Diabetes can lead to memory loss, depression and other cognitive impairment in older adults

Many complications of diabetes, including kidney disease, foot problems and vision problems are generally well recognized. But the disease's impact on the brain is often overlooked.

For the past five years, a team led by Beth Israel Deaconess Medical Center (BIDMC) neurophysiologist Vera Novak, MD, PhD, has been studying the effects of diabetes on cognitive health in older individuals and has determined that memory loss, depression and other types of cognitive impairment are a serious consequence of this widespread disease.

Now, Novak's team has identified a key mechanism behind this course of events. In a study published in the November 2011 issue of the journal Diabetes Care, they report that in older patients with diabetes, two adhesion molecules – sVCAM and sICAM – cause inflammation in the brain, triggering a series of events that affect blood vessels and, eventually, cause brain tissue to atrophy. Importantly, they found that the gray matter in the brain's frontal and temporal regions -- responsible for such critical functions as decision-making, language, verbal memory and complex tasks – is the area most affected by these events.

"In our previous work, we had found that patients with diabetes had significantly more brain atrophy than did a control group," explains Novak, Director of the Syncope and Falls in the Elderly (SAFE) Program in the Division of Gerontology at BIDMC and Associate Professor of Medicine at Harvard Medical School. "In fact, at the age of 65, the average person's brain shrinks about one percent a year, but in a diabetic patient, brain volume can be lowered by as much as 15 percent."

Diabetes develops when glucose builds up in the blood instead of entering the body's cells to be used as energy. Known as hyperglycemia, this condition often goes hand-in-hand with inflammation. Novak wanted to determine if chronic inflammation of the blood vessels was causing altered blood flow to the brain in patients with diabetes.

To test this hypothesis, Novak's team recruited 147 study subjects, averaging 65 years of age. Seventy one of the subjects had type 2 diabetes and had been taking medication to manage their conditions for at least five years. The other 76 were age and sex-matched non-diabetic controls.

Study subjects underwent a series of cognitive tests, balance tests and standard blood-pressure and blood-glucose tests. Serum samples were also collected to measure adhesion molecules and several other markers of systemic inflammation. To determine perfusion (blood flow) measures in the brain, patients also underwent functional MRI testing, in which a specialized imaging technique known as arterial spin labeling (developed by BIDMC MR physicist David Alsop, PhD) was used in conjunction with a standard MRI to measure vascular reactivity in several brain regions and to show changes in blood flow.

As predicted, the scans showed that the diabetic patients not only had greater blood vessel constriction than the control subjects, but they also had more atrophied brain tissue, particularly gray matter. The results also showed that, in the patients with diabetes, the frontal, temporal and parietal regions of the brain were most affected. Similarly, the team's measurements of serum markers confirmed that high glucose levels were strongly correlated with higher levels of inflammatory cytokines.

"It appears that chronic hyperglycemia and insulin resistance – the hallmarks of diabetes – trigger the release of adhesion molecules [sVCAM and sICAM] and set off a cascade of events leading to the development of chronic inflammation," says Novak. "Once chronic inflammation sets in, blood vessels constrict, blood flow is reduced, and brain tissue is damaged. "

This discovery now provides two biomarkers of altered vascular reactivity in the brain. "If these markers can be identified before the brain is damaged, we can take steps to try and intervene," says Novak, explaining that some data indicates that medications may improve vascoreactivity.

But more important, she says, the new findings provide still more reason for doctors and patients to focus greater attention on the management – and prevention – of diabetes.

"Cognitive decline affects a person's ability to successfully complete even the simplest of everyday tasks, such as walking, talking or writing," says Novak. "There are currently 25.8 million cases of type 2 diabetes in the United States alone, which is more than eight percent of our total population. The effects of diabetes on the brain have been grossly neglected, and, as our findings confirm, are issues that need to be addressed."

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Does space flight impact astronauts' eyes and vision?

