Can we finally cure Parkinson’s? Cognitive decline?

Well, it’s official: 2020 is half-way through. Not that we’re complaining. But, we can’t deny that there’ve been some bright spots in this otherwise gloomy year. For instance, thanks to the hard work of neuroscientists everywhere, we learned about coffee’s brain-saving effects, a workout that essentially de-ages the brain, and landmark neuro milestones that may help countless patients. And it seems that there’s still more good news to come. This week, we’re highlighting some of the most fascinating findings as they relate to one of the most complex organs in the human body. From a breakthrough test for brain tumor diagnosis to a therapy with the potential to eliminate Parkinson disease, read the latest edition of the NeuroBrief to stay up to date on the latest neurology news.

Neuro Flashback

Do you know when stroke was first recognized as a medical malady? Take a wild guess. Over 2,400 years ago! Hippocrates, the father of medicine, is responsible for the first recorded appearance of stroke, then called “apoplexy,” meaning “struck down by violence” in Greek. But, it wasn’t until the mid-17th century that Johann Jakob Wepfer discovered that patients who died with apoplexy had bleeding in the brain. He also found that a blockage in one of the brain’s blood vessels could cause apoplexy. Years later, in 1928, apoplexy was classified into categories based on the cause of the blood vessel problem, which led to the terms stroke (or cerebral vascular accident). Unlike the ancient days of Hippocrates, there’s now a wealth of information available on the cause, risk, prevention, and treatment of stroke. Despite the fact that there’s no cure for stroke, most patients now have good chances for survival, recovery, and improved quality of life. 

In the News

New targets for seizure control. In one of the largest sequencing projects of its kind, international researchers identified and measured levels of more than 1 billion strands of microRNAs to determine whether they were changed in epilepsy. They found a small set of microRNAs—small molecules that control gene activity in the brain—that were always higher in epilepsy. So, to target these, they designed three drug-like molecules. Computer simulations were used to show how the molecules affected molecular networks inside brain cells by altering the inflammatory response, which is thought to contribute to seizures. In preclinical trials, the molecules were found to stop seizures. The findings—which come after 7 years of research involving 35 scientists based in 8 different European countries across the fields of neuroscience, genetics, computer science, and synthetic chemistry—are a significant step towards developing new drugs for treatment-resistant epilepsy.

A gamble on Parkinson’s. Researchers have found new ways to make deep brain stimulation (DBS) safer and more effective. DBS has been shown to reverse some motor-related symptoms of PD, ultimately reducing disability and improving quality of life. Unfortunately, the procedure also comes with some bad side effects, namely poor impulse control and reckless behavior. So, researchers set out to determine whether there was a difference in the way DBS was affecting the brains of those who developed these psychiatric side effects, and how to stop it happening. Overall, they found that when DBS affected certain brain regions, it was linked to impulsivity and harmful, reckless behavior.

Specifically, researchers used diffusion MRI to reconstruct the connections between nerve cells in the brain that were stimulated by implanted electrodes in 55 patients. Using a previously developed “virtual casino,” they looked at how patients’ brain networks affected by DBS influenced gambling. Patients played the virtual casino before and after receiving DBS. Researchers discovered that when stimulation affected the prefrontal cortex—the brain region responsible for planning behavior and inhibition—patients were more likely to place higher, riskier bets after DBS. During follow-up, the patients who later developed clinically significant, harmful changes in behavior after DBS had a strong link between the stimulation site and the orbitofrontal cortex—a part of the brain involved in evaluating goals against actual outcomes, as well as in behavior modification. The researchers speculated that these patients developed such significant problems because their brains couldn’t make the connection between poor choices and negative outcomes. In all, the researchers believe that this new insight will help neurologists and neurosurgeons decide where best to place the DBS electrodes and how to adjust the device postoperatively so that only the brain regions responsible for treating PD motor symptoms are stimulated.

Game-changing insight into dementia. A new study suggests that a pulse-pressure-induced pathway of cognitive decline may explain why previous treatments for dementia may have failed. Pulse pressure is the difference between systolic and diastolic blood pressure, and it commonly increases with age. The researchers posited that high pulse pressure in blood traveling to the brain can cause inflammation, oxidative stress, mechanical stress, cellular dysfunction, and cell death in the blood-brain barrier (BBB) that leads to brain damage. In fact, there’s a wealth of evidence supporting the disruption of the BBB as a key driver of cognitive decline and dementia. Following this line of thought, pulse pressure may be a promising new therapeutic target for preventing or slowing cognitive impairment, according to the researchers.

