Game-changing strategies detect Alzheimer’s extremely early, common condition found to be leading cause of dementia deaths, and more
This week we’ve got lots of good news (and a little bad) about Alzheimer’s disease—from incredible advancements in assessing risk factors (up to 50 years before onset) to the potential for a faster, cheaper, more accessible diagnosis, and even new ways a leukemia drug might make a big difference for patients suffering from the all-too-common neurologic condition. This week’s Neuro Brief is chock full of insights for those looking to manage a disease that’s notoriously difficult to treat (how difficult, exactly? Skip ahead to the Neuro Trivia section to find out). But that’s not all. Keep reading for new insights in perinatal stroke, new Parkinson’s risk factors, hereditary headaches, and so much more.
Ah, the brain. The house of human intelligence. The command center of cognition. The nucleus of neurology. It’s the only organ that’s capable of appreciating its own mesmerizing and mysterious power. But, interestingly enough, it took us quite some time to realize just how important our brains really are. The Ancient Egyptians and Ancient Greeks—two groups whose wisdom continues to impress us thousands of years later—believed the heart was in control of sensation, thought, and body movement. In Ancient Egypt, this point of view, called the cardiocentric hypothesis, went as far back as 2600 BCE. Believers assumed the brain was an insignificant organ—during mummification, it was dug out and disposed of, while the heart was left in the body so it could be weighed in the afterlife by the god Anubis (if it was heavier than a feather, your poor soul would be consumed by the Devourer). The Greeks bought into the hypothesis too (not so wise after all, huh Aristotle?), until physician and anatomist Alcmaeon of Croton set the record straight around 500 BCE, giving us the cephalocentric view we still know—and love—today.
In the News
Here’s some bittersweet news on dementia. Risk factors for Alzheimer’s dementia may be apparent as early as our teens and 20s. Yes, you read that correctly. Thanks to three new studies presented at the Alzheimer’s Association International Conference, we might be able to assess risk factors for Alzheimer’s 40 to 50 years before most early-onset Alzheimer’s disease occurs. So what are these risk factors? Researchers point to heart health factors (hypertension, high cholesterol, and diabetes), BMI, and social factors like education quality. But it can’t all be good news, so here’s the bad: Most of these risk factors are disproportionately prevalent in African Americans.
In one study of 714 African Americans, researchers found that hypertension, diabetes, and poorer heart health were associated with worse cognition later in life, even after accounting for potential confounders. In the second study (the first to report on this issue), researchers monitored 5,104 older adults and found that higher BMI in early adulthood (ages 20-49) was associated with higher late-life dementia risk. Finally, in the third study, researchers found that in a cohort of more than 2,400 people followed for more than 21 years, higher quality early-life education was associated with better language and memory performance and lower risk of late-life dementia. “By identifying, verifying, and acting to counter those Alzheimer’s risk factors that we can change, we may reduce new cases and eventually the total number of people with Alzheimer’s and other dementia,” said Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer.
More good (but also kinda bad) news. Good news first: In people with psychiatric conditions, rates of ischemic heart disease (IHD) and stroke have decreased during the last 25 years. Now the bad news: They’re still experiencing 2- to 2.5-times higher relative risk of IHD and stroke than people without psychiatric conditions. In a study published in the British Journal of Psychiatry, researchers pulled population-based records from 1991 to 2015 to create retrospective cohorts. They found that incidence of IHD and stroke decreased over time, but relative risks decreased only for patients with depression. In 2015, relative risks were 2- to 2.5-fold higher in people with psychiatric disorders, and relative (but not absolute) risks were generally higher in women than men.
So, what’s causing this increased risk? “A wide spectrum of factors,” researchers wrote, “including lifestyle behaviors, increased risk of diabetes, and side-effects of psychotropic medication.” Researchers also pointed to the possibility of poorly understood physiological effects of mental disorders (like glucose homeostasis), shared genetic links between psychiatric disorders and cardiometabolic disorders, and poor screening and undertreatment for psychiatric disorders.