A new study sponsored by NASA finds that space flights lasting six months or more can cause a spectrum of changes in astronauts' visual systems. Some problems, including blurry vision, appear to persist long after astronauts' return to Earth. The results are affecting plans for long-duration manned space voyages, such as a trip to Mars.

The study team included ophthalmologists Thomas H. Mader, MD, of Alaska Native Medical Center and Andrew G. Lee, MD, of The Methodist Hospital, Houston, Texas. Their report is published in October's Ophthalmology, the journal of the American Academy of Ophthalmology.

The researchers studied seven astronauts, all of whom were about age 50 and had spent at least six continuous months in space. All reported that their vision became blurry, to varying degrees, while on the space station. Vision changes usually began around six weeks into the mission and persisted in some astronauts for months after their return to Earth. Drs. Mader and Lee agree that the eye abnormalities appear to be unrelated to launch or re-entry, since they occurred only in astronauts who spent extended time in microgravity.

In-depth examination of the seven astronauts revealed several abnormalities. All of the subjects had one or more of the following changes in the tissues, fluids, nerves and other structures in the back of the eye:

• Flattening of the back of the eyeball (five subjects);
• Folds in the choroid, the vascular tissue behind the retina, which is the light sensitive area in the back of the eye (five subjects); and
• Excess fluid around and presumed swelling of the optic nerve (five subjects).

Such abnormalities could potentially be caused by increased intracranial pressure−that is, pressure inside the head. However, none of these astronauts experienced symptoms usually associated with intracranial pressure, such as chronic headache, double vision, or ringing in the ears. Researchers believe other factors may be involved, such as abnormal flow of spinal fluid around the optic nerve, changes in blood flow in the choroid, or changes related to chronic low pressure within the eye, which is known as intraocular pressure. They hypothesize that these changes may result from the fluid shifts toward the head that occur when astronauts spend extended time in microgravity.

The visual system changes discovered by the researchers may represent a set of adaptations to microgravity. The degree and type of response appear to vary among astronauts. Researchers hope to discover whether some astronauts are less affected by microgravity and therefore better-suited for extended space flight, such as a three-year round trip to Mars.

In their report, Drs. Mader and Lee also noted a recent NASA survey of 300 astronauts that found that correctible problems with both near and distance vision were reported by about 23 percent of astronauts on brief missions and by 48 percent of those on extended missions. The survey confirmed that for some astronauts, these vision changes continue for months or years after return to Earth. The possibility of near vision problems has been recognized for decades, and special "space anticipation glasses" to improve visual sharpness have been provided on all spacecraft dating back to John Glenn, who had a pair in his space capsule.

"In astronauts over age 40, like non-astronauts of the same age, the eye's lens may have lost some of its ability to change focus," said Dr. Mader. "In the space program's early days most astronauts were younger, military test-pilots who had excellent vision. Today's astronauts tend to be in their 40s or older. This may be one reason we've seen an uptick in vision problems. Also, we suspect many of the younger astronauts were more likely to 'tough out' any problems they experienced, rather than reporting them."

As part of ongoing research all astronauts now receive comprehensive eye exams and vision testing. Diagnostic tests include pre- and post-flight magnetic resonance imaging, optical coherence tomography, which magnifies cross-section views of parts of the eye, and fundus photography, which records images of the retina and back of the eye. Intraocular pressure measurement and ultrasound imaging take place in flight, as well as pre- and post-mission.

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Is pupillary light reflex really controlled by the brain?

You’ve seen it on television: A doctor shines a bright light into an unconscious patient’s eye to check for brain death. If the pupil constricts, the brain is OK, because in mammals, the brain controls the pupil. Or does it? Now, researchers at Johns Hopkins have discovered that in most mammals, in fact in most vertebrates, the pupil can constrict without any input from the brain. Their work, which also describes for the first time the molecular mechanism underlying this process, appears in the Nov. 3 issue of Nature.

