Authors: Sharon Salt, Editor
Aducanumab has seen a whirlwind of headlines this year – from the decision to discontinue the global Phase III trials for Alzheimer’s disease (AD) in March, to Biogen (MA, USA) and Eisai (Tokyo, Japan) turning the tables with their announcement in October that they are going to pursue regulatory approval for the drug. With little to no information provided about both circumstances, researchers were left eagerly waiting for any kind of results that would help explain why or what has been happening. Finally, this month, Biogen presented detailed data to help explain why aducanumab had resurfaced from their initial decision to discontinue trials.
The use of blood biomarkers has substantially increased this year for various neurological diseases. In AD, a blood test was able to demonstrate 94% accuracy in diagnosis. The researchers reported that levels of amyloid-β in the blood could be measured and used to predict protein accumulation in the brain. But how might we translate these blood biomarkers into the clinic? We heard from Henrik Zetterberg (University College London, UK) about this, which you can watch here. We also reported on the use of blood biomarkers to predict glioblastoma prognosis, seizure occurrence and recovery time after concussion.
Chronic traumatic encephalopathy (CTE)
Two years ago, a group of scientists discovered the atomic structures of tau filaments that contribute to AD. In line with this, this year saw the discovery of atomic structures of abnormal tau filaments related to CTE, which were reported to be different to those found in AD. The investigators reported that one remarkable variance between tau filaments in AD and CTE was the formation of cavities in the CTE filaments, which were filled with other molecules. On another note, a different study also highlighted in a group of former professional athletes who experienced multiple concussions that over 50% were reported to have higher levels of tau protein biomarkers in their CSF.
A paper published in Nature dominated the headlines earlier this year when scientists reported that they were able to restore circulation and cellular activity in a pig’s brain 4 hours after its death. This was a finding that not only raised ethical and legal questions about the nature of death and consciousness, but also challenged the long-held assumptions about the irreversible nature of cessation of some brain functions after death. While the research has no immediate clinical application, the team anticipate that their results may one day be able to help clinicians find ways to salvage brain function in stroke patients.
This year has seen increasing traction with regards to early detection for neurodegenerative diseases. For Parkinson’s, researchers have reported that they uncovered the earliest signs of the disease many years before individuals presented with any symptoms. The study provided the first evidence of a central role for serotonin in the very earliest stages of disease, which could act as a key early warning signal. Additionally, a second study indicated that a skin odor test may also be utilized as an early indicator for Parkinson’s, as individuals with the disease might have a unique scent that is secreted by their skin.
Frontiers in TBI
At the Frontiers in Traumatic Brain Injury (TBI) conference we had the pleasure of hearing about the exciting developments taking place in the world of TBI research, including machine learning, criminality, big data, digital technology and much more. One aspect that has been echoed across multiple conferences was related to how CTE presents in individuals as a broad mixture of pathologies (e.g., tau pathology, neurofibrillary tangles, Lewy bodies, etc.). Due to this complex pathology, it was concluded that CTE may actually be a co-morbidity and at present, it could be too early for us to define the disease.
Since the groundbreaking results from IONIS-HTTRx (RG6042) for Huntington’s disease, genetic therapies for neurodegenerative diseases have become a remarkable avenue for potentially slowing and preventing disease. When RG6042 was demonstrated to be safe for use in patients earlier this year, we spoke with the lead investigator to find out what technological advancements could bring these therapies to the clinic more quickly. We also heard from another lead investigator about the core challenges in bringing gene-silencing treatments to the clinic with regards to a first-in-human, gene-silencing treatment for AD.
A wide array of studies have indicated that high blood pressure in midlife is a key risk factor of developing dementia later in life. Not long ago, a study published in The Lancet Neurology revealed that changes in blood pressure in individuals as young as 36 could be linked to markers of poorer brain health. The researchers noted that higher blood pressure at the age of 53 and quicker rises in blood pressure between 43 and 53 were associated with more signs of ‘mini strokes’. In addition to this, a different study also reported that age-related cognitive changes may be reduced with intensive blood pressure control.
International Women’s Day
Steering away from neurodegenerative diseases, we marked International Women’s Day this year by celebrating the works of two inspiring women in neuroscience. In our first interview, we heard from Tamara Miller (Actinogen Medical) about what led her to pursue a career in the biotechnology and pharmaceutical industries, and whether she has faced any challenges in her field due to her gender. In our second interview, we spoke with Selina Wray (University College London) to hear more about what could be done to promote gender equality in science, including how we might include more males in gender inequality discussions.
