallpox virus first emerged have been at odds with historical records. Now, a new study reveals that the virus dates back 2,000 years further than scientists have previously shown, verifying historical sources and confirming for the first time that the disease has plagued human societies since ancient times.
The paper appears in the journal Microbial Genomics, published by the Microbiology Society.
Smallpox, caused by the variola virus, is perhaps best known for being the only infectious human disease to be eradicated worldwide. But the disease was a major cause of death until relatively recently, killing at least 300 million people in the 20th century. This is roughly the equivalent of the population of the United States.
Until relatively recently, the earliest genetic evidence for smallpox was only from the 1600s. Then in 2020, a study that sampled skeletal and dental remains of Viking-age skeletons recovered multiple strains of variola and confirmed the virus’ existence at least another 1,000 years earlier.
However, some historians believe that smallpox has been around since long before the Vikings. Suspicious scarring on ancient Egyptian mummies (including the Pharoah Ramses V who died in 1157 BC) leads some to believe that the history of smallpox stretches back at least 3,000 years. So far, the missing piece of scientific evidence to support this theory has remained hidden.
By comparing the genomes of modern and historic strains of variola virus, researchers at the Scientific Institute Eugenio Medea and University of Milan in Italy have traced the evolution of the virus back in time. They found that different strains of smallpox all descended from a single common ancestor and that a small fraction of the genetic components found in Viking-age genomes had persisted until the 18th century.
They also worked out an estimate for when the virus originated. In their estimate, the researchers accounted for something called the ‘time-dependent rate phenomenon’. This means that the speed of evolution depends on the length of time over which it is being measured, so viruses appear to change more quickly over a short timeframe and more slowly over a longer timeframe. The phenomenon has been well-documented in DNA viruses like variola.
Using a mathematical equation, scientists can account for the time-dependent rate phenomenon to give more accurate dates for evolutionary events, such as the appearance of a new virus. This gave the team a new estimate for the first emergence of smallpox: more than 3,800 years ago. Just as historians have long suspected.
The researchers hope these findings will settle a longstanding controversy and provide new insight into the history of one of humanity’s deadliest diseases.
“Variola virus may be much, much older than we thought,” said Dr Diego Forni, first author of the study. “This is important because it confirms the historical hypothesis than smallpox existed in ancient societies. It is also important to consider that there are some aspects in the evolution of viruses that should be accounted for when doing this type of work.”
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The research, published in The Lancet Public Health, brought together a variety of different types of evidence — including previous studies, new data on women’s preferences, and case studies of existing practice across the globe — to develop a model, which could be used to help design services in a way that better meets the needs of women and their partners.
Researchers found that, currently, health services only view women to either be pregnant or not pregnant, and do not consider their health in the in-between stage — before trying to conceive. This can have an important influence on both their chances of becoming pregnant and of having a healthy pregnancy as well as affect their own health in the short and long term.
As 90% of women of reproductive age have at least one modifiable risk factor affecting pregnancy (such as a low or high BMI), the health of women before they become pregnant is an important factor in maternal deaths and a contributor to the inequalities seen in the rates of maternal deaths in marginalised groups.
Alongside health services, the team found that educational settings and social media could also be more supportive in helping people to consider their reproductive preferences.
As a result, they are calling for societal-wide efforts to help bring together family planning, contraception, and preconception care. And they have developed a framework that can be adapted both to different settings and the healthcare system.
The model suggests that children could be taught about reproductive needs — such as preconception health advice and contraception — in school. Meanwhile, social media campaigns could be used to raise awareness of the opportunities and benefits of choosing if or when to have children.

Additionally, professionals could routinely ask patients about their reproductive preferences and digital tools could be made available to direct people to appropriate sources of advice or services.
Lead author Dr Jenny Hall (UCL EGA Institute for Women’s Health) said: “The model proposed in this paper can be adapted and implemented across a range of primary care settings, including general practice and sexual and reproductive health services, with appropriate training for health professionals.