“It was established more than 40 years ago that animals like amphibians and fish have photosensitive irises and don’t necessarily require the brain for the pupillary light reflex, whereas it was thought that mammals generally required brain circuitry,” says King-Wai Yau, Ph.D., professor of neuroscience and ophthalmology at the Johns Hopkins University School of Medicine and member of the Institute for Basic Biomedical Sciences Center for Sensory Biology. “But in neither case did anyone know what the molecular switch was, and now we have found that it’s the pigment melanopsin.”

The research team examined isolated irises from a wide range of mammals by attaching a tiny meter that measures the force of the sphincter muscle that constricts the pupil. They then shined a bright light onto this muscle and measured any contraction. Irises from nocturnal animals including mouse, rat, hamster, dog, cat, rabbit and the Nile grass rat all showed responses to light. Irises from diurnal animals including guinea pig, ground squirrel and pig did not, nor did those from rhesus monkey, marmoset, owl monkey and bush baby, even though the owl monkey and bush baby are nocturnal.

“Most non-primate mammals are considered nocturnal or crepuscular — active at dawn and dusk — including those, like dogs, that have been domesticated and have picked up human circadian rhythms,” says Yau. “We don’t really know why primates, including us, as well as other daytime functioning animals don’t have this ability.” According to Yau, the eyes of nocturnal animals, because they function in the dark, contain more cells that are sensitive to low light and exposure to bright light could cause eye damage. Perhaps, he suggests, the built-in pupil reflex is a good way to protect the eye.

“So we wanted to know what pigment molecules are involved in triggering pupil constriction,” says Yau. Having previously genetically engineered mice to lack melanopsin, the team first tested the pupillary light reflex on irises from these mice. “That was a really exciting result—they didn’t respond to the light,” says Tian Xue, a research associate with Yau. They also tested mice engineered to lack other light-capturing pigments, but all of them responded normally, suggesting that only melanopsin is required for the local pupil reflex. Using mouse genetics, the team then continued to try to identify other proteins that work with melanopsin to cause the pupil to contract in response to light.

Because melanopsin is closely related to the pigment responsible for capturing light in fly eyes, and that molecular pathway has been well studied, Yau’s team hypothesized that the mammalian counterparts to these fly molecules might be what works with melanopsin. So they tested mice engineered to lack some of these molecules. They found that irises from mice lacking the PLC enzyme were unresponsive to light, showing that PLC also is involved in this reflex.

There still are a lot of things we don’t know that we would like to study,” says Yau. “Now that we know what captures the light and starts the local reflex, we would like to know what proteins in the muscle trigger the actual contraction.”

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Nature's Editorial Summary: "Mammalian pupil sees the light"

Contraction of the mammalian iris in response to light has been thought to require neuronal circuitry connecting the retina to the brain. Now King Yau and colleagues report the surprising observation that in a wide variety of mammals, the eye's pupil is intrinsically photosensitive. Iris muscles isolated from nocturnal mammals such as mice — but not from primates — contract when exposed to light through the action of a melanopsin-based signalling pathway that partially overlaps with its retinal counterpart. Previously, the intrinsic pupillary reflex was thought to be an exclusive property of lower vertebrates such as fish, amphibians and birds. For those who want to read the article in detail, please click here.

First patient receives novel gene therapy for a type of blindness

The first patient to receive gene therapy for an incurable type of blindness was treated at the John Radcliffe Hospital in Oxford this week as part of a trial led by Oxford University.

If successful, the advance could lead to the first-ever treatment for choroideraemia, a progressive form of genetic blindness that first arises in childhood and is estimated to affect over 100,000 people worldwide.

‘This disease has been recognised as an incurable form of blindness since it was first described over a hundred years ago. I cannot describe the excitement in thinking that we have designed a genetic treatment that could potentially stop it in its tracks with one single injection,’ says Professor Robert MacLaren of the University of Oxford, who is leading the trial.