Look out, toxic proteins. Scientists have uncovered a new ‘toolkit’ that can help repair damaged DNA, a potential cause of neurological conditions like motor neuron disease (MND). Published in Nature Communications, the research shows that a protein called TEX264 is able to recognize and ‘eat’ toxic proteins that can stick to DNA and cause cells to become damaged. Accumulation of these types of damaged cells can lead to MND and other ill effects, including cellular aging and cancer.
In the damage repairing process, TEX264 recruits help from two other enzymes—p97 and SPRTN—before localizing to its targets, associating with DNA replication forks, and counteracting DNA replication. Until now, ways of repairing this sort of DNA damage have been poorly understood. However, “our finding of TEX264…significantly changes the current understanding of how cells repair the genome and protect us from accelerated aging, cancer, and neurodegeneration,” study authors said. While researchers are already exploring this discovery’s potential for cancer therapy, next steps include testing whether the behavior and properties of TEX264 are altered in neurological disorders like MND.
As if 2020 wasn’t weird enough, robots are coming for your brain. Don’t worry, they’re friendly. Surgeons from Thomas Jefferson University are pioneering the use of robotics to help perform neuroendovascular procedures via the blood vessels of the neck and brain. In a study published in the Journal of NeuroInterventional Surgery, researchers demonstrated that the use of these robots to aid surgeons during diagnostic cerebral angiograms and transradial carotid artery stenting was both safe and effective in 10 patients, with no complications reported.
There are three key benefits of this robotic approach, according to the authors. First, robots would allow neurosurgeons to intervene remotely on patients suffering from strokes, potentially opening up lifesaving surgery to underserved patients. Secondly, use of robots during neuroendovascular procedures would give surgeons more precise control of the microcatheter and microwire. Finally, the technology reduces risk to physicians by limiting their exposure to radiation from the X-rays. “The next generation of robots are ready to be launched, and as soon as they are approved by the FDA we will be able to move to the next step, which is performing interventions inside the brain,” authors said.
How many investigational therapies have failed since the last drug for Alzheimer’s was approved in 2003?
More than 200. A study examining 244 compounds in 413 clinical trials for Alzheimer’s between 2002 and 2012 uncovered a 99.6% failure rate—one of the highest of any disease area.
Faster, cheaper, more accessible diagnosis. That’s the appeal behind a novel blood test for Alzheimer’s that could be available in the next two to three years, according to an international team of researchers. Results of their study, published in JAMA, showed that the test identified signs of Alzheimer’s in those patients with the genetic mutation that causes the disease 20 years before cognitive decline would have been expected. The test can also differentiate between Alzheimer’s and other forms of dementia, they noted.
In the study, which included 1,402 patients across three cohorts, plasma P-tau217 discriminated Alzheimer’s disease from other neurogenerative diseases with performance that was significantly better than established plasma- and MRI-based biomarkers, but not significantly different from key CSF- or PET-based biomarkers. The test was 96% accurate in determining whether people with dementia had Alzheimer’s vs other neurodegenerative disorders. “This blood test very, very accurately predicts who’s got Alzheimer’s disease in their brain, including people who seem to be normal,” the authors told the New York Times. “Accurate, low-cost diagnosis is really exciting, so it’s a breakthrough.”
Keeping an eye on Parkinson’s. Vision loss is rough. It’s associated with lower quality of life, independence, mobility, and worse mental health and cognition. As if that weren’t enough, a new study published in Movement Disorders finds that low visual acuity is associated with the development of Parkinson’s disease, suggesting that visual dysfunction might be one of the disease’s premotor symptoms. To arrive at these findings, researchers pulled data from South Korea’s mandatory National Health Insurance Service and identified nearly 23,000 people who were diagnosed with Parkinson’s disease during the study period between 2009 and 2012.