“Doing so will bridge the gap between contraception and antenatal services, providing services in a way that better meets women’s needs as they move through their reproductive life course, in line with the ambitions of the recent Women’s Health Strategy.”
The Women’s Health Strategy for England was launched in August 2022 and cites Fertility, pregnancy, pregnancy loss and postnatal support as one of its priority areas.
Ten-year ambitions for this area include supporting women through high-quality information and education to make informed decisions about their reproductive health, including if and when to have a child. And, giving children a high-quality, evidence-based education from an early age on fertility, contraception and pregnancy planning, maternity care and pregnancy loss.

Dr Hall said: “The review of evidence and model put forward in our study shows how preconception healthcare in the community can shift from concept to reality and how the gap between contraception and antenatal services can be bridged to holistically support women’s needs across their reproductive life course.”
The project was funded by Public Health England and NIHR.
Study limitations
Researchers examined studies published in English and from high-income countries, which could limit how the model is used. Wider considerations of healthcare systems for the delivery of preconception care, stakeholders involved, and socio-cultural practices influencing health behaviours in the preconception period may need to be taken in to account when considering the translation of this model to low-and middle-income countries.
There is still a lack of evidence on the impact of preconception interventions and outcomes, so the literature used was on a small scale. And some studies experience selection bias by only focusing on women from certain socioeconomic backgrounds and education levels.

LMU parasitologists have shown that a complex of two protein variants plays a significant role in toxoplasmosis infection.
One of the most widespread zoonoses worldwide, toxoplasmosis is an infectious disease that is caused by the parasite Toxoplasma gondii. Although cats are the final host, the parasite can infest any warm-blooded animal, including humans. In an investigation of how the pathogen manages to infect such a broad range of hosts, a team led by Prof. Markus Meissner, Chair of Experimental Parasitology at LMU, has identified a central protein complex.
Toxoplasma belongs to a phylum of unicellular parasites known as Apicomplexa. In contrast to Toxoplasma, most species in this group are restricted to specific hosts and cell types. The malaria pathogen Plasmodium, for example, is very species-specific and can infect only liver cells and red blood cells. In the view of the scientists, the broad host range of Toxoplasma suggests that the parasite can recognize multiple structures of the host cell, leading to the activation of a central invasion complex.
“Our hypothesis was that this invasion complex is strongly conserved and present both in Toxoplasma and in Plasmodium,” says Dr. Mirko Singer, lead author of the study. “To investigate the invasion mechanisms and possible reasons for the different host specificity, we compared the factors involved in the invasion of the host for Toxoplasma and Plasmodium.”
Interplay of two variants
In their analysis of the invasion factors, the researchers concentrated on a family of huge Cysteine Repeat Modular Proteins (CRMPs), which were already suspected of playing a role in the invasion. Plasmodium possesses four of these proteins, whereas Toxoplasma has just two. By means of various experiments, the scientists managed to demonstrate that there are two CRMP variants which interact in pairs — Variant A interacting with Variant B in each case. The entire complex is assembled within Toxoplasma and then moves to the surface of the parasite, where it initiates the invasion of the host cell. If one of the partners is removed, the parasite cannot penetrate its host cell — the complex thus functions as a central “master key” to access the host.
Furthermore, the scientists identified two additional little helper proteins in Toxoplasma that each bind specifically to one of the variants. “Without these helpers, it is harder for Toxoplasma to invade cells,” says Meissner. “Interestingly, they are absent in Plasmodium, which could explain Toxoplasma’s broader host range.”
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For the millions of people living with diabetes, insulin is a life-saving drug. Unlike many other medicines, though, insulin cannot be easily delivered by swallowing a pill — it needs to be injected under the skin with a syringe or pump. Researchers have been making steps toward an insulin pill, and now, a team reports in ACS Nano that they’ve delivered insulin to the colons of rats using an orally administered tablet powered by chemical “micromotors.”