Jonathan Wyatt, 63, an arbitration lawyer from Bristol had the surgery at the Oxford Eye Hospital based at the John Radcliffe – the main NHS centre for this trial. He is the first of 12 people in this initial human trial that will receive the novel gene therapy. Mr Wyatt was diagnosed with choroideraemia in his late teens and has suffered progressive sight loss ever since. He now sees only blackness except for a small area of a few degrees in diameter in the centre of his vision.

Choroideraemia is a genetic disease that leads to progressive degeneration of the retina in the eye. It generally affects males only and there is no treatment. The diagnosis is usually made in childhood and leads to blindness in men by their forties. It occurs due to deficiency of the REP1 gene located on the X chromosome.

The novel gene treatment was developed by Professor MacLaren at Oxford University, in collaboration with Professor Miguel Seabra at Imperial College, London. It is designed to provide the gene missing in people with choroideraemia to stop the deterioration that gradually leads to blindness.

It uses a virus essentially as a delivery vehicle that ferries DNA including the missing gene into the right part of the eye. The virus has been engineered to infect the light-sensitive cells in the retina known as photoreceptors. There the gene is switched on and becomes active.

With this particular gene therapy, the treatment could provide a one-off permanent correction of the disease because the gene is thought to remain in the retinal cells indefinitely.

‘This trial represents the world’s first ever attempt to treat this disease and the first time that gene therapy has been directed towards the light-sensitive photoreceptor cells of the human retina,’ says Professor MacLaren. ‘This represents a major breakthrough and is highly significant for patients who are losing sight from other photoreceptor diseases, such as retinitis pigmentosa.’

The trial will see 12 patients undergo surgery in which the gene therapy is injected into one eye. The other eye would then act as a control against which to assess any treatment effect. The researchers would however aim to go on to treat the second eye, should the treatment be proven to be effective.

The aim of the trial is primarily to assess safety, but it will also gain initial data on how effective the treatment is. The researchers estimate that it will take two years to know whether or not the degeneration has been stopped completely by the gene therapy.

‘While safety appears so far to be fine, the efficacy of the gene therapy will only be evident after 24 months. We need this time to measure any effect as the degeneration caused by choroideraemia is slow,’ explains Professor MacLaren, who is also an honorary consultant at the Oxford Eye Hospital and Moorfields Eye Hospital.

The clinical trial is funded by a grant awarded to the University of Oxford by the Health Innovation Challenge Fund – a translational award scheme funded jointly by the Wellcome Trust and the Department of Health.

Professor Seabra, who played a key role at Imperial College London in identifying the gene causing choroideraemia and in eliciting the mechanism of cell death in the retina, comments: ‘The ability to offer a gene replacement treatment for these patients was the final objective of 20 years of intense research in my laboratory. This is a moment of fulfilment for us and a dream come true for all choroideraemia patients.’

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Possible new treatment for Complicated Retinal Detachments with Proliferative Vitreo-Retinopathy (PVR)

Proliferative vitreoretinopathy (PVR), or the formation of scar tissue within the eye, is a serious, sight-threatening complication in patients recovering surgical repair of retinal detachment. A new study conducted by investigators at the Schepens Eye Research Institute, the Department of Ophthalmology at Harvard Medical School, and the Massachusetts Eye and Ear Infirmary in Boston, USA, published in the December issue of the American Journal of Pathology, suggests that a cocktail containing reagents to neutralize a relatively small subset of vitreal growth factors and cytokines may be an effective treatment.

The investigators, lead by Andrius Kazlauskas, PhD, of The Schepens Eye Research Institute and the Department of Ophthalmology, Harvard Medical School, found that a combination of 7 classes of growth factors and cytokines was essential for PVR to develop in animal models of the disease. By neutralizing them, they were able to prevent PVR-relevant signaling, and inhibit contraction of collagen gels containing primary retinal pigment epithelial cells derived from a human PVR membrane (RPEMs). These findings suggest a potential therapeutic approach to reduce the incidence of PVR in patients undergoing surgery to repair a detached retina.