Groups with low visual acuity showed a higher incidence of PD compared with those who had good visual acuity. Adjusted hazard ratios were 1.315 for the group with acuity between 20/20 and 20/60, 1.357 for the group with visual acuity between 20/60 and 10/100, and 1.267 for the group with visual acuity less than 10/100. To explain the association, researchers pointed to retinal thinning, which is more common in those with Parkinson’s, as well as visual sensory deprivation, which has been associated with deterioration of dopamine pathways, and lower exercise frequency in people with poor visual acuity.
Thanks for the headache, mom. Cluster headaches are incredibly painful. They also might be a generational gift from your parents, according to a new systematic review published in JAMA Neurology. Data from the review suggest that cluster headache is an inherited disorder in a subset of patients, and that the pattern of inheritance could be the result of multiple susceptibility genes and other environmental factors, including circadian patterns, inflammation, and exposure to toxins in tobacco.
In 22 large cohort studies included in the review, the positive family history rate of cluster headache varied between 0% and 22%. The five largest studies had a positive family history that varied between 2% and 18%. Taken together, this suggests that the familial rate of cluster headache could be as common as 1 in 10 or even 1 in 5 individuals. Researchers found an unexpectedly high preponderance of women and girls with familial cluster headache. They suggested that genetic subanalyses limited to the female study participants are necessary, as the data may have been otherwise masked due to the higher number of male participants with cluster headache in the review. Since the study only involved 70 families, further studies with larger cohorts are warranted.
Getting ahead of perinatal stroke. There’s almost no scarier time for a stroke than in the weeks and days leading up to pregnancy. Thankfully, researchers have discovered unique inflammatory biomarker signatures associated with perinatal stroke diseases. These findings, published in Neurology, suggest the possibility that at-risk pregnancies might be identified, empowering clinicians to develop prevention strategies. The study included 197 participants: 27 with neonatal arterial ischemic stroke (NAIS), eight with arterial presumed perinatal ischemic stroke (APPIS), 12 with periventricular infarction (PVI), and 150 controls.
Investigators used hierarchical clustering analysis to create heat maps, then used linear discriminant analysis to build projection models that could pinpoint the boundaries between the different types of strokes and controls. Linear analysis had high accuracy in using cytokine profiles to pinpoint the groups: NAIS separation was accurate (77% sensitivity and 97% specificity), and APPIS mapping was distinguishable from NAIS (86% sensitivity and 99% specificity). “These results suggest that distinct, altered inflammatory environments are often present around the time of certain forms of perinatal stroke,” the authors wrote. “This knowledge may further inform the delineation of perinatal stroke pathophysiology and the possible development of biomarkers by which high risk pregnancies can be identified.”
Disease-modifying therapies and disability. For patients with secondary progressive multiple sclerosis (SPMS), relapses can speed up disability progression, according to a new study in JAMA Neurology. Fortunately, disease-modifying therapies were linked to a slower rate of disability accumulation in these patients. To arrive at these results, investigators pulled patient data from the MSBase international registry between 1995 and 2018, identifying 4,997 patients with SPMS and 1,621 who were eligible for inclusion in the study.
Among those 1,621 patients, 40.8% experienced superimposed relapses during SPMS. During the secondary progressive disease stage, higher relapse rates were associated with an increased risk for becoming wheelchair-dependent (1.87 hazard ratio). But patients who experienced superimposed relapses during SPMS and who received disease-modifying therapies were significantly more likely to experience a reduced rate of disability progression and a lower risk for wheelchair-dependence than those who did not. It’s promising news, but SPMS remains a challenging frontier. “Although early active treatment during relapsing-remitting MS is associated with a delay in the onset of SPMS, the rate of disability accumulation once the secondary progressive phase has commenced is not substantially modified by early treatment decisions,” the authors wrote.
Good news for patients with autoimmune encephalitis (AE). Rituximab is an effective second-line agent for patients with AE—a rare but debilitating neurological disease where the body develops antibodies against neuronal cell surface/synaptic proteins—according to a systematic review and meta-analysis published in Acta Neurologica Scandinavica. Researchers pooled available evidence on rituximab, which is an anti-CD20 chimeric monoclonal antibody that has shown promise in observational studies, from studies across PubMed, Web of Science, Google Scholar, WANFANG, CNKI, and J-STAGE.
