Probiotics & cannabis for Parkinson disease, a possible treatment for glioblastoma, and does size of the hippocampus really matter?
It may feel like it’s January 65th, but take heart, February is just around the corner, and spring is just a little closer. Researchers, however, have been keeping us busy with all sorts of new studies on all things neurologic. For example, the evidence for a gut-brain connection just got a little more compelling. Using a roundworm model, researchers from Edinburgh found that a probiotic bacterium could prevent and even reverse the toxic protein buildup that causes Parkinson disease. In other news, researchers from the NIH have just blown a hole in the link between herpes virus (specifically HHV6) and Alzheimer disease. And, did you know that a bigger hippocampus may not always be better in your patients with suspected cognitive decline? Read on to find out why.
Nearly 150 years ago, Scottish surgeon Sir Will Macewen, CB, FRS, FRCS, performed the first successful intracranial surgery. In 1879, he removed a left frontal meningioma from a teenage girl. He located the lesion site by studying preoperative focal epileptic signs demonstrated by the patient. These epileptic signs consisted of twitching of the face and arms on the opposite side of the lesion. Based only on these clues, Dr. Macewen deduced that there was evidence of an “irritation to the lower and middle portions of the ascending convolutions…in the left frontal lobe.” Through a trephined hole in the patient’s skull, near the suspected location of the tumor, Dr. Macewen found a large, subdural tumor, which he removed. He successfully used this technique repeatedly throughout the rest of his career, operating on brain abscesses, hematomas, and on the spine. And Dr. Macewen’s pioneering spirit did not stop at brain surgery. His work also contributed to the development of bone graft surgery and the surgical treatment of hernia and pneumonectomy (the removal of the lungs). You might say he was a true surgical Renaissance man!
In the News
A protein brake for Alzheimer disease? After correlating about a million single-nucleotide polymorphisms (SNPs) with brain images, researchers identified a specific SNP (n the FAM222 gene) that is linked to different patterns of regional brain atrophy that’s. They also found evidence that the protein encoded by FAM222A may be associated with Alzheimer disease-related beta-amyloid plaques and regional brain atrophy. These aggregates attach to amyloid beta peptide, a plaque component that aids in plaque formation. Mice injected with aggregates of the protein made from the FAM222A gene exhibited accelerated plaque formation, with more neuroinflammation and cognitive dysfunction, which occurred because the protein bound directly to the amyloid beta peptide, aiding both aggregation and plaque formation. When the protein was suppressed, plaques, neuroinflammation, and cognitive impairment were reduced. Imagine being able to slow the progression of Alzheimer disease by tamping down a protein!
Toxic roads and highways? Did you know that living near major roads or highways may be associated with higher incidences of dementia, Parkinson disease (PD), Alzheimer disease, and multiple sclerosis (MS)? After analyzing data from 678,000 adults in Metro Vancouver, researchers from the University of British Columbia concluded that living fewer than 50 meters (about 165 feet) from a major road or fewer than 150 meters (about 500 feet) from a highway is associated with increased risks of developing all of these neurological conditions. What’s more, the increased risk is likely due to the increased exposure to air pollution. Living near major roads or highways increased the risk of non-Alzheimer dementia by 14% and increased the risk of PD by 7%. But, the good news is that living near green spaces—parks, forests, wooded areas—can protect against the increased risks for these neurological diseases. This news may just inspire you to sit in on your city planning meetings and advocate for more green spaces!
Herpes/Alzheimer link refuted? Nearly 30 years ago, researchers in the United Kingdom first discovered higher levels of DNA strands of herpes simplex virus in the postmortem brain samples of patients with Alzheimer disease (AD). Since then, several studies have supported a link between AD and herpes simplex virus 1 (HSV1), HHV6A, and HHV6B (although, causality remains to be proven). But now, researchers of a recent, large, three-cohort analysis say this may not be the case.