But, the discoveries don’t stop there. The researchers theorized that high pulse pressure may have also prevented previous treatment strategies from working against dementia. For the past 20 years or so, a primary focus of drug development for Alzheimer’s disease has been the molecule amyloid-beta. But, that approach has yet to be successful. The researchers suggested that targeting amyloid-beta alone to treat dementia may not work since concurrent elevated pulse pressure will continue to cause inflammation and disrupt the BBB. They speculated that reducing elevated pulse pressure could aid in the efficacy of other therapeutic approaches like anti-amyloid-beta drugs or stem cell therapy.

Sex differences in Alzheimer disease. A new study shows that APOE4, the main genetic risk factor for the most common type of Alzheimer disease (AD), alters astrocytes’ signaling mechanisms in male mice, which could be key for the development of this pathology. But, in females, this change occurs in different variants of APOE. The study findings not only further the understanding of APOE functions in the brain as well as its role in AD development, but also shows how AD can affect each sex differently.

Specifically, researchers found that APOE4 causes changes in the astrocytes’ lysosomes—organelles involved in the breakdown of substances that the cell doesn’t need anymore. These changes in the lysosomes increase calcium signals, the main system cells use to respond to stimuli and block their modulation by lipids. The calcium signaling pathway also allows astrocytes to regulate neuronal connections, including learning and memory. Previous mouse studies have shown that beta-amyloid plaques affect calcium signaling. But in this study, researchers showed that defects in calcium signaling appear in astrocytes well before amyloid plaque accumulation, with APOE4 playing a significant role in this dysfunction. The study also shows that changes in calcium signals appear in female mice with APOE3 or APOE4 variants. Interestingly enough, the age or lipid regulation may denote a positive evolution for females with E3, according to the researchers. Overall, the study supports pharmacological interventions focused on replacing intracellular calcium signaling in patients with APOE4 and cognitive alterations. The findings could also lead to new medical therapies to slow AD progression in patients with the APOE4 variant.

Neuro Trivia

Which unusual sexual disorder with neuropsych underpinnings is marked by spontaneous sexual arousal or orgasm primarily affecting women? 

This one’s a toughy. So, if you guessed “persistent genital arousal disorder,” we tip our hats to you. In people who suffer from persistent genital arousal disorder (PGAD), orgasms are unpleasant. Although some patients may find relief through masturbation, most are sent for psychiatric treatment. But, some researchers posit that there may be neurological factors involved in PGAD. Previous studies suggest that many cases of PGAD are caused by unprovoked firing of C-fibers in the regional special sensory neurons involved in sexual arousal. And some PGAD symptoms may share pathophysiologic mechanisms with neuropathic pain. Plus, neurological treatment following neurological evaluation has been shown to help some patients.

Novel Diagnostics

Eye blood vessels predict AD. Researchers have discovered that early-stage Alzheimer disease (AD) affects the integrity of small blood vessels in the retinas. This finding could help with early diagnosis of the disease through the retina—which, luckily, is easily accessible for live, noninvasive imaging. It’s the first study to shed light on the molecular and cellular mechanisms critical for cognitive function. For their study, researchers looked at 62 post-mortem eye tissues of 29 patients with AD, 11 patients with mild cognitive impairment, and 22 individuals with normal cognition. In patients with AD, the researchers discovered three abnormalities within tiny blood vessels in their retinas—high death rates for pericytes (cells that lines the vessels, help regulate blood flow, and maintain the brain-blood barrier), low levels of PDGFRβ (a protein receptor that promotes cell growth), and buildup of toxic amyloid-beta forms.

Turns out, amyloid-beta deposits in the blood vessels and the low levels of PDGFRβ were strongly linked to pericyte degeneration in the retinas of patients with AD. The researchers also found that the most toxic forms of amyloid-beta accumulated within the pericytes themselves. These changes paralleled those in the brains of the patients. The retinal abnormalities were found in patients with mild cognitive impairment. Overall, these findings provide new insights into how AD develops, with major clinical implications. The researchers plan to develop a non-invasive, high-resolution retinal imaging tool to target pericytes and the molecular changes they discovered in blood vessels for AD diagnosis.

New biomarker for rapid ALS diagnosis. A new study shows that sequencing microRNA within brain exosomes—microscopic packets containing genetic material that are shed by tissues into the blood—can definitively distinguish blood samples of patients with amyotrophic lateral sclerosis (ALS) from healthy individuals. Specifically, researchers purified brain exosomes from blood plasma by targeting a unique protein on the exosome surface. Using the brain exosomes, they extracted microRNA, and found that eight different microRNA sequences together form a unique genetic fingerprint that distinguishes blood samples of ALS patients from healthy individuals.