In the field of autism spectrum disorders, one of our biggest stories included an article on how investigators have utilized artificial intelligence techniques to reveal that mutations in so-called ‘junk’ DNA may cause autism. This study was the first to functionally link such mutations to the neurodevelopmental condition. However, according to the researchers, the implications of this work extend beyond the field of autism, with the investigators stating that this was also the first clear demonstration of non-inherited, noncoding mutations causing any complex human disease or disorder.
Following on from last year’s news on how a nasal spray formulation of ketamine, termed Spravato™ (esketamine), held promise in the rapid treatment of symptoms for major depression, the US FDA announced that the formulation had received approval (alongside an oral antidepressant) for treatment-resistant depression in adults this year. This marked the first new major depression treatment to gain approval since Prozac hit the market more than 30 years ago. The nasal spray formulation was reported to show statistically significant effects compared with placebo on the severity of depression and some effects were even observed within 2 days.
A big question in the field of Alzheimer’s includes whether there is a causal link between cholesterol levels in the blood and disease risk. This brings us to our next popular news piece of the year, where researchers revealed that individuals with elevated LDL levels were most likely to have early-onset Alzheimer’s disease compared with people whom had lower cholesterol levels. According to the team, this was still observed to be true even after they controlled for cases with the APOE mutation. Additionally, the team discovered that disease cases were higher in participants with the rare gene variant APOB, which is involved in cholesterol metabolism.
To mark World Mental Health Day (10 October) this year, we wanted to shine a spotlight on how mental health issues are affecting early-career researchers in academia. In line with this, our wonderful columnist, Dani Beck, wrote an editorial that not only discussed the extent to which a career in academia could impact mental health, but importantly, what could be done about this. For example, he noted how research group leaders should receive comprehensive training to understanding mental health problems that their employees and students could be facing, in addition to providing support to students at a level that helps eliminate stigma.
Switching to the field of neuro-oncology, another highlight of our year included a feature on the Nativis Voyager® for the treatment of glioblastoma. Originally published in CNS Oncology, the Nativis Voyager is a nonsterile, noninvasive, nonthermal, nonionizing and portable medical device that uses localized, ultra-low radio frequency energy for the treatment of malignant solid tumors. In our feature, we wanted to delve behind the scenes of this paper to hear more about the problems facing treatments for glioblastoma and how this groundbreaking technology could begin to overcome these problems, which proved to be a very popular read!
Globally, there has been no new drug approvals for Alzheimer’s disease since 2003 until a recent announcement from Green Valley Pharmaceuticals changed this in November. According to the company, China’s regulatory agency approved oligomannate as a new drug for the treatment of mild-to-moderate Alzheimer’s disease. The compound has been reported to work by decreasing neuroinflammation in mice by reshaping their gut microbiome. However, albeit the positive news, this has been met with some skepticism in the field as other researchers have argued that interpreting if inflammation is increased based on cytokine levels is difficult.
Another topic that was popular on our website revolved around brain plasticity. Earlier this year, a group of researchers from the University of Queensland (Australia) indicated that vitamin D affects perineuronal nets within the brain, which could facilitate the loss of brain plasticity and might lead to disorders such as depression and schizophrenia. Alongside this, a different study that also gained traction this year shone a light on a novel mechanism for synaptic plasticity and reports that their findings, which investigated the molecular structure of AMPA receptors, could hold potential as a new treatment option for epilepsy.
Steering closely alongside blood biomarkers for quick diagnosis of neurological diseases, Cognetivity (London, UK) have created a new test for detecting dementia and AD by focusing on image cognition and the brain’s ability to analyze visual information. Utilizing artificial intelligence, the company have produced an app that can determine whether a person has, or is at risk of developing, dementia in only 5 minutes. In a similar approach, a separate group has also employed an artificial intelligence-based technique to demonstrate how this, coupled with chemical analysis of blood samples, could speed up brain tumor diagnosis.
Aging and genetics are the largest risk factors for developing AD. As such, our interview from 2018 with Catherine Kaczorowski (Jackson Laboratory, ME, USA) gained popularity this year as she introduced us to the topic of ‘risk versus resilience’ and understanding the role of genetics in AD. As the article proved to be very popular, we integrated the topic into our ‘Ask the Experts’ column on the future of dementia research, where we asked thought leaders from our partnered institutions about the challenges involved in translating genetic data (e.g., risk genes) into potential therapeutics in the field of dementia.
