Mutations in TYROBP are not a common cause of dementia in a Turkish cohort

Mutations in TYROBP and TREM2 have been shown to cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. Recently, variants in TREM2 were also associated with frontotemporal dementia and Alzheimer’s disease. Given the functional proximity between these two genes we investigated the genetic variation of TYROBP in a Turkish cohort of 103 dementia patients. No mutations or copy number variants predicted to be pathogenic were identified. These results indicate that mutations in TYROBP are not a common cause of dementia in this Turkish cohort.📍

Parkinsonian Features in Aging GFAP.HMOX1 Transgenic Mice Overexpressing Human HO-1 in the Astroglial Compartment

Epigenetic influences mediating brain iron deposition, oxidative mitochondrial injury and macroautophagy in Parkinson disease (PD) and related conditions remain enigmatic. Here, we show that selective overexpression of the stress protein, heme oxygenase-1 (HO-1) in astrocytes of GFAP.HMOX1 transgenic mice between 8.5 and 19 months of age results in nigrostriatal hypodopaminergia associated with locomotor incoordination and stereotypy; downregulation of TH, DAT, LMX1B, Nurr1, Pitx3 and DJ-1 mRNA and/or protein; overproduction of α-synuclein and ubiquitin; oxidative stress; basal ganglia siderosis; mitochondrial damage/mitophagy; and augmented GABAergic systems (increased GABA, GAD67 and reelin).📍

Adjusting Microglia Proportions as a Basis for the Treatment of Parkinson’s Disease

The balance between different types of the immune cells known as macrophages is becoming a stronger theme these days, a line of research that falls somewhere into the broad overlap between regeneration, inflammation, and aging. I’ve seen quite a number of interesting papers on this topic in the past year, which seems to me a leap in the level of interest shown by the research community of late. While possibly oversimplifying a more complicated reality, we can think of macrophages as having a few different types, or polarizations. The M1 polarization tends towards aggressive destruction of problem cells, the creation of inflammation, and hindrance of regeneration. The M2 polarization tends towards suppression of inflammation and other behaviors that encourage regeneration. The cancer research community would like to be able to adjust macrophage populations towards the M1 type, more willing to destroy cancerous cells, while the regenerative medicine community would like to be able to adjust macrophage populations towards the M2 type to spur enhanced regeneration and tissue maintenance.

It may be that the increased interest in macrophage polarization is a function of the emergence of tools that now allow for cost-effective attempts to shift the balance of macrophage types. The infrastructure of biotechnology is advancing rapidly, and progress spurred by falling costs is a common theme in many parts of the field. Today I’ll offer up another example of macrophage polarization research, this time involving microglia, a form of macrophage resident in the central nervous system. Changes in microglia have been shown to be important in any number of age-related neurodegenerative conditions: the immune system declines with age in the brain, just as elsewhere in the body, falling into a dysfunctional and inflammatory state. This affects regeneration and tissue maintenance as is the case for macrophages beyond the brain, but microglia also have additional roles in the correct function of neurons and neural connections, an area of our biochemistry that is still comparatively poorly understood. It is possible to achieve benefits for patients by coercing more microglia into the M2, pro-regenerative polarization? In this open access paper, researchers examine the question in the context of Parkinson’s disease.

Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson’s Disease

A growing body of evidence suggest that neuroinflammation mediated by microglia, the resident macrophage-like immune cells in the brain, play a contributory role in Parkinson’s disease (PD) pathogenesis. In the central nervous system (CNS), the innate immune response is predominantly mediated by microglia and astrocytes. Microglia play a vital role in both physiological and pathological conditions. Microglia appear to be involved in several regulatory processes in the brain that are crucial for tissue development, maintenance of the neural environment and, response to injury and promoting repair. Similar to peripheral macrophages, microglia directly respond to pathogens and maintain cellular homeostasis by purging said pathogens, as well as dead cells and pathological gene products.

Microglia participate in both physiological and pathological conditions. In the former, microglia restore the integrity of the central nervous system and, in the latter, they promote disease progression. Microglia acquire different activation states to modulate these cellular functions. When classically activated, microglia acquire the M1 phenotype, characterized by pro-inflammatory and pro-killing functions that serve as the first line of defense. The alternative M2 microglial activation state is involved in various events including immunoregulation, inflammation dampening, and repair and injury resolution.