To determine whether HHV6A and HHV6B are, in fact, associated with AD, the researchers used RNA sequencing data to search for viral transcripts, the Pathseq algorithm to find microbial sequences, and tested DNA samples from 708 healthy or diseased brains. In the end, they found no evidence of increased RNA or DNA levels of HHV6A or HHV6B in patients with AD compared with healthy individuals. Furthermore, they found no association between other viral transcripts that have also been linked to AD, including Epstein-Barr virus and cytomegalovirus. The bottom line so far: The jury is still out on this association, and further studies are ongoing.
What are netrins and semaphorins?
Netrins and semaphorins are neuronal guidance molecules. Netrins are a family of secreted proteins, and semaphorins are a large family of glycoproteins. During embryonic development, they aid in the patterning of the nervous system. Recently, researchers found that netrins and semaphorins may also guide development in other systems like the vascular system. And, there’s mounting evidence that these molecules may also play a role in regulating endothelial quiescence.
Just a simple blood test. Because there are significant clinical overlaps between frontotemporal lobar degeneration (FTLD) spectrum disorders and late-onset primary psychiatric disorders (PPD), diagnostics that can differentiate between them are desperately needed. In light (pun intended) of the known elevations in cerebrospinal fluid levels of neurofilament light chain (NfL) and new ultrasensitive analytical methods that allow for the discovery of serum NfL, researchers are now looking for ways to meld the two together. NfL is a biomarker of axonal damage that occurs in a range of neurological diseases.
In a recent study, researchers from Finland discovered that serum NfL levels have great potential as a diagnostic tool to distinguish FTLD spectrum disorders from PPD. Indeed, serum NfL levels in patients with FTLD spectrum disorders were higher compared with those in the PPD group. Furthermore, serum NfL levels were higher in the various separate clinical subtypes of FTLD compared with different psychiatric manifestations. Furthermore, simple serum testing could differentiate between FTLD spectrum disorders and PPD with 80% sensitivity and 85% specificity. It may also differentiate between behavioral variant frontotemporal dementia and PPD with 79% sensitivity and 85% specificity. What a great diagnostic tool this would be!
Bigger isn’t always better. A larger hippocampus doesn’t necessarily equate to better learning and memory abilities in older adults, according to researchers from Michigan State University. The researchers found that hippocampal size or volume is only a marker of learning in older adults who have more intact limbic white matter. They analyzed two different types of MRI brain scans from 330 older adults. In the first scan, they evaluated hippocampal size. In the second scan, they assessed the white matter circuitry connecting the hippocampus to other brain regions involved in learning. Participants were also given learning and memory tests. Only those who had both a large hippocampus and a more uniform white matter circuitry exhibited faster learning. Thus, researchers highlighted the importance of measuring not only the hippocampus but its connectivity to the rest of the brain when diagnosing memory decline in older adults. These results also have potential implications for the earlier diagnosis of age-related memory disorders like Alzheimer disease because cognitive decline may be overlooked in those with larger hippocampi. Who says bigger is better?
Why not both? Deciding which of your patients with stroke would benefit from endovascular thrombectomy is easier than you might think. Rely on CT. Both simple CT and advanced CT perfusion. Used separately and used together. It’s that simple. Researchers of the multicenter Optimizing Patient Selection for Endovascular Treatment in Acute Ischemic Stroke (SELECT) study found that when used separately, simple, non-contrast CT and advanced CT perfusion with contrast dye both accurately predicted which patients with stroke would benefit from endovascular thrombectomy for large cerebral clot excision. But, when used together, their predictive powers were even more accurate. Among the 361 enrolled patients, many were candidates for endovascular thrombectomy, as judged from both CT and CT perfusion results. These patients also had significantly higher odds of actually receiving endovascular therapy, as well as higher 90-day functional independence rates after their recovery (58%). In addition, 38% achieved functional independence even when the imaging modalities didn’t match, which was better than patients who did not undergo thrombectomy. The best outcomes were in patients with favorable profiles on both modalities, and reasonable outcomes were seen even in those with a favorable profile on at least one. The SELECT2 study is currently underway to determine the efficacy and safety of thrombectomy in patients with unfavorable profiles.
