A new key to preventing neurodegeneration? Aspirin for Alzheimer’s, a popular diet for seizure prevention, and more

This week, we’re zooming in on new strategies neurologists can use to help patients during the COVID-19 pandemic, as well as a few old strategies that might not make much sense in this strange new world. Don’t worry though, we’re experiencing a bit of pandemic fatigue, too—that’s why we’re also bringing you some hopeful news about the ways erectile dysfunction drugs and oxytocin (you may know it as the “love hormone”) are poised to ease the burden of cognitive decline, plus a mountain of fresh data to help you navigate Alzheimer’s treatment, and so much more.

Neuro Flashback

The Ancient Romans were relentless pursuers of scientific advancements, but there was one small problem that prevented them from learning more about the human body: it was illegal to dissect them. That didn’t stop Galen of Pergamon, the personal physician of then-emperor Marcus Aurelius, from shedding new light on human neurology that was way ahead of the times (129-200 AD, to be exact). Rather than dissecting human bodies, he’d head to the local market and take his pick from an assortment of Barbary apes, pigs, and even parrots, which he dissected live or dead to learn how the nervous system worked. Galen was the first to discover that cutting the spinal cord at different levels could paralyze certain parts of the body, and that an undamaged connection between the brain and spinal cord was necessary for muscle contractions. While his understanding of the nervous system wasn’t perfect, it went on to dominate Western medicine for the next 1,300 years.

In the News

An aspirin a day to keep dementia away? Physicians who prescribe aspirin in an attempt to delay the onset of dementia use a plausible line of reasoning: If aspirin is an anti-inflammatory and antiplatelet agent, and if inflammation is one of the driving forces in Alzheimer’s disease pathology, then perhaps aspirin could help slow cognitive decline. Maybe it could even help manifest a reduction in amyloid pathology. And if aspirin helps prevent strokes, perhaps it could help prevent vascular dementia, too. It all sounds pretty convincing, right? Unfortunately, the key takeaway from a randomized, placebo-controlled trial on the effects of aspirin on dementia and cognitive decline found that aspirin did not have protect against cognitive decline. While observational data suggests that aspirin could have neuroprotective abilities, the bottom line is that “there has been a dearth of large high-quality randomized controlled trials of NSAIDs, particularly those investigating the effects of low-dose aspirin,” the authors wrote.

In their study, investigators randomized 19,114 individuals 65 years or older 1:1 to receive 100 mg of daily aspirin or placebo over the course of 4.7 years. The participants had no cardiovascular disease, physical disabilities, or diagnosed dementia. A total of 964 participants triggered further dementia assessments, and researchers found 575 adjudicated dementia cases, 41% of which were classified as probable Alzheimer’s disease. In the end, researchers found no substantial difference between the aspirin and placebo groups in the risk of all dementia triggers, probable Alzheimer’s disease, or mild cognitive impairment.

Erectile dysfunction drugs…for neurodegenerative disorders? There may be a connection, according to a recent studypublished in the Proceedings of the National Academy of Sciences. Researchers tested the ability of PDE5 inhibitors—including the erectile dysfunction drugs sildenafil and tadalafil—to lower the accumulation of mutant proteins, reduce cell death, and prevent anatomical defects in zebrafish models of neurodegeneration. We know, we know…animal studies mean this treatment is nowhere near a reality, but there’s still reason for excitement: the buildup of misfolded proteins is a hallmark of Alzheimer’s and Parkinson’s disease. And, despite a ton of research into this topic in recent decades, there’s still no effective means to remove or prevent their accumulation in humans.

In this study, researchers sought to enhance the activity of the proteasome, one of the primary molecular machines that cells use to destroy proteins (especially damaged or folded proteins). Previous research suggested that PDE5 inhibitors can increase degradation of mutant proteins by raising levels of cGMP, a molecule that acts as an intracellular messenger. The research team found that raising cGMP both enhanced the addition of ubiquitin to proteins—which increased the marking of proteins for degradation—and enhanced the proteasome’s ability to destroy them. “For a long time, we thought that the proteasome mindlessly destroyed proteins that are tagged with ubiquitin,” the authors said. “Our work is beginning to uncover that the proteasome is a lot smarter than we thought it was—and is making decisions through mechanisms that we still don’t fully understand.” While this is inspiring news, the authors caution that there’s no reason to prescribe ED drugs for neurodegenerative disease—at least not yet.