Upon activation to the M1 phenotype, microglia elaborate pro-inflammatory cytokines and neurotoxic molecules promoting inflammation and cytotoxic responses. In contrast, when adopting the M2 phenotype microglia secrete anti-inflammatory gene products and trophic factors that promote repair, regeneration, and restore homeostasis. Relatively little is known about the different microglial activation states in PD, and the distribution of microglial M1/M2 phenotypes depends on the stage and severity of the disease. Understanding stage-specific switching of microglial phenotypes and the capacity to manipulate these transitions within appropriate time windows might be beneficial for PD therapy. The transition from the M1 pro-inflammatory state to the regulatory or anti-inflammatory M2 phenotype is thought to assist improved functional outcomes and restore homeostasis. The induction of M1 phenotype is a relatively standard response during injury. For peripheral immune cells it is thought that M1 polarization is terminal and the cells die during the inflammatory response. Although a shift from M1 to the M2 phenotype is considered rare for peripheral immune cells, microglia can shift from M1 to M2 phenotype.

To inhibit the pro-inflammatory damage through M1 activation of microglia, its downstream signaling pathways could be targeted. The M1 phenotype is induced by IFN-γ via the JAK/STAT signaling pathway and targeting this pathway may arrest M1 activation. In fact, studies show that inhibition of the JAK/STAT pathway leads to suppression of the downstream M1-associated genes in several disease models. Another approach to suppress M1 activation would be to target the pro-inflammatory cytokines such as TNF-α, IL-1β and IFN-γ, and decrease its ability to interact with its receptors on other cell types. Alternatively, molecules with the capability to activate the anti-inflammatory M2 phenotype or promote the transition of pro-inflammatory M1 phenotype to anti-inflammatory M2 could be useful in the treatment of PD. Anti-inflammatory molecules such as IL-10 and beta interferons produce neuroprotection by altering the M1 and M2 balance.

The critical role of microglia in most neurodegenerative pathologies including PD is increasingly documented through many studies. Until recently, microglial activation in pathological conditions was considered to be detrimental to neuronal survival in the substantia nigra of PD brains. Recent findings highlight the crucial physiological and neuroprotective role of microglia and other glial cells in neuropathological conditions. Studies on anti-inflammatory treatments targeting neuroinflammation in PD and other diseases by delaying or blocking microglial activation failed in many trials due to the lack of a specific treatment approach, possibly the stage of disease and an incorrect understanding of mechanisms underlying microglial activation. With the updated knowledge on different microglial activation states, drugs that can shift microglia from a pro-inflammatory M1 state to anti-inflammatory M2 state could be beneficial for PD. The M1 and M2 microglial phenotypes probably need further characterization, particularly in PD pathological conditions for better therapeutic targeting. We support targeting of microglial cells by modulating their activation states as a novel therapeutic approach for PD.


Seniors Miss Out On Clinical Trials

More than 60 percent of cancer patients are older adults — and that will rise to 70 percent by 2040.  Yet seniors continue to be underrepresented in clinical trials, making it difficult to assess how treatments are likely to help or harm them.

The newest evidence of the problem comes from a Food and Drug Administration analysis, which found that only 25 percent of patients participating in cancer clinical trials were 65 and older. The analysis, which has not yet been published, was presented at the American Society of Clinical Oncology’s annual meeting in June.

Clinical trials investigate the safety and effectiveness of new drugs and therapies, as well as ways to prevent illness and detect conditions early. Their discoveries help guide medical practice.

Yet, older adults are often not included in research studies to any significant extent. This is especially true for cancer patients in their 70s and 80s, according to the FDA’s data:

  • While 19 percent of breast cancer patients are 75 or older, only 4 percent of breast cancer clinical trial participants are of this age.
  • Although 33 percent of colon cancer patients are in the 75-and-up group, a mere 8 percent of patients studied by researchers fell in that age group.
  • While 37 percent of lung cancer patients are 75 or older, only 9 percent of people of that age are represented in lung cancer clinical trials.

The sobering conclusion: “It’s difficult to practice evidence-based medicine in an older population because the data isn’t there,” said Dr. Stuart Lichtman, professor of medicine at Weill Cornell Medical College in New York City and president of the International Society of Geriatric .