Patients with diabetes have trouble regulating their blood glucose levels because they produce little or no insulin. Synthetic insulin has existed for over a hundred years, but it is often administered with an injection or an implanted pump. People affected by diabetes often take insulin multiple times per day, so frequent injections can be painful, and as a result, some patients do not take the recommended dose at the correct times.
An oral form of the drug would be ideal, but the harsh environment of the stomach breaks down and neutralizes the hormone before it can be absorbed by the intestines and get into the bloodstream. Previous attempts at oral administration protected the hormone from stomach acids with micro- or nanocarriers but relied on insulin to passively diffuse into the cells that line the colon, which isn’t very efficient. A better approach could be actively moving the medicine around the body instead, such as with a recently reported robo-capsule that delivers its cargo by drilling itself into the thick, mucosal layer of the small intestine. Yingfeng Tu, Fei Peng, Kun Liu and colleagues wanted to achieve a similar effect with their an insulin-loaded mini-tablets, which featured tiny, chemical “micromotors” that could deliver insulin to the colon safely and effectively.
To make these tablets, the researchers covered magnesium microparticles with a layer of an insulin-containing solution and a layer of liposomes. They then mixed these particles with baking soda, pressed them into mini-tablets that were about 3 mm long then covered them with an esterified starch solution. The starch protected the tablets from stomach acid, allowing them to reach the colon intact. As they broke down, the magnesium microparticles reacted with water to generate a stream of hydrogen gas bubbles, which acted as micromotors that propelled insulin toward the colon’s lining to be absorbed. The team also tested their mini-tablets in rats and found that they could significantly reduce the animals’ blood glucose levels for over five hours. In fact, they could maintain a glucose level almost as low as injection-delivered insulin. Though more work is needed, the researchers say that this is a concrete step toward creating more oral formulations of traditionally injection-only medications.
The authors acknowledge funding from the National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Foundation and the Key Research and Development Project of Lishui.
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What it means to be conscious is more than just a philosophical question. Researchers continue to investigate how conscious experience arises from the electrochemical activity of the human brain. The answer has important implications for the way brain health is understood, from coma, wherein a person is alive but unable to move or respond to his or her environment, to surgical anesthesia, to the altered thought processes of schizophrenia.
Recent research suggests that there’s no one location in the brain that causes consciousness, pointing to a network phenomenon. However, tracing the various linkages between regions in the brain networks that give rise to awareness and wakefulness has been elusive.
A new approach using functional MRI, an imaging technique that allows you to see and measure brain activity through changes in blood flow over time, provides new insight into how we describe and study conscious states.
“Consciousness is complex and studying it is like solving a scrambled Rubik’s cube,” said Zirui Huang, Ph.D., research assistant professor in the University of Michigan Medical School Department of Anesthesiology. “If you look at just a single surface, you may be confused by the way it is organized. You need to work on the puzzle looking at all dimensions.”
When it comes to consciousness, these dimensions can include 1) arousability, that is, the ability of the brain to be awake; 2) awareness, or what we actually experience, like the redness of a rose; and 3) sensory organization, or how sights and sounds and feelings become woven together to create our seamless conscious experience.
For decades, though, these dimensions were just considered conceptually, without any mapping to brain activity itself. In the study by Huang, George Mashour, M.D., Ph.D., professor and chair of the Department of Anesthesiology and founder of the Center for Consciousness Science, and Anthony Hudetz, DBM, Ph.D., director of the Center for Consciousness Science, the investigators sought to find those dimensions of the mind in the geometry of the brain.

Typically, brain imaging studies assess discrete, well-defined brain areas. To understand this, consider the state of Colorado on a map of the United States. It has very clear boundaries in an almost rectangular shape.
However, the borders separating, for example, Colorado and Wyoming, are arbitrary. By contrast, looking at the topology of the mountains across Colorado and Wyoming give you a more informative, natural view of the region. The investigators did something very similar in this neuroimaging study: instead of looking at clearly defined brain regions, they investigated the topology or gradients across brain regions.