A high-level view of Alzheimer’s prevention. That’s what we’ve got thanks to a new systematic review and meta-analysis published in the Journal of Neurology, Neurosurgery & Psychiatry that includes 243 observational prospective studies and 153 randomized controlled trials. Based on the consolidated evidence, researchers have proposed 21 suggestions to be taken into account when considering Alzheimer’s prevention.

First, several of the suggestions cover the importance of a healthy lifestyle. Those looking to prevent Alzheimer’s should keep a close eye on weight (overweight and underweight are both risk factors), participate in mentally stimulating activities and games, and get enough sleep. Data suggested that eight comorbidities increased the risk of Alzheimer’s: diabetes, cardiovascular disease, head trauma, frailty, hypertension, depression, atrial fibrillation, and stress. Interestingly, researchers found that getting as much general education as possible early in life reduced the risk of Alzheimer’s, as did vitamin C intake—either in the diet or taken as supplements. Finally, the authors write that postmenopausal women should not use estrogen replacement therapy for Alzheimer’s prevention. Similarly, acetylcholinesterase inhibitors should not be used by people with cognitive impairment. Want to read the suggestions in detail? Go check out the study.

Another reason to love Keto. A new meta-analysis published in the journal Seizure suggests that the ketogenic diet is a viable treatment option for patients with Dravet syndrome. How viable, you ask? There’s sufficient evidence to suggest it should be used as a first-line treatment. In the seven studies involving 167 patients that met inclusion criteria, evidence revealed that 63%, 60%, and 47% of patients who responded achieved at least a 50% seizure reduction at 3, 6, and 12 months, respectively, which is at least as effective as available antiepileptic medications. The pooled retention rate of the ketogenic diet at months 6 and 12 was 78% and 49%, respectively. What’s more, researchers claimed that the diet was safe and adverse events were mostly acceptable (except in three reported cases—two had severe vomiting and one had blood lipids that were 10 times higher than normal).

Evidence from the meta-analysis supports the efficacy and safety of the ketogenic diet, but there’s no doubt that more research is needed. It remains difficult to study patients with such a rare disease (it affects roughly one in every 20,000 infants) and there are currently no randomized controlled trials of the ketogenic diet in this population. Still, leading scientists suggest the ketogenic diet—a high-fat, adequate-protein, low-carbohydrate diet—should remain a first treatment choice for patients with Dravet syndrome, as there are no medications that reduce seizures more effectively.

Neuro Trivia 

How did dementia pugilistica, a variant of CTE, get its name?

CTE was originally studied in boxers in the 1920s as dementia pugilistica. It was first described by forensic pathologist Dr. Harrison Stanford Martland. The initial diagnosis of dementia pugilistica was derived from the Latin word for boxer (pugil), which comes from pugnus (fist) and pugnare (to fight). So dementia pugilistica essentially translates to “Boxer’s Dementia.”

Novel Diagnostics

What is POEMS syndrome? POEMS is a paraneoplastic disorder resulting in severe neurologic disability, and its cause is currently unknown. But, here’s some good news: a new retrospective longitudinal cohort study in the journal Neurology moves us a bit closer to some answers. Researchers followed 100 patients with POEMS (which stands for polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin lesions) from 1998 to March 2019, using hospital databases to collate presenting features, investigations, therapies, and response. Their goal? To understand POEMS’ features and figure out how it responds to treatment so we can move toward better diagnoses and management.