Rapid advancements in neurostimulation technologies have emerged over the last year, particularly for Parkinson’s disease. A cutting-edge treatment that was developed by Canadian researchers was able to significantly restore movement in individuals with Parkinson’s disease, as researchers hailed the technology as going ‘beyond their wildest dreams’. In another instance, a group of engineers also developed a neurostimulator device that could monitor and simulate electric currents in the brain simultaneously – an application that the team hope could lead to a new treatment option for people with epilepsy or Parkinson’s disease.
Taking a leap into the spotlight, we saw therapeutic targets for Parkinson’s disease hit our top content list for various features. In the first instance, a groundbreaking trial offered hope for restoring damaged brain cells, as researchers investigated whether boosting levels of GDNF could regenerate these cells and reverse the conditions in patients. Moreover, a drug that is typically used to treat enlarged prostate – known as terazosin – was implicated to slow down the progression of Parkinson’s disease. We also had the brilliant opportunity of interviewing Patrik Brundin about what other novel therapeutic targets were emerging in this field.
Although this year has seen more positive news in terms of clinical trials in AD, especially compared with last year, we did see two pivotal Phase II/III studies being discontinued for umibecestat in the field. A regular pre-planned assessment of the BACE1 inhibitor identified worsening in some measures of cognitive function and thus, a collective decision was made between Amgen (CA, USA), Novartis (Basel, Switzerland) and the Banner Alzheimer’s Institute (AZ, USA), which concluded that the potential benefit for participants in the study did not outweigh the risk.
The gut–brain connection has climbed the ladder this year in terms of content popularity. In Parkinson’s, researchers provided additional evidence that supports the idea that the disease originates among cells in the gut and travels up the vagus nerve to the brain. The investigators described this pathway in a new mouse model that they developed, where they injected mouse α-synuclein preformed fibrils into the gastrointestinal muscles densely innervated by the vagus nerve. They noted that transmission of the pathologic α-synuclein from the gut to the brain occurred but not in mice that had their vagal nerve fibers cut.
World Health Organization
The World Health Organization (Geneva, Switzerland) has made the headlines for neurological diseases twice this year. In May, the WHO launched their first-ever guideline on reducing the risk of dementia, which provided a knowledge base for healthcare providers to advise patients on what they can do to help prevent cognitive decline and dementia. Additionally, they also published their first global report on the burden of epilepsy and what can be done to improve the lives of those living with the neurological disease. They propose that a culturally appropriate, multipronged strategy is required to improve awareness and education worldwide.
It’s no surprise that sex-specific differences have made the list again this year. Four new papers that were presented at the Alzheimer’s Association International Conference (CA, USA) reported sex-specific variances in the risk and progression of AD, including sex differences in the spread of tau protein, risk genes and levels of brain glucose metabolism. We also heard about sex-specific effects of microbiome perturbations in a mouse model of AD, new sex-specific insights into why migraines are more common in women and how signs of dementia could be detected earlier in women with a new diagnostic criteria.
Tying in nicely with the previous letter, we featured an article in relation to the Y chromosome that focused on the ‘extreme male brain’ theory of autism spectrum disorder. It’s well known that autism is much more prevalent in males than females, however, the reason behind this remains uncertain. It could be down to testosterone – which would be the obvious culprit – but researchers revealed that there was no evidence of a link between cognitive empathy and testosterone in this study. It’s best to caution that further studies with larger representative samples are needed to confirm this but the scientists state that perhaps the field has been ignorant on this.
Sleep science has been an extremely interesting area of research throughout the last year, particularly with regards to the differences in brain function between ‘night owls’ and ‘morning larks’. Researchers determined that individuals whose body clocks dictated that they go to bed and wake up very late have lower resting brain connectivity in many regions of the brain linked to the maintenance of consciousness. We’ve also seen headlines about whether or not catching up with sleep on the weekend could help with sleep deprivation and if ‘night owls’ could ‘retrain’ their body clocks to improve mental wellbeing.
With all the great research 2019 has seen, we’re looking forward to seeing what exciting new discoveries 2020 will hold for neuroscience and neurology!