Change your gut, change your mind. Could a probiotic bacterium be useful in reversing or preventing Parkinson disease (PD)? Researchers think they have found evidence that it may. Toxic clumps formed by misfolded alpha-synuclein proteins in the brain are the hallmarks of PD. These clumps are believed, by some researchers, to lead to the loss of brain cells controlling movement. But, much is still unknown about the mechanisms leading to PD. UK researchers have focused their efforts on studying whether changing the gut microbiome could modify the risks of developing PD. They used a nematode worm model that was genetically engineered to express a human version of the alpha-synuclein protein. Within 72 hours of hatching, these worms begin to develop alpha-synuclein clumps. However, when the worms were fed a diet containing the probiotic strain Bacillus subtilis PXN21, researchers observed almost zero clumping. Although the worms still produced the alpha-synuclein protein, it failed to aggregate in the same way. In worms that had already developed protein aggregates, the B. subtilis-rich diet cleared the aggregates from affected cells. Researchers followed some worms longer to compare the effects of a B. subtilis-rich diet with a conventional one. They found that the aggregates in those fed B. subtilis were much lower than that with the standard diet. They concluded that B. subtilis PXN21 “inhibits and reverse [alpha-synuclein] aggregation in a [roundworm] model.” And, this effect was seen in a number of different strains of the bacteria, which also offered older animals protection from alpha-synuclein aggregation and improved motor skills in those first fed a standard diet. More research is being done, but you may want to run to the vitamin store and stock up on probiotics!
Potential Tx for uncontrolled focal seizures? Cenobamate may be effective in patients with uncontrolled focal (partial)-onset epilepsy as an adjunctive treatment. In a multicenter, double-blind, randomized, placebo-controlled, dose-response study done at 107 epilepsy/neurology centers in 16 countries, researchers studied the effects of adjuvant once-daily oral cenobamate (100, 200, or 400 mg) vs placebo in adults with uncontrolled focal seizures. Median percentage change in seizure frequency were greatest in those treated with the 400- and 200-mg doses (-55% for both) of cenobamate, followed by those treated with 100-mg (-35.5%) cenobamate and placebo (-24.0%). During the 12-week maintenance phase, response rates were greatest again in the 400-mg study drug group (64% [61 of 95 patients]), followed closely by those in the 200-mg group (56% [55 of 98 patients]). Treatment-emergent adverse events were common, particularly with the 400-mg dose, but led to discontinuation in 20% or less of patients in all groups. These great results may lead to a potential new treatment for your patients with epilepsy, among whom over one-third are treatment resistant.
BLASTing glio-BLAST-oma. Heavy ion therapy, which blasts tumors with positively charged nuclei of carbon, oxygen, or helium, may be effective in treating patients with glioblastoma. Researchers used mouse models and cell cultures to test the reaction of glioblastoma tumors to irradiation with carbon atoms. To do this, they accelerated charged carbon particles to more than three-fourths of the speed of light, which can cover about 225,000 km/sec. The charged particles were able to penetrate up to 30 cm deep into tissue with nary a sign of weakening. What this accomplishes is the release of most of the energy on the tumor. And the carbon ions cause irreparable damage to the tumor DNA, killing hypoxic cells. This, in turn causes favorable immune system changes, unlike conventional radiation therapy. This is really great because conventional radiation therapy using gamma or x-rays is not as effective on glioblastoma as it is on other tumors.
