A newly identified neurodegenerative condition, diabetes meds for cognitive impairment, and a biomarker to detect clinical decline
This week, we bring you some good news about new biomarkers, therapies, and patient management strategies that are poised to ease the burden of neurological disorders like Alzheimer’s disease—the cost of which might be higher than you think. (Want to know exactly how much? Skip ahead to the Trivia section.) This week’s issue of the Neuro Brief also uncovers new revelations about neural pathways and physical strength, the neurological underpinnings of psychiatric disorders, a new approach to Parkinson’s treatment, and so much more.
How in the world did we arrive at the wonders of modern neurology, with all its incredible advancements? Well, first we had to go through a bit of an awkward phase.
Let’s turn back the clock all the way to the Stone Age. Netflix and Amazon didn’t exist yet, so we’re not quite sure how humans survived this wild period of history. The science suggests it probably had a little something to do with our natural penchant for experimentation and invention, which we flexed pretty hard on the rest of the Animal Kingdom during this period by creating knives, axes, and all sorts of other sharp objects that we could use to stab and slice things.
But what does this have to do with neurology? No sooner did we learn to create stabby, slicey stuff than we turned them on each other—not only as weapons, but as surgical devices, too. In ancient Peru, some of the first neurosurgeons (we use that term very loosely) were beginning to experiment with trepanation—the process of boring holes in people’s skulls, which is similar to a modern craniotomy—something we touched on in an earlier issue. But how did we get from there to modern neuro surgery? For a while, things seemed pretty bleak. The mortality rate of these procedures was a little high (100%, according to the archeological evidence), but by the 1400s, the ancient Inca Empire had produced some pretty deft surgeons, and as many as 90% of trepanned patients were now surviving their procedures. Ancient surgeons even learned to avoid areas of the head that could cause serious injury and used herbs to reduce infections and manage pain.
So next time you’re surgically implanting a deep brain stimulator during a craniotomy, remember that you’re standing on the shoulders of Stone Age giants.
In the News
Speaking of head injuries. As the ancient Incans probably learned through some rather grisly trial and error, traumatic head injuries don’t bode well for cognitive functioning. That’s the hypothesis tested in a recent Neurology study, wherein investigators found that repeated head injuries (RHI) and traumatic brain injuries (TBI) have pretty serious long-term neuropsychiatric and cognitive consequences.
To arrive at these results, researchers studied a pool of 13,000 patients and identified 725 who had experienced RHI (mostly through contact sports and abuse) and more than 7,000 who reported TBI. Compared to those who hadn’t experienced head injuries, those with TBI and RHI scored much worse on tests that measured depression and overall cognition. Those who had experienced both TBI and RHI expectedly fared worst of all, suggesting that physicians should include questions about head injuries as part of a thorough patient history related to depression and cognitive decline.
How to get a super swole nervous system. Ever get upset when you don’t see results immediately after hitting the gym? Us too. But there’s good reason for the delay in outward results: the first few weeks of training strengthen the nervous system, not the muscles, according to a new study in The Journal of Neuroscience.
Researchers discovered that increased body strength may stem from the reticulospinal tract (RST), one of two major neural highways descending to the spinal cord. In a weight-training experiment involving two macaque monkeys, they found that output from the RST became more powerful over several weeks of increased weight training. The monkeys were trained to pull a handle with one arm every day for a period of 8 to 9 weeks, during which the amount of weight was progressively increased (final weight was approximately 6 kg, close to each animal’s own body weight). Electrical response—indicating strengthened signaling—was increasingly elicited from stimulation of the primary motor cortex and RST, while no increase was observed from corticospinal tract stimulation. Interestingly, the results persisted through a two-week period without weights. The monkeys then trained for another 3 months, after which the researchers noted that stimulation of the RST elicited a greater response on the side of the spinal cord that was connected to the trained arm. This suggests that improvement in the effectiveness of the RST pathway might be a necessary precursor to those sweet, sweet gains we get at the gym.
Delirium’s cognitive toll. Researchers have long known that delirium is associated with increased hospital costs, greater overall healthcare complications, and worse mortality, but the long-term consequences of delirium on cognition hadn’t yet been pulled together in one reliable study.
Enter researchers from Columbia University in New York, who synthesized the available evidence from 23 studies in a meta-analysis published in JAMA Neurology this month. The literature (a grand total of 1,583 articles pooled from PubMed, Cochrane, and Embase from 1965 to 2018) suggests a significant association between delirium and long-term cognitive decline. In every study included in the meta-analysis, study participants who experienced delirium—both surgical and non-surgical—had worse cognition at the final point of measurement in their studies. It may seem like a “Duh” moment in medicine, but proving the obvious is an effective way to influence perceptions and policy. “Think about the number of studies that had to be published for people to realize that smoking is bad for you,” said Ronald J. Iannotti, PhD, a psychologist at the National Institutes of Health in an interview. “There are some subjects where it seems you can never publish enough.”