Here’s what they found: the mean symptom onset to diagnosis was 15 months, and 54% of patients were initially misdiagnosed with chronic inflammatory demyelinating polyneuropathy. Initial presentation was painful neuropathy in 96% of patients, with 35% in a wheelchair or bed-bound. Five-year and 10-year survival rates were 90% and 82%, respectively. Patients who were not treated with autologous stem cell transplantation, those with non-hematologic response, and those with non-vascular endothelial growth factor response were at higher risk for death. Key findings include favorable outcomes for therapy for POEMS, and that patients at high risk of death or progression can be identified early, which may allow for better management down the road.

Novel Parkinson’s prognosticator. A new study published in Neurology suggests that the patterns of striatal dopaminergic denervation—loss of nerve and dopamine supply in the striatum—have a prognostic implication in patients with early-stage Parkinson’s disease. To arrive at this finding, authors enrolled 205 drug-naïve patients with early-stage Parkinson’s who underwent testing scans and received Parkinson’s medications for at least 3 years. Researchers quantified dopamine transporter availability in each striatal subregion, conducted analysis to simplify the identification of striatal dopamine depletion patterns, and assessed the effect of these factors on the development of levodopa-induced dyskinesia (whether it wore off, whether freezing of gait occurred, and whether dementia was present on follow-up).

Investigators found that selective dopamine depletion in the sensorimotor striatum was associated with a higher risk for developing levodopa-induced dyskinesia, and that selective involvement of the anterior putamen was associated with a higher risk for dementia conversion. On the other hand, patterns of striatal dopamine depletion did not affect the risk of freezing of gait. If further studies can replicate these results, these patterns in striatal dopaminergic denervation could become an important Parkinson’s prognosticator.

Liver fibrosis and cognition. A new study published in the European Journal of Neurology, which evaluated the associations between a validated liver fibrosis index and cognitive measures in people aged 60 and older, found that liver fibrosis may be an independent risk factor for cognitive impairment in older adults. The study included 3,217 adults with a mean age of 69 years, of which 54% were women. Study participants were measured against their performance on four standardized cognitive tests of immediate and delayed verbal learning, verbal fluency, and attention/concentration, adjusted for potential confounders.

While most participants had standard liver chemistries that were in the normal range, 5% had liver fibrosis. Higher liver fibrosis scores were associated with worse immediate recall, language fluency, and attention/concentration, but not delayed recall, as shown in linear regression models. Based on these data, it was inferred that in older adults, liver fibrosis, including subclinical liver fibrosis, may be an independent risk for cognitive impairment.

A ‘feeling’ for dementia. Subjective feelings don’t typically play an important role in scientific endeavors. But, when it comes to diagnosing Alzheimer’s disease, the way a patient subjectively feels about their memory loss and cognitive impairment might hold some objective prognostic value, according to a new study published in Neurology. In the study, which involved 449 older adults, those with subjectively felt memory problems also exhibited measurable cognitive deficits that were associated with abnormalities in the CSF.

Study participants underwent various tests of their mental abilities. In addition to memory performance, focus was placed on attention capacity and the ability to concentrate. In addition, CSF of 180 study participants—of which 104 were experiencing subjective cognitive decline (SCD)—was analyzed. “We found that our study [participants] with SCD had mild cognitive deficits on average and that these deficits were associated to proteins that indicate early Alzheimer’s disease. Therefore, we assume that both the subjective complaints and the minimal objective cognitive deficits are due to Alzheimer’s processes.” Early diagnosis and therapy development could benefit from these findings.

Novel Treatments

Valproic acid gets upstaged when it comes to fertility. Many male patients with epilepsy are forced to face an uncomfortable truth—while they can usually have normal sex lives, their condition often means they’ll have lower sperm counts and more difficulty conceiving children. But a new study published in Acta Neurologica Scandinavica finds that switching from valproic acid to levetiracetam (LEV) or lamotrigine (LMG) critically improves sperm counts and parameters, increasing the chances that these patients’ female partners will spontaneously conceive a child.

In this observational prospective study, 17 infertile male patients were recruited. A total of nine patients were switched from valproic acid to LEV, and nine were switched to LMG. In both cases, mean sperm counts and sperm motility increased following withdrawal from valproic acid (there were minimal differences between patients who switched to either LEV or LMG.) Three patients reported that their partners had spontaneous pregnancies without additional clinical interventions. The study is small, but the benefits on fertility are promising.