Take it all out. Removing the entire tumor in patients with brainstem high-grade gliomas—one of the rarest, deadliest forms of brain cancer—could add months or even years to their survival, which is more time than that gained by treatment with radiation and chemotherapy. Researchers at Johns Hopkins Kimmel Cancer Center have found a way to safely access these tumors through “brainstem safe entry zones,” and have been able to surgically treat previously inoperable tumors this way. Using data from the SEER database, they analyzed outcomes from 103 patients with brainstem high-grade gliomas who had a biopsy or other surgical intervention for their tumors. Of the 85% who had surgery, 19% had total surgical removal. Patients who underwent surgery, researchers found, had significantly longer survival time. Those with partial resection survived 11 months compared with the 8-month survival time typical after a biopsy-confirmed diagnosis. And, those who underwent gross total resection survived even longer—about 16 months. In some patients with other factors associated with longer survival—such as younger age—median survival with total resection was up to four times longer than survival after biopsy.
New in Patient Management
Earliest treatment of spina bifida best. Kids as young as age 6 who underwent fetal surgery to repair myelomeningocele—the most serious form of spina bifida—are more likely to be able to walk by themselves and have fewer follow-up surgeries than kids who had traditional corrective surgery after birth. These results come from a follow-up to the landmark 2011 Management of Myelomeningocele study—which showed that prenatal surgery for spina bifida is better than surgery after birth for this disabling neural tube defect. Researchers reassessed 161 children in the follow-up study. At the time of follow-up study participants were between 6 to 10 years of age. Of these children, 79 had prenatal surgery and 82 had traditional surgery. Kids from the former group were capable of walking independently more often than those in the latter group (93% vs 80%, respectively). Further, kids who underwent prenatal surgery had fewer shunt placements for hydrocephalus (49% vs 85%) and fewer shunt replacements (47% vs 70%). Ability to communicate, social skills, and daily living skills weren’t different between the groups, but motor skills were better in the kids operated on prenatally. Significant physical and emotional benefits for these children!
Cannabis derivative for Parkinson disease? HU-308—a derivative of cannabis that acts as a cannabinoid agonist—may reduce dyskinesias caused by long-term treatment for Parkinson disease (PD). In fact, researchers from Sydney showed that—in mice—HU-308 is as effective as amantadine. Even better: When the two drugs are combined, they’re more effective than either drug used alone. Unlike cannabis, HU-308 works on cannabinoid receptor type 2 (CB2), rather than on both CB1 and CB2. (CB1is responsible for the psychoactive effects of cannabis.) HU-308 works to reduce inflammation in the brain, allowing immune cells to support rather than inhibit normal neural function. Researchers believe they may have found an important prototype drug that won’t interfere with day-to-day activities, and are busy with more studies on HU-308.
Small medical device, big migraine help. Neuromodulation may be getting closer to becoming mainstream thanks to a tiny new device. Researchers at West Virginia University are currently studying a cell phone-sized device that stimulates the vagus nerve. For years, an implantable vagus nerve stimulator has been used to control seizures in patients with epilepsy. This new device, however, is non-invasive. When applied to the neck, it stimulates the vagus nerve and effects changes in the areas of the brain stem involved in the migraine process. It can downregulate these areas and even disrupt an ongoing migraine attack. When used daily (three times), it can also prevent migraines. Because researchers of previous preclinical trials showed the efficacy of this device in disrupting and preventing migraines, researchers are now conducting a 6-month study in patients with migraine. They also plan to study another neuromodulation device—applied to the arm to stop migraines once they’ve started—and wearable sensors to track the physiologic changes before, during, and after migraine attacks. Lots of great results and devices to look forward to in the area of migraine!
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Upcoming Medical Meetings
53rd Annual Recent Advances in Neurology, in San Francisco, CA, February 12-13, 2020
American Society of Spine Radiology (ASSR) 2020 Annual Symposium, in Dana Point, CA, February 12-16, 2020
International Stroke Conference 2020, in Los Angeles, CA, February 18-21, 2020
North American Spine Society’s (NASS) Evidence & Technology Spine Summit, in Park City, UT, February 19-22, 2020