To develop a map of these so-called cortical gradients of consciousness, the team used fMRI data from study participants who were awake, anesthetized, in a form of coma, or who had psychiatric diagnoses such as schizophrenia.
The team was then able to arrange recordings from 400 different brain regions into gradients and compare how they change in relation to these states or diagnoses. They found three cortical gradients that seemed to align with the dimensions of consciousness, including arousability, awareness, and sensory organization.
“What used to be mapped only as a helpful diagram of conscious states might now be mapped in the brain itself,” said Hudetz, senior author on the study.
“Our study opens a new view of the link between consciousness and the brain,” said Huang. Furthermore, he notes, the results have the potential for developing brain-based diagnoses or assessment for neurologic patients.
“This article represents an important contribution to the science of consciousness and aligns with our mission of achieving deeper understanding while advancing clinical care,” said Mashour.

A team led by researchers at NYU Langone Health’s Perlmutter Cancer Center has identified a gene that drives development of the second most common type of lung carcinoma, offering greater insight into how the disease might be treated.
There is currently no approved, targeted, first-line therapy for lung squamous carcinoma (LUSC), a cancer that forms in cell layers lining the organ and is responsible for 20 to 30 percent of lung carcinoma deaths. But a new study, publishing in the Jan. 9 edition of Cancer Cell, found that deleting a gene called KMT2D caused normal (basal) lung cells grown in complex cultures called organoids to transform into LUSC cells.
According to the study authors, KMT2D regulates the activity of genes that enable the building of protein tyrosine phosphatases, enzymes that restrain the cell-growth-encouraging signals sent through another enzyme set called receptor tyrosine kinases (RTKs). Two RTKs, called EGFR and ERBB2, are known to take part in the abnormal activation of the RTK-RAS signaling pathway, wherein a molecular switch gets “stuck in the on mode,” causing cells to continually multiply as part of cancer.
“Our study identifies KMT2D as a pivotal contributor to the development of lung squamous cancers, and offers vital clues about how to target KMT2D-deficient LUSC,” says co-corresponding author Kwok Kin-Wong, MD, PhD, director of the Division of Hematology and Medical Oncology at NYU Langone Health. “The same genetic changes that cause the gene to contribute to cancer also create tumors that are very sensitive to existing drugs that target a related pathway.”
New Approaches Suggested
The new study confirms prior evidence that the KMT2D gene encodes a protein (a histone methyltransferase) that determines the degree to which the tyrosine phosphatase genes can be accessed by the cellular machinery trying to read them.
Given the better understanding of LUSC mechanisms resulting from the new study, the research team chose to test in study mice a combination of two drugs — SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib. ERBB is made more active by KMT2D signaling flaws, and the enzyme SHP turns up the RTK-KAS pathway, much like EGFR and ERBB2, which are rendered more active by the lack of KMT2D. The team reasoned that experimental drugs designed to inhibit SHP might also counter the effect of KMT2D deficiency when used alongside the ERBB inhibitor.
Indeed, they found that the combination slowed lung tumor growth in mice with LUSC that had been engineered to lack KMT2D, as well as in tumors in mice derived from the human LUSC tumors with KMT2D mutations.
“Multiple SHP2 inhibitors are currently testing in clinical trials, and afatinib is already available,” says co-corresponding author Hua Zhang, MD, PhD, formerly an instructor in the Department of Medicine at NYU Langone Health, and now an assistant professor in the Department of Medicine, Division of Hematology and Oncology, at University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center. “Our findings warrant the design of clinical trials that test these therapies in KMT2D-deficient patients with LUSC.”

Two separate eye diseases may contribute to age-related macular degeneration (AMD), a leading cause of blindness in the United States, according to a new study from New York Eye and Ear Infirmary of Mount Sinai.