In animal models, platelet-derived growth factor receptor α (PDGFRα) is associated with PVR and strongly promotes experimental PVR. Vitreal growth factors outside of the PDGF family promote an indirect route to activate PDGFRα. Importantly, indirectly activated PDGFRα engages a characteristic set of signaling events and cellular responses that are tightly associated with PVR. This study sought to identify the factors that would induce those events, and develop therapeutic approaches to prevent patients from developing PVR.

Vitreous was obtained from normal rabbits or those in which PVR was either developing or stabilized. Normal vitreous was found to contain substantial levels of growth factors and cytokines, which change quantitatively or qualitatively as PVR develops. A set of nine growth agents was found to be most abundant and therefore most likely to contribute to PVR. Neutralizing a subset of these factors in rabbit vitreous eliminated their ability to induce PVR-relevant signaling and cellular responses. A single dose of neutralizing reagents effectively protected rabbits from developing retinal detachment.

To identify growth factors likely to be driving PVR in humans, the investigators quantified the level of growth factors and cytokines from human donors that had either PVR, or a non-PVR retinal condition. Fourteen of the 24 agents quantified were present in large concentrations in PVR vitreous. Neutralizing just 7 of these prevented vitreous-induced activation of PDGFRα. Furthermore, the cocktail also suppressed the contraction of these cells in collagen. Therefore, the same neutralization strategy that prevented PVR in rabbits also prevented human PVR vitreous from inducing PVR-relevant responses. These results strongly suggest that a dose of neutralizing reagents may also protect humans from PVR.

Although it sounds encouraging, the investigators feel they need to test the effectiveness of this treatment on alternate models of retinal detachment. They are considering a combinatorial approach to therapy. For example, the antioxidant N-acetylcysteine (NAC) is known to prevent retinal detachment in rabbits by blocking intracellular processes. A combined therapy involving the neutralization approach by these investigators, along with NAC treatment, would target PVR at both the extracellular and intracellular levels, thus possibly helping in treatment.

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New technique to revolutionize cataract surgery

Two new studies add to the growing body of evidence that a new approach to cataract surgery may be safer and more efficient than today's standard procedure of phacoemulsification.

The new approach, using a special femtosecond laser (more info here and here), is FDA-approved in the United States, but not yet widely available in the US. Research reported at the 2011 American Academy of Ophthalmology conference in Orlando by William W. Culbertson, MD, of the Bascom Palmer Eye Institute at the University of Miami School of Medicine, and by Mark Packer, MD, of Oregon Health and Sciences University, confirms several advantages of laser cataract surgery.

Dr. Culbertson's team studied how pre-treating cataracts with the femtosecond laser affected the level of ultrasound energy needed to soften the cataracts. This emulsification is performed so that the cataracts can be easily suctioned out. Surgeons want to use the lowest possible level of ultrasound energy, since in a small percentage of patients, it is associated with slower recovery of good vision after surgery and/or problems with the cornea, which is the clear outer layer of the eye. Ideally, in appropriate cases, ultrasound use would be eliminated altogether.

In Dr. Culbertson's prospective, randomized study, patients had laser cataract surgery with a femtosecond laser in one eye and the standard cataract procedure, called phacoemulsification, in the other. Laser surgery included a laser capsulotomy, which is a circular incision in the lens capsule, followed by laser lens fragmentation, then ultrasound emulsification and aspiration. Lens fragmentation involved using the laser to split the lens into sections and then soften it by etching cross-hatch patterns on its surface. Standard surgery included a manual incision, followed by ultrasound emulsification and aspiration. After cataract removal by either method, intraocular lenses were inserted into eyes to replace the natural lens and provide appropriate vision correction for each patient.