Coping with decreasing independence. What’s the best way for a patient to handle the symptoms of Parkinson’s disease (PD)? First, make a concerted effort to cope. A recent study published in the British Medical Journal found that patients who chose to actively cope with their condition experienced shorter disease duration, fewer motor impairments, lower non-motor burden, improved cognitive function, and fewer depressive symptoms than those with a passive coping style. Employing active coping strategies means practicing awareness of stressors (in Parkinson’s patients, these might be loss of independence, loss of control, feelings of helplessness), and making an effort to reduce their negative outcomes, rather than ignoring them. Passive (or avoidant) coping, on the other hand, is characterized by ignoring problems or abandoning personal responsibility to address them.
Previous studies had shown that patients who employed a passive coping style (those who felt powerless to change their gradual loss of independence) were more likely to experience greater depression and functional impairment, poorer health-related quality of life, and poorer physical health. Similarly, patients who combined active and passive coping strategies experienced poorer cognitive function compared with those who employed active coping strategies. This study suggests physicians should try to steer patients toward active coping in order to improve long-term outcomes in Parkinson’s.
How much does Alzheimer’s cost Americans each year, and what are those costs attributed to? According to a 1998 study published in the American College of Clinical Pharmacy Journals, Alzheimer’s disease costs us approximately $100 billion each year. That’s enough to buy 250 Boeing 747s, the palace of Versailles, a few fleets of naval warships, 4 years of college for 757,000 students, or an end to world hunger. Keep in mind that the consumer price index has increased by more than 50% since 1998, so that $100 billion would be equivalent to about $157 billion today.
To make matters worse, as society ages, those costs will (and almost certainly have in the 22 years since this study was published), continue to rise. They include nursing home care, in-home day care, lost patient and caregiver productivity, and more. There is some good news, though. As medical treatments improve and become more widely available, there could be a reduction in the rates of cognitive decline, which could reduce caregiver hours and improve quality of life and delay institutionalization for patients.
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What’s progressive dysexecutive syndrome? Mayo Clinic researchers have defined an early Alzheimer’s disease (AD) subtype—dubbed progressive dysexecutive syndrome—that strikes patients as young as 48 years old. What does that look like? It’s characterized by “predominant dysfunction in core executive functions, relatively young age of onset, and positive biomarkers for Alzheimer’s pathophysiology,” according to the investigators.
In a study published in Brain Communications, a cohort of 55 patients all reported general “memory problems,” but upon closer inspection they exhibited problems with core executive functions of working memory, cognitive flexibility, and cognitive inhibitory control. CSF or neuroimaging biomarkers were consistent with Alzheimer’s disease pathophysiology, and testing revealed a consistent pattern of hypometabolism in parieto-frontal brain regions supporting executive functions with relative sparing of the medial temporal, occipital, and left temporal lobes. Because of these findings, investigators now propose that progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype and have proposed diagnostic criteria to facilitate additional research.
Getting ahead of Alzheimer’s & Parkinson’s. Biomarkers are a beautiful thing (extra beautiful when they tell us what we want to hear), and researchers are getting a little closer to identifying one that can help predict clinical decline in Parkinson’s disease (PD)—and they’re present in the CSF of patientss with Alzheimer’s disease (AD). In a study published in the Annals of Neurology, researchers from the University of Pennsylvania analyzed AD CSF biomarkers in early PD compared with healthy controls, and then tested baseline CSF biomarkers to see if they could predict clinical decline in PD.
The data suggest that baseline CSF AD biomarkers might have some prognostic value in early PD, and that the changes in these biomarkers (although rather modest over a 3-year period) still suggest that biomarker profiles in PD may deviate from healthy aging. Researchers uncovered three key findings: 1) lower overall AD CSF biomarker values in patients with PD vs healthy controls; 2) modest but novel measurable group level changes in AD CSF biomarkers over time in patients with PD that were distinct from healthy controls, with greater overall decline in patients with PD; and 3) preliminary evidence for the value of CSF for cognitive decline, motor, and autonomic function in patients with PD. More studies are needed, but the data point to a promising new biomarker.
More biomarkers, please. In a study published last month in Brain Communications, UK researchers set out to identify whether non-coding RNA in serum could be used as ALS biomarkers. After profiling samples, they were able to discriminate ALS samples from healthy controls using an analysis with 93.7% accuracy, with promise in predicting patients’ progression rates. The result? A potential new biomarker candidate for ALS.