Results showed that good functional outcome (defined as mRS ≤2) occurred in 72.2% of patients at last follow-up after rituximab therapy. Mean mRS scores decreased by 2.67, and relapses following rituximab therapy only occurred in 14.2% of patients. Adverse events included infusion-related reactions (15.7% of patients), pneumonia (6%), and severe sepsis (1.1%). It’s worth noting, though, that rituximab’s side effect profile (and its efficacy) were comparable to outcomes seen when the drug was used in other autoimmune and inflammatory central nervous system disease.
FDA accepts application for dementia-related psychosis drug. Pimavanserin, a drug approved in 2016 for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis, has moved one step closer to receiving an additional approval for dementia-related psychosis, according to Acadia Pharmaceuticals, the drug’s manufacturer. The FDA accepted pimavanserin’s supplemental new drug application for the treatment of hallucinations and delusions associated with dementia-related psychosis on July 20, and is slated to make an approval or rejection decision in April 2021.
Pimavanserin’s application is supported by results from the phase 3 HARMONY study, which met its primary endpoint when it demonstrated that pimavanserin reduced the risk of psychosis relapse by 2.8-fold compared with placebo. The application also includes efficacy results from two placebo-controlled studies that both met their primary endpoints—a phase 2 study in patients with Alzheimer’s disease psychosis and a phase 3 study in patients with Parkinson’s disease psychosis. “If approved, [pimavanserin] would be the first therapy indicated for the treatment of hallucinations and delusions associated with dementia-related psychosis,” an Acadia spokesperson noted.
Leukemia drug for Alzheimer’s? Preclinical evidence suggested that nilotinib, a drug approved by the FDA for leukemia, might help improve Alzheimer’s disease phenotypes. A new study, published in the Annals of Neurology, finds that the drug is safe and can achieve pharmacologically relevant CSF concentrations. What’s more, biomarkers of disease were altered in response to nilotinib treatment, supporting larger, longer studies of nilotinib for Alzheimer’s. To arrive at their results, researchers conducted a single-center, phase 2, randomized, double-blind, placebo-controlled study to investigate nilotinib’s safety, tolerability, and pharmacokinetics, as well as to measure the biomarkers in 37 patients with mild-to-moderate Alzheimer’s-related dementia.
Overall, nilotinib was well-tolerated, although adverse events (particularly mood swings) were noted when patients were given a 300-mg dose, suggesting that a lower dose of 150 mg daily may be preferable in future studies. Compared with the control group, those who took nilotinib experienced significant reductions in CNS amyloid burden in the frontal lobe. CSF Aβ40 was reduced at 6 months and Aβ42 was reduced at 12 months in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (−27%) at 12 months and phospho‐tau‐181 was reduced at 6 months and 12 months in the nilotinib group. For next steps, researchers plan to measure the nilotinib’s efficacy in a phase 3 trial.
New in Patient Management
Dementia and pneumonia. We all know dementia predisposes for deadly complications and decreased life expectancy, but how are people with dementia dying? The answers could help improve treatment. According to a new study, people with dementia are at much higher risk of dying from pneumonia than the general population is. To arrive at their findings, researchers studied autopsy reports on 207 deceased individuals with clinically diagnosed neurocognitive disorders/dementia and 200 neurocognitively healthy individuals for the same age range (median age of 79). The two most frequent causes of death in the population with dementia were pneumonia (34.3%) and acute myocardial infarction (30.4%). In the healthy group, myocardial infarction registered as the leading cause of death (42.5%), while circulatory failure came in second (12.5%).
But what’s causing this relative risk of pneumonia mortality in patients with dementia? It may be explained by their relatively high frequency of hospitalization, which increases exposure to pathogens. Patients with dementia also have impaired immune response and respiratory defense dysfunction due to brain disease-related impairment in the nervous system. Another factor: patients with dementia are more at risk for being bedridden for long periods, during which immobility might aggravate their illnesses and lead to fatal outcomes. Finally, patients with dementia experience a higher presence of comorbidities and poorer maintenance overall—this total morbidity might contribute to high mortality from pneumonia.
Here’s to late-night snacking. Responsible late-night snacking, that is. A new study published in Nutrients covers the dos and don’ts of munching before bed, which can be particularly helpful for people managing insomnia. To start, we regret to inform you that chocolate before bed won’t help you catch any Zs—it’s typically packed with caffeine and small amounts of theobromine, a bitter alkaloid found in the cacao plant that can increase heart rate and cause sleeplessness. Dried fruit is another late-night no-go, because its high-fiber, low-water content can lead to excess gas and cramping all night long. Other sleepless snacks include matcha and green teas, chips, and oranges.
On the flip side, there are plenty of healthy foods that can help you sleep. Nuts are heart-healthy and contain melatonin, the hormone responsible for regulating sleep. Cottage cheese is high in lean protein and contains tryptophan, an amino acid known to increase serotonin (plop some raspberries or other fruits on top for extra melatonin, too). Whole grains like popcorn, oatmeal, or whole-wheat crackers with nut butters are much better choices before bed than complex carbs like white bread, pasta, or sugary baked items. And finally, the old adage is true—a warm glass of milk (or herbal tea) gets the job done, thanks in part to the psychological, ritualistic value, but also to milk’s tryptophan and melatonin, as well as tea’s inherent relaxation powers (as long as it’s caffeine-free).
Look out for depression. Especially in late-life. A new study in Acta Psychiatrica Scandinavica confirms that incident late-life depression is associated with higher risk of dementia within the three years following diagnosis, after which the association was not seen. The link between depression and dementia was strongest between ages 65 and 74 and became weaker with advancing age. To the authors’ knowledge, their study was the first to show significant differences in the pattern of the temporal association between incident late-life depression and subsequent dementia in different age groups and across sexes.
Overall, researchers observed that patients who received a depression diagnosis experienced a 2.04-fold risk of receiving a dementia diagnosis within the next 3 months. That risk levelled off but remained significant for about 3 years. “These data support the assumption that late-life depression can be a prodrome for dementia, which also does not exclude consideration of mid-life depression as a risk factor,” study authors wrote. “Early detection and treatment of depression in the elderly (eg, with selective serotonin reuptake inhibitors [SSRIs]), might have a positive effect on cognition deterioration and incident dementia, although well-conducted randomized clinical trials are needed for further examination.”
Hypertension flying under the radar. A new study published in JAMA Neurology set out to uncover whether stroke survivors had adequately managed hypertension. The answer? Not quite. In an analysis of nationally representative cross-sectional surveys conducted between 2005 and 2016, 37% of the roughly 6.4 million adults with a history of stroke had uncontrolled blood pressure, despite 80% of them taking antihypertensive medications. The most commonly used medications were ACE inhibitors or ARBs, with diuretics becoming less frequently used over time. Overall, no particular class of medication had statistically significantly higher rates of hypertension control.
The good news is that the 37% of people with a history of stroke who had high blood pressure likely represents a reduction over time—from 1999 to 2004, previous data suggests more than 50% of these patients had uncontrolled hypertension. “Although this study reveals a gap in secondary prevention of stroke, future studies are needed to determine preferential antihypertensive medication in patients after stroke. Studies on the efficacy of the class and number of antihypertensive medications in this patient population may be particularly beneficial,” the authors wrote.
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Upcoming Medical Meetings
The following meeting has been rescheduled:
Congress of Neurological Surgeons (CNS) Annual Meeting, to be held in Miami, FL, has been rescheduled for October 16-20, 2021, in Austin, TX.
Neuroscience 2020: The Society for Neuroscience (SfN) 50th Annual Meeting, Washington DC, October 24-28.
The following meeting has 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, 2021, in San Francisco, CA.