The research, published January 9 in Eye is the first to demonstrate that two different types of deposits in the retina may contribute to early AMD, which can progress to advanced AMD and blindness. These two diseases could be diagnosed, studied, and treated separately with appropriate early intervention to prevent vision loss and other complications.
Age-related macular degeneration results from damage to the central area of the retina called the macula, which is responsible for reading and driving vision for driving Nearly 20 million Americans age 40 and older are living with some form of AMD, according to the Centers for Disease Control and Prevention. AMD in its early form is currently considered to be a single disease with cholesterol-containing deposits. These deposits are known as drusen and subretinal drusenoid deposits (SDDs). Early AMD may progress to blindness in two advanced forms, commonly called wet and dry AMD. The advanced dry form is also called geographic atrophy (GA) by eye specialists.
“An amazing fact is that the retina can generate a fluorescent light, similar to that of a light fixture, but a million times dimmer. For the first time, we were able to measure this dim light, called autofluorescence (AF), with ultra-sensitive detectors to study advanced AMD. We found it was consistently twice as bright in the patients with SDDs as those with drusen when they reached advanced AMD, and came from a unique diseased layer,” explains lead author R. Theodore Smith, MD, PhD, Professor of Ophthalmology at the Icahn School of Medicine at Mount Sinai. “Combined with our prior research, this provides conclusive evidence that two different disease processes in AMD are taking place, one with darker fluorescence and drusen, and one with brighter fluorescence and SDDs, and they need to be treated differently.”
Drusen formation can be slowed by appropriate vitamin supplements to prevent vision loss. Currently, there is no known treatment for SDDs, and they pose a greater threat of advanced AMD. However, in a recent previous study, Dr. Smith and a team of Mount Sinai researchers found that patients with SDDs are likely to have heart damage from heart failure and heart attacks, or advanced heart valve disease, or strokes associated with carotid artery disease.
“We think the SDDs result from deficient blood flow to the eye caused by these vascular diseases. We therefore believe that patients with SDDs should be warned they may have life-threatening undetected heart conditions that should be evaluated and treated. Further research needs to be done in women and disadvantaged groups where neglected heart disease is a serious issue. Eye scans for SDDs and routine cholesterol blood tests could address this. Additionally, treating the cardiovascular condition and restoring the eye’s blood supply may also help the SDDs. This work should prompt retinal specialists to look for both drusen and SDDs with optical coherence tomography (OCT), a standard retinal imaging technique, to best counsel patients.
The new research measured the autofluorescence and evaluated OCT scans in 18 patients (32 eyes) with advanced AMD and geographic atrophy (GA). Because GA can happen in multiple regions of the retina, investigators analyzed 52 GA regions overall. They also selected only patients who had OCT scans over the three previous years so they could determine whether the diseased regions started with drusen, SDDs, or both. 18 of these regions originated from drusen, 12 originated from SDDs, and 22 originated from mixtures of drusen and SDDs. The team then measured the brightness of the fluorescent light coming from these regions with a very sensitive light meter. They found it was twice as bright in patients with SDDs when compared to those with drusen. Specifically, the brightness readings averaged 72 in SDD subjects and 36 in drusen subjects, with values in the mixed group falling in between.
“All these numbers translate into one basic fact — there are two different diseases in AMD, one with drusen and one with SDDs,” says Dr. Smith. “The good news for patients and eye specialists is that in the clinic, we will not need advanced AF measurements to know which form of AMD the patient has. As our research showed, the two forms are associated with drusen and SDDs, and those deposits can be identified by standard retinal imaging. It therefore becomes important to diagnose which form of AMD the patient has for treatment and prevention of disease.”
This study was funded by a Regeneron Pharmaceuticals Investigator-Initiated Study, a Research to Prevent Blindness Challenge Grant, the Macula Foundation, a Bayer-Global Ophthalmology Award, and the International Council of Ophthalmology-Alcon Fellowship.