‘Love hormone’ could be used to treat cognitive disorders. A team of scientists from Japan has looked at oxytocin, a hormone widely known for its role in the female reproductive system and in inducing feelings of love and well-being, as a new potential way to regulate learning and memory performance. While the study involved mice, it remains the first of its kind and carries the potential to unlock new pathways to treat cognitive disorders like Alzheimer’s.

In the study, Japanese researchers perfused slices of the mouse hippocampus with amyloid β (Aβ) and confirmed that Aβ impairs neurons’ synaptic plasticity. Upon additional perfusion with oxytocin, the signaling abilities increased, suggesting that oxytocin can reverse the impairment of synaptic plasticity caused by Aβ. “This is the first study in the world that has shown that oxytocin can reverse Aβ-induced impairments in the mouse hippocampus,” researchers remarked. But keep in mind, this is only a first step toward understanding the effects of oxytocin on cognitive disorders. Further research remains to be conducted in vivo in animal models and then in humans before we can determine whether oxytocin can gain traction as a potential treatment for Alzheimer’s.

Tackling insomnia: with or without drugs? It might seem like combo therapy  is the best way to manage insomnia while saving patients time and money, but a new study suggests the most efficient long-term strategy is cognitive behavioral therapy, which doesn’t require drugs at all. The sequential multiple-assignment randomized trial, published in JAMA Psychiatry, concluded that behavioral therapy was equally as effective as the sedative zolpidem for treating patients with insomnia.

A total of 211 participants with chronic insomnia were assigned to first-stage therapy with either behavioral therapy (BT) or sublingual zolpidem taken nightly at bedtime. After 6 weeks of therapy, those in remission were followed up for the next 12 months while receiving maintenance therapy. Nonremitters were randomized to a second-stage psychological or drug therapy. Researchers found that first-stage therapy with BT or zolpidem produced equivalent weighted percentages of responders (BT, 45.5%; zolpidem, 49.7%) and remitters (BT, 38.03%; zolpidem, 30.3%). “The issue of treatment preference is very important,” researchers noted. “The current study indicates that the highest dropout rates were observed in conditions where patients were treated only with medications…whereas the lowest dropout was observed in the treatment sequences involving behavior therapy followed by cognitive therapy.”

Big wins for patients with Parkinson’s. In a new study published in the Journal of Neuroimmunology, evidence suggests that this two-drug combo promoted clinical and immunological improvements, a peripheral proinflammatory effect, and regulatory peripheral immune response in patients with Parkinson’s disease. The 2-year prospective study compared the effect of levodopa alone and levodopa/pramipexole combination therapy on several regulatory and pro-inflammatory immune cell populations.

Researchers were able to demonstrate that patients with Parkinson’s showed decreasing circulating levels of several important regulatory subpopulations, as determined by flow cytometry. “These results suggest that a regime based on levodopa alone may promote a pro-inflammatory-type response in PD patients, but when combined with pramipexole, it promotes a clinically beneficial regulatory-type environment,” the authors wrote.

New in Patient Management

COVID-19 and cognition? Coronavirus is not just life and death—there’s a world of unknowns in between, and many of them aren’t pretty. Take Hannah Davis, for example. When the 32-year-old Brooklynite fell sick in late March, her symptoms quickly became so severe that she could hardly follow the plot of her favorite movies. When checking her texts, she couldn’t weave together a coherent conversation. Over time, her flu-like symptoms eased up, but that cognitive fogginess hasn’t relented. In fact, it has only become worse and brought new symptoms with it—like sporadic blurred vision and insomnia.