And it’s not just cancer. Across medical conditions that disproportionately affect seniors, people 65 and older have a poor showing in clinical trials.

“There’s often an assumption that drugs only need to be tested in younger people and results can be extrapolated,” said Dr. Consuelo Wilkins, an associate professor of medicine at Vanderbilt University Medical Center who, with colleagues, is overseeing a major grant to help bring more seniors,  blacks, Hispanics and other groups into clinical trials. “But we know that how older adults respond to medications and interventions and their risk for adverse events is different based on their physiology.”

Difficulties enrolling older people in research studies extend to Alzheimer’s disease. With National Institutes of Health research funding now at nearly $1.4 billion a year, “we’re going to be seeing more and more clinical trials, but it’s already difficult to get enough people to participate,” said Keith Fargo, director of scientific programs at the Alzheimer’s Association.

Fewer than one-third of people diagnosed with Alzheimer’s are eligible to join clinical trials, he said.

Researchers often find older adults unsuitable for trials for multiple reasons:  Seniors may have multiple illnesses — diabetes and hypertension, as well as cancer or Alzheimer’s disease — that could complicate the study’s results, or they may be taking several medications already that could interact with therapies being examined.

Also, older adults may live alone, and not have someone who can accompany them to the study site for tests and procedures — a significant concern for Alzheimer’s trials, which typically require a caregiver to provide input about the patient’s condition and progress. Or, seniors can’t get around easily. Or they’re frail.

Responsibility falls to a large extent on physicians, said Dr. Richard Schilsky, chief medical officer for ASCO, noting “they don’t ask older adults whether they want to participate or not. It’s a combination of concern that older patients might be unable to comply with a trial’s requirements, which are usually quite rigorous, and concern that specified therapies might be too toxic.”

Two years ago, ASCO issued new recommendations calling for older adults to be included in more clinical trials. But progress has been slow, acknowledged Dr. Hyman Muss, director of geriatric oncology at the Lineberger Comprehensive Cancer Center at the University of North Carolina-Chapel Hill.

“My view is that every patient I see, if they’re eligible for a clinical trial I’ll tell them about it,” he said.

Don’t assume your doctor will be equally forthcoming. “Absolutely, you should take the initiative and ask,” Schilsky recommended. And don’t assume you need to have run out of options before doing so. “Clinical trials aren’t just for people who have no treatment options left — that’s a common misconception,” Schilsky said.

Debbie Earp, 67, joined a trial at the Lineberger this year, after getting a diagnosis of stage 2 breast cancer in early January. Her responsibilities over the four-month study: wearing a Fitbit, tracking how much exercise she was getting on a daily basis, and filling out a questionnaire about how she was feeling each time she got chemotherapy.

Earp said she agreed to participate because “I’ve always exercised and I felt, from a physical and psychological point of view, anything that was going to motivate me during treatment to exercise more would be a good idea.” The goal of the trial was to examine how physical activity affects older breast cancer patients’  response to chemotherapy.

Of course, clinical trials aren’t for everyone. Some older adults are reluctant to consider them because they’re skeptical of unproven therapies. Others may choose to focus on their quality of life instead of aggressive treatments.

There are good resources about clinical trials on the internet, if you know where to look. The National Institute on Aging has prepared materials for older adults, including a list of questions that seniors should ask before deciding whether to join a trial. The FDA has a patient-oriented site that delves into issues such as informed consent — making sure you’re fully informed about the potential benefits and harms of a research study, among other essential information.

For those who want to look for trials on their own, the NIH sponsors, a database of studies across the world, searchable by disease and geography. Trials Today is an effort to make the NIH site more consumer-friendly, created at Vanderbilt University. ResearchMatch is another Vanderbilt effort where people who want to participate in studies can sign up and be matched with clinical trial sponsors. And TrialMatch is a one-stop-shop for clinical trials for people with Alzheimer’s disease, their caregivers, and people interested in preventing dementia, currently listing nearly more than 250 scientific studies.

Make sure you run whatever prospects you find by your doctor. “Very few patients have the expertise to understand if a clinical trial is appropriate for them,” Schilsky said. “You really need an expert opinion to help you understand what you find.”