Researchers’ tactics were cross-validated using a geographically distinct cohort of samples from the UK and Germany (which contained ALS and control samples). Because it was tested across two discrete groups, they found that this new RNA biomarker signature can categorize between 73% and 90% of individual samples into two groups: ALS or non-ALS patients. “The high prediction accuracy of this non-coding RNA-based biomarker signature, even across heterogeneous cohorts, demonstrates the strength of our approach as a novel platform to identify and stratify [ALS] patients,” the researchers wrote. The big takeaway: New biomarkers like this one could help make it easier to asses emerging therapies and improve the diagnostic pathway for ALS.
The neurodevelopmental underpinnings of psychiatric disease. A recent study published in JAMA Psychiatry found that as young patients aged, there were genetic similarities between interregional variations in cortical thinning that took place in their brains. What does that mean? There could be specific cellular and molecular pathways in the brain that determine our susceptibility to common psychiatric disorders. To arrive at their findings, authors completed a multicohort analysis from three community-based studies. Interregional profiles of age-related cortical thinning were associated with gradients in the expression of genes associated with dendrites, dendritic spines, and myelin. The variance in thinning explained by the gene panels across different points ranged from 0.45% to 10.55% for the dendrite panel, 0% to 9.98% for the spine panel, and 0.19% to 26.39% for the myelin panel. These genes and their co-expression networks were enriched for genes associated with several psychiatric disorders.
Findings suggested overlapping neurological molecular underpinnings of psychiatric disease. According to the authors, many psychiatric disorders can be conceptualized as disorders of brain maturation during childhood and adolescence. With that in mind, discovering the neurobiological underpinnings of brain maturation may uncover molecular pathways that allow us to pinpoint who is vulnerable and who is resilient to disorders like schizophrenia and depression.
Take diabetes drug, reduce cognitive impairment? That’s the big question raised by the research team behind REWIND, a randomized, double-blind placebo-controlled trial published this month in The Lancet Neurology. Since diabetes is an independent risk factor for cognitive impairment, the team aimed to explore the association between dulaglutide—a GLP-1 receptor agonist commonly prescribed for patients with diabetes—and cognitive impairment.
Between 2011 and 2013, 9,901 participants were randomly assigned to either dulaglutide or placebo. During median follow-up of 5.4 years, 8,828 participants provided a baseline and one or more follow-up test scores. Of those, 4,456 were assigned dulaglutide and 4,372 were assigned placebo. After adjustment for individual scores, study participants who took dulaglutide saw their baseline scores on tests measuring the hazard of substantive cognitive impairment reduced by 14%. The results are promising, but not convincing. “Further studies of this drug focused on brain health and cognitive function are clearly indicated,” investigators wrote.
Novel regenerative approach promising for Parkinson’s. A single-step method that converts astrocytes (brain cells that produce an RNA-binding protein called PTBP1) into functional dopaminergic neurons could one day be used to treat Parkinson’s and other neurodegenerative diseases, researchers suggest.
Currently, the goal of most treatment strategies for Parkinson’s is to prevent neuronal loss or protect vulnerable neuronal circuits. This study was different—it aimed to test the validity of replacing lost neurons to reconstruct disrupted circuits. Researchers initially attempted to construct a cell line in which PTBP1 expression was reduced so that they could study the functional impact it has on its target genes. Unexpectedly, such cells initially grew very slowly in culture, and soon stopped growing altogether. The cells were kept in an incubator for a few weeks, and much to the researchers’ surprise, the cells all became neurons. “The simplicity of this approach and the broad range of potential applications make it a very attractive option for future cell replacement therapy of neurological and neurodegenerative disorders such as Parkinson’s disease,” said Ernest Arenas, MD, PhD, of the Karolinska Institute.
Trimetazidine (not) for Parkinson’s. Trimetazidine (TMZ), a drug used to treat angina pectoris, is contraindicated for movement disorders. Apparently that’s not enough to stop a “non-negligible part of trimetazidine users” who have Parkinson’s disease (PD) from taking it, though, according to a recent study published in Scientific Reports. The team of Hungarian researchers leading the study set out to determine how using TMZ was affecting people with PD by building a study designed to help them do what those patients should’ve been doing all along—not taking it.
Discontinuation of TMZ resulted in clinically relevant improvements measured by the Unified Parkinson’s Disease Rating Scale (a roughly 25% to 30% reduction), the Non-Motor Symptoms Scale (a 25% reduction), and the Montgomery-Asberg Depression Rating Scale (a 20% reduction). Quality of life significantly improved, too. Discontinuation of TMZ and modification of antianginal treatment did not lead to any cardiovascular events at 1 year of follow-up. While it’s unclear exactly how many patients with Parkinson’s are taking TMZ, physicians should be wary that many who do take this contraindicated drug are likely experiencing much worse symptoms.