Davis is not alone. Many survivors point to the possibility that COVID-19 is not just a transient respiratory disease, but one that brings neurological and physical symptoms that persist months after the tell-tale signs subside. Dr. Anthony Fauci, leading member of the White House’s Coronavirus Task Force, noted that some survivors’ symptoms resemble those of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a debilitating and poorly understood condition associated with some viral infections. While it hasn’t been thoroughly studied, we do know that ME/CFS is characterized by insomnia, difficulty thinking and concentrating, pain, and dizziness—all symptoms familiar to the neurology community. As the pandemic continues, neurologists should stay abreast of the latest evidence and be prepared for a potential uptick in patients presenting with cognitive difficulties related to previous COVID-19 infection.

Type 2 diabetes-related polyneuropathy + pain = worse outcomes. It’s understood that type 2 diabetes-related polyneuropathy (DPN) is associated with increased risk of vascular events and mortality, but researchers hadn’t studied the effects of pain in DPN. Does pain mean patients with DPN are more likely to experience worse outcomes? Indeed it does, according to a new studypublished in The Journal of Clinical Endocrinology & Metabolism. Researchers conducted a retrospective cohort study within a large health system on adult patients with type 2 diabetes from 2009 to 2016, classifying patients as having no DPN, DPN plus pain (DPN + P), or DPN without pain (DPN – P). Primary outcomes included number of vascular events and time to mortality.

Of 42,945 patients with type 2 diabetes, 13,910 (32%) had DPN. Of those, 9,104 (65%) had pain and 4,806 had no pain. Vascular events occurred in 15% of those with no DPN, 21% of those with DPN – P, and 26% of those with DPN + P. “Our study found a significant association between pain in DPN and an increased risk of vascular events and mortality. This observation warrants longitudinal study of the risk factors and natural history of pain in DPN,” the authors wrote.

Post-stroke cognitive outcomes and sex. At 90 days post-stroke, women had significantly worse cognitive outcomes than men, according to a new study published in the Journal of the American Heart Association. The study sample included 1,227 participants from the 2009-2016 Brain Attack Surveillance in Corpus Christi project who had first-ever ischemic stroke or intracerebral hemorrhage and survived 90 days after stroke. Researchers assessed post-stroke cognitive function with the Modified Mini-Mental State Examination, which had a range from 0-100.

Women scored 2.96 points worse on this exam than men at 90 days post-stroke, and the prevalence of dementia in women was 8% higher than in men (35.6% and 27.6%, respectively). What do researchers believe causes this disparity? “The differences were attributable to sociodemographic and pre-stroke characteristics, especially widowhood status,” the authors wrote. “Potential mechanisms linking widowhood to dementia in the acute post-stroke stage warrant further investigation to inform interventions addressing the unique care needs of women stroke survivors with dementia and cognitive dysfunction.”

Can children with epilepsy benefit from telemedicine? In the age of COVID-19 and at a time when many kids spend more time with their screens than just about anything else, it only seems natural that medical professionals turn to telemedicine to reach kids. But is telemedicine an effective way to deliver care to children with epilepsy? It seems that way, according to a new studyconducted during the COVD-19 pandemic in an underserved area of India with rugged terrain.

In the study, researchers collected data from clinical and epilepsy-related telephonic consultations for children from 1 month to 18 years of age performed between March 26 and May 17. Using voice call, text messages, and picture/video messages, physicians performed suitable changes in the dose and brand of antiepileptic drug (AED) regimens, prescriptions for new AEDs, and referrals for hospitalization. They found that telemedicine can act as a feasible and effective option in children with epilepsy even in remote regions and during a pandemic, and that clinicians can accurately change AEDs and cue emergency response over teleconsultation in children with uncontrolled epilepsy. The success of telemedicine in such a remote location during a pandemic suggests that the technology can be an effective strategy for the management of epilepsy in most circumstances.

Latest in Journal Summaries

High heat generation is associated with good neurologic outcomes in out-of-hospital cardiac arrest survivors

Sleep should be added to heart health metrics, study finds

Pulse pressure variability associated with unfavorable outcomes in ischemic stroke treated with IV thrombolysis

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Upcoming Medical Meetings

The following meetings have been changed to virtual conferences:

Spino-Plastics Reconstruction Conference, Houston, TX, August 1.

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.

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