The use of ultrasound energy use was reduced by 45 percent in the laser pre-treated eyes compared with the eyes that received the standard cataract surgery procedure. Also, surgical manipulation of the eye was reduced by 45 percent in eyes that received laser pre-treatment as compared to manual standard surgery. This study involved the most common types of cataracts, those graded 1- 4. Dr. Culbertson notes that these findings may not apply to higher grade cataracts.In clinical practice, surgeons would expect safer, faster cataract surgery when laser pre-treatment is performed before cataract removal, as per Dr. Culbertson, with the combination of precision and simplification possible with the femtosecond laser represents a major advance for this surgery.

Laser lens fragmentation also demonstrates that it can protect the corneal endothelial cells. Dr. Packer and his colleagues at the Oregon Health and Sciences University in Portland, Oregon, assessed the safety of laser cataract surgery vis-a-vis loss of corneal endothelial cells, as measured after cataract surgery. Measuring endothelial cell loss (measured by a test referred to as specular microscopy) is one of the most important ways to assess the safety of new cataract surgery techniques and technology. These cells are important since they preserve the clarity of the cornea, which is important, since they do not regenerate and hence have to last a lifetime to preserve corneal clarity. Dr. Packer's study found that with laser lens fragmentation, there was no loss of endothelial cells, while eyes that received standard treatment had cell loss of one to seven percent.

Earlier studies of femtosecond laser cataract surgery have found other advantages. The laser allows the surgeon to make smaller, more precise incisions, and to perform improved capsulotomies (the initial cut in the anterior capsule of the lens to ease in removal of the cataract and insertion and secure placement of the intraocular lens (IOP) placement). This secure placement reduces the possibility of displacement of the IOL. Also, laser cataract surgery appears to improve results in patients who opt for advanced technology IOLs, plus corrective corneal incisions, to achieve good all-distance vision.

Femtosecond lasers have been used by ophthalmologists for years in refractive surgery such as LASIK, in-corneal transplants, and in other procedures. In 2009, a new type of femtosecond laser that could reach deep enough into the eye to be used in cataract removal was approved by the FDA.

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Phase I/IIa Gene Therapy trial for Usher Syndrome type 1B approved

Oxford BioMedica plc, the leading gene-based biopharmaceutical, has announced that the US Food and Drug Administration (FDA) has approved its Investigational New Drug (IND) application for the Phase I/IIa clinical development of UshStat®, a novel gene-based treatment for Usher syndrome type1B. UshStat® was designed and developed by Oxford BioMedica using the Company's proprietary LentiVector® platform technology and is the third programme to enter clinical development under the Phase I/II ocular collaboration agreement signed with Sanofi in April 2009.

The approval of the IND follows the decision by the US Recombinant DNA Advisory Committee (RAC) to approve the UshStat® Phase I/IIa protocol in May 2011. The open label, dose escalation Phase I/IIa study will enrol up to 18 patients with Usher syndrome type 1B at the Oregon Health and Science University’s Casey Eye Institute, Portland, Oregon, USA. The study, led by Professor Richard Weleber, will evaluate three dose levels for safety, tolerability and aspects of biological activity and is expected to be initiated by the end of 2011.

Usher syndrome is the most common form of deaf-blindness, which affects approximately 30,000-50,000 patients in the US and Europe. One of the most common subtypes is Usher syndrome type1B. The disease is caused by a mutation of the gene encoding myosin VIIA (MY07A), which leads to progressive retinitis pigmentosa combined with a congenital hearing defect.

UshStat® uses theCompany's LentiVector® platform technology to deliver a corrected version of the MYO7A gene toaddress the vision loss associated with the disease. On the basis of pre-clinical data, it is anticipated that a single application of UshStat® to the retina could provide long-term or potentially permanent stabilisation of vision. There are currently no approved treatments available for Usher syndrome type1B. UshStat® has received European and US Orphan Drug Designation which brings development, regulatory and commercial benefits.

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