Common drugs and dementia risk, blood pressure and memory, and new insight into the brain’s pliancy

The world in general seems crushed under the weight of the COVID-19 pandemic, as researchers hurry to nail down the novel coronavirus and how to treat it. But research in other specialties—like neurology—goes on, and disorders of the brain, their causes, new diagnostics, and new treatment and management options take center stage.

Neuro Flashback

Over 100 years ago, in 1906, Alzheimer disease (AD) was first described by Alois Alzheimer, MD. He described a patient known as “Auguste D” who had died of an unusual mental illness. The woman had experienced memory loss, language difficulties, paranoia, and unpredictable behavior. Upon autopsy, Dr. Alzheiemr described shrinkage in and around nerve cells in the patient’s brain. He also noted the presence of many abnormal clumps—now known as amyloid plaques—and tangled bundles of fibers (now call neurofibrillary or tau tangles). Today, these “clumps” and “tangles” are still considered the hallmarks of AD.

In the News

Neuropsych and COVID-19. The link between COVID-19 and CNS symptoms is growing, and includes things like an increased incidence of stroke, delirium, and the loss of olfactory and tasting abilities. But, even after the current coronavirus pandemic, there may be a neuropsychological price to pay, according to researchers. In fact, history has shown us that neuropsychiatric symptoms—including encephalopathy, mood changes, psychosis, neuromuscular problems, and demyelinating effects—often accompany acute viral infections or come later in patients who have recovered. And studies of past respiratory viral pandemics have shown that a wide array of neuropsychiatric symptoms can arise, including insomnia, anxiety, depression, mania, suicidality, and delirium. These researchers warn that the effects of the current pandemic on neuropsychiatric states is as yet unknown, but it may be significant and long-lasting. They urged monitoring of neuropsychiatric symptoms and neuroimmune status in anyone exposed to SARS-CoV-2.

It’s all about growth. The regenerative powers of the brain are incredible. New preclinical findings explain that when adult brain cells in the cortex are injured, they revert to their “brand-new” embryonic state. And because they’ve reverted to such an immature state, they can re-grow new connections and help restore lost functions. This completely blows away previous thinking that the adult brain is “static, terminally differentiated, fully established and immutable,” noted researchers. The findings also up-ended more recent research showing that both the hippocampus and the subventricular zone constantly produce new brain cells to replenish these regions throughout life by showing that the brain can repair and replace cells not only in these two areas, but in the cortex as well.  But wait—they’re not done with their findings yet. These researchers also found that the Huntingtin gene (HTT) is intrinsically involved in promoting neuronal growth and repair. And HTT mutations cause Huntington disease. In mice genetically lacking the HTT gene, neuronal regeneration and sprouting were significantly decreased after spinal cord injuries.

What the heck is ‘reverse dipping’? Something called “reverse dipping” could magnify the bad effects of hypertension. But what in the world is “reverse dipping”? In most of us, nighttime BPs go down—something known as dipping. But for some, night-time pressures either stay the same, or go up—reverse dipping. The bad news for them is that this reverse dipping, coupled with hypertension, was associated with an increased risk for vascular damage and memory problems, according to a recent study of subjects (mean age: 59 years) enrolled in a Venezuelan study of aging. Most had high blood pressure (59%). At night, BP dipped in 50%, while in 40% it remained stable, and in 10%, it increased.

Researchers used brain scans to search for white matter hyperintensities