Pre-Stroke metformin. Here’s the key takeaway of a recent study published in Neurology: protective metformin use results in better outcomes in strokes and thrombolysis. Researchers found that patients with type 2 diabetes who underwent pretreatment with metformin had less severe strokes and better outcomes after undergoing intravenous thrombolysis than those who weren’t taking metformin.
All in all, metformin garnered positive results. According to the study’s European research team, study participants taking metformin also experienced improved stroke mortality rates (12.5% vs 18% in patients who weren’t taking metformin) and better functional outcomes at 3 months. The only advantage not seen in the metformin group was in the frequency of symptomatic intracerebral hemorrhages, which were consistent across both groups.
New in Patient Management
How breathing affects brain function. Ask any Buddhist philosopher or yoga teacher: It all starts with the breath. Your brain function is no exception to this rule, according to Northwestern University investigators, whose research suggests that small changes in the way you breathe can lead to big changes in electrical activity in the brain. They found measurable differences in the way participants made emotional judgements and in the quality of their memory recall depending on whether they were inhaling or exhaling, or whether they were breathing through their noses or mouths. “When you breathe in, we discovered you are stimulating neurons in the olfactory cortex, amygdala, and hippocampus, all across the limbic system,” said lead author Christina Zelano, PhD, assistant professor of neurology.
Zelano and her team first discovered these differences while studying seven patients with epilepsy who were scheduled for brain surgery. One week prior to surgery, a surgeon implanted electrodes into their brains to identify the origin of their seizures. This allowed scientists to acquire electro-physiological data directly from their brains. The recorded electrical signals showed brain activity fluctuated with breathing. This study highlights the importance of nasal breathing vs mouth breathing and highlights an emerging link between breathing phase and the power of cognition related to the amygdala and hippocampal functions.
Sleep it off. Snoozing is definitely not losing for people with migraines. New research published at the annual meeting of the American Headache Society suggests that the quality of sleep in people with episodic migraine is tied to their likelihood of experiencing headaches during the next 6 months.
In fact, poor sleep quality in patients with episodic migraine was linked to a more than 20% higher rate of headache recurrence during the following 6 weeks. Researchers studied 98 adults with episodic migraine—88% were women, the average age was 35, and the average number of migraines per month was five. Participants reported 823 individual headaches throughout the study period. Poor sleep quality was associated with a 22% higher rate of headache recurrence. “Taken together with other studies that report increased sleep complaints in those with chronic migraine, we believe that baseline assessment of poor sleep quality in those with episodic migraine may help identify those at risk of developing chronic migraine,” the authors noted.
Less is more for arteriovenous malformations. Researchers recently called it quits on a randomized trial of unruptured brain arteriovenous malformations. Turns out an interim analysis showed that medical management alone was superior to the combination of medical management and interventional therapy when it comes to preventing symptomatic stroke and death. The ARUBA trial was a non-blinded randomized trial completed at 39 clinical centers in nine countries. Adults diagnosed with an unruptured brain arteriovenous malformation who had never undergone interventional therapy were included.
Of the 1,740 patients screened, 226 were randomly assigned to medical management alone or medical management plus interventional therapy. The incidence of death or symptomatic stroke was lower with medical management alone (15 of 110) than in those with medical management plus interventional therapy (41 of 116). Although the trial was initially scheduled to continue for 5 years, it was discontinued after 33 months because of the results of the interim analysis, which included higher rates of adverse events and two patient deaths attributable to interventional therapy.
Keep an eye on vision in patients with Parkinson’s. Visual impairment is pretty dangerous in the general population, where it’s associated with increased risk of hip fractures, depression, anxiety, and dementia. Combine that with the gradual loss of motor function, as seen in Parkinson’s disease, and those risks might be even more intense, according to new research published in Movement Disorders.
In a cross-sectional analysis of Medicare beneficiaries with PD from 2010 to 2014, researchers found that visual impairment was significantly more prevalent in patients with PD (1.7%) than in those with non-PD (0.71%), and that less than 60% of patients with PD had a yearly eye exam. Furthermore, they found that visual impairment was associated with an increased risk of depression, anxiety, dementia, and death in those patients. Physicians should be prepared to discuss vision loss with their patients with Parkinson’s, and encourage them to pursue active coping strategies to manage the simultaneous loss of motor function and vision.
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Upcoming Medical Meetings
Neuroscience 2020: The Society for Neuroscience (SfN) 50th Annual Meeting, Washington DC, October 24-28.
The following meetings have been rescheduled:
American Academy of Neurology 73rd Annual Meeting (AAN 2021), to be held in Toronto, Ontario, Canada, has been rescheduled for April 17-23 in San Francisco, CA.
2nd Asia-Pacific Neuro-Oncology CME Conference, to be held in Lahaina, HI, August 3-7, has been rescheduled for August 2021.