The researchers believe that their methods may lead to the ability to rapidly diagnose ALS from a single blood sample, which is significant, considering that patients currently have to wait for more than a year for a confirmed diagnosis. Diagnostics aside, this newly discovered genetic fingerprint could serve as a biomarker that may allow opportunities for novel drug discovery. This could help researchers and clinicians in assessing the efficacy of new drug candidates, and also enable patients to receive experimental treatments at an earlier disease stage. Given the lack of treatments for ALS, physicians and researchers understand the importance of having a new biomarker to help in assessing the effectiveness of new drug candidates, and in enabling patients to receive experimental treatments at an earlier stage of the disease.

Blood test for brain tumor diagnosis. Current methods to diagnose and classify brain cancer subtypes based on molecular information rely on invasive, high-risk surgical procedures to obtain tissue samples. Now, researchers have developed a simple, non-invasive, highly sensitive blood test for accurate diagnosis and classification of different types of brain tumors. This is a major breakthrough because, prior to this development, it was thought to be impossible to detect any brain cancers with a blood test due to the brain-blood barrier.

For their study, the researchers compared cancer origin and type from patient brain tumor samples with the analysis of cell-free DNA circulating in the blood plasma in 221 patients. Using this method, they were able to match the circulating plasma circulating tumor DNA (ctDNA) to the tumor DNA, confirming their ability to detect brain tumor DNA circulating in the blood of these patients. Then, using a machine learning approach, they created a computer program to classify the brain tumor type based on the ctDNA. The best part is the test can pick up on even the smallest amounts of highly specific tumor-derived signals in the blood. The blood test can also accurately identify kidney cancer from circulating cell-free DNA obtained either from plasma or from urine.

Novel Treatments

Reversal Tx for a neurodegenerative disease. Using a mouse model of Parkinson disease (PD), researchers have discovered that blocking or eliminating a single gene that encodes PTB—a protein that binds to RNA and influences which genes are turned “on” or “off” in a cell—can generate new neurons. Even better, the experimental process eliminated Parkinson disease (PD) in the mice. (We’ll give you a minute to wrap your head around that.) How does it all work? The researchers created a noninfectious virus that carries an antisense oligonucleotide sequence—an artificial piece of DNA designed to bind the RNA coding for PTB, which degrades it and stops it from being transformed into a functional protein for neuronal development. They then administered the PTB antisense oligonucleotide treatment directly to the midbrains of mice. (The midbrain is key for regulating motor control and reward behaviors; it’s also the brain region that typically loses dopamine-producing neurons in PD.) A control group of mice received mock treatment with an empty virus or an irrelevant antisense sequence.

Unlike in control mice, who showed no change, neuron levels increased by about 30% in treated mice. Plus, dopamine levels were restored to a level similar to that in normal mice, and neurons grew and sent their processes into other parts of the brain. By measuring limb movement and responses, the researchers found that treated mice returned to normal within just 3 months following a single PTB treatment—and they remained symptom-free for the rest of their lives. So, what is it about PTB that makes this treatment a success? Apparently, the protein is found in a lot of cells, and forcing PTB to go away tricks cells into turning on the gene needed to produce neurons. The researchers cautioned that the study model isn’t a perfect replica of PD in humans, so further study is needed. But, the study does provide proof of concept. The researchers have patented the PTB antisense oligonucleotide treatment to launch testing in humans.

Promising tumoricidal treatment. Researchers have developed a powerful new technique that targets cancer cells with a drug (5-ALA) that sensitizes them to sound waves, and then hits them with focused ultrasound. The sound waves cause tiny bubbles to develop inside the cells, causing the cells to die. The process is proving to be useful against glioblastoma and several other cancers.

To determine the potential of their new focused ultrasound technique, the researchers looked at its effects on both rat and human cell samples. After looking at the benefits of the 5-ALA drug and focused ultrasound both separately and in combination, the researchers found that the combo was far more effective than either alone. The drug reduced the number of viable cancer cells by 5%, while focused ultrasound reduced it by 16%. Together, they yielded a reduction of 47%. The work is still in the early stages, with researchers testing the concept on cell samples in lab dishes, but the results so far are promising and may have therapeutic value for other cancers such as lung cancer, breast cancer, and melanoma. The researchers posit that their technique may be useful in treating cancers in difficult-to-access and sensitive regions of the body.

New in Patient Management

IBD tied to dementia. A new, large population-based study shows that inflammatory bowel disease (IBD) is linked to a two-fold risk of developing dementia. The study also shows that dementia was diagnosed much earlier in people with IBD vs those without the disorder. Previous research has suggested that IBD may play a role in the development of Parkinson disease, but it’s not clear if IBD may also be tied to increased dementia risk. To find this out, researchers analyzed data from about 1,800 people aged 45 years and older with either ulcerative colitis or Crohn disease (diagnosis given between 1998 and 2011) who were registered with the Taiwan National Health Insurance program. The researchers tracked the participants’ cognitive health for 16 years following their IBD diagnosis, and compared results with that of ~17,500 matched controls.

During the follow-up period, a larger proportion of those with IBD developed dementia (5.5%), including Alzheimer disease, than those without (1.5%). People with IBD were also given a diagnosis of dementia about 7 years earlier than those without IBD. After adjusting for confounding factors, the researchers discovered that people with IBD have double the risk of dementia vs those without IBD. Of all the dementias, the risk for Alzheimer disease was greatest. In fact, those with IBD were six times more likely to develop Alzheimer disease vs those without IBD. Interestingly, neither sex nor IBD type affected the findings. But, the longer a person has IBD, the greater their risk of dementia. The study adds to a growing body of evidence implicating gut imbalance with chronic inflammation and cognitive decline.

Obesity-dementia link. The number of risk factors for dementia just keeps going up. Case in point: A new study shows that obesity is linked to a higher risk of dementia—up to 15 years later! Researchers analyzed data from 6,582 people in a nationally representative sample of the English population aged ≥ 50 years from the English Longitudinal Study of Ageing. Doctor diagnosis, informant reports, and hospital episode statistics were used to define dementia. People with a BMI ≥ 30 (obese level) at the start of the study had a 31% increased risk of dementia at an average follow-up of 11 years vs those with a BMI from 18.5 to 24.9 (normal level). There was also a significant sex difference in the risk of dementia from obesity. Women with abdominal obesity had a nearly 40% increased risk of dementia vs those with a normal level. But, this association was not found among the male participants. When the researchers viewed BMI and waist circumference in combination, obese study participants of either sex showed a 28% greater risk of dementia vs those in the normal range.

They speculated that obesity might be driving increased dementia risk through its direct influence on cytokines and hormones derived from fat cells or through its indirect influence through an adverse effect on vascular risk factors. Previous researchers have suggested that excess body fat may heighten dementia risk through metabolic and vascular pathways that contribute to the buildup of amyloid proteins or lesions in the brain. Still, the researchers acknowledge that the link between obesity and dementia might be mediated by other conditions like hypertension or anticholinergic treatments. They plan to find out whether there’s an interactive effect between obesity and midlife risk factors (eg, hypertension, diabetes, APOE ε4 carrier status) in relation to dementia in further clinical trials.

Cannabis and neurobehavioral problems. Recent reviews have suggested that the use of current high-tetrahydrocannabinol (THC) cannabis products may result in greater intoxication and impairment, but there’s been no empirical data to determine the actual risk profile of these products. Now, a new observational study shows that use of legal-market cannabis flower and concentrate is linked to delayed recall memory and balance impairment. Researchers randomized 133 cannabis users to higher and lower-THC potency products. All participants had used cannabis at least four times in the previous month, had no adverse reaction to the highest cannabis potency assigned, did not use any other non-prescription drugs within the previous 60 days, did not use tobacco, drank ≤ 2 times weekly and had ≤ 3 drinks per occasion, were not pregnant, and were not being treated for a psychotic or bipolar disorder. Participants completed mobile lab tests before, immediately after, and 1 hour after ad libitum use. Flower users were randomized to either 16% or 24% THC flowers, while concentrate users were randomized to either 70% or 90% THC concentrate, bought from a dispensary.

In all, 55 regular flower cannabis users (41.4%) and 66 regular concentrate cannabis users (49.6%) had complete data across the primary outcomes. Compared with flower users, concentrate users had higher plasma THC levels and 11-hydroxy-THC across all points. After ad libitum cannabis use, mean plasma THC levels were 1,016 mcg/mL in concentrate users and 455 mcg/mL in flower users. Most neurobehavioral measures weren’t affected by short-term cannabis use. But, delayed verbal memory and balance function were impaired after use. Concentrate users also showed similar or lower levels of subjective drug intoxication and short-term impairment vs users of lower-potency flowers. The researchers emphasized the need for clinicians to educate themselves about the different forms and quantities of cannabis their patients may use.

Latest in Journal Summaries

Neuropsychological outcomes after pediatric epilepsy surgery

The link between PTSD and Parkinson disease in war vets with traumatic brain injury

Higher risk of dementia in English older individuals who are overweight or obese

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Upcoming Medical Meetings

The following meeting has been rescheduled:

14th European Congress on Epileptology, to be held in Genève, Switzerland, July 4-8, 2020. Please check the conference website for up-to-the-minute information.

The following meeting has been changed to a virtual workshop:

Neurology in Clinical Practice 2020, to be held in Grand Cayman, Cayman Islands, July 9-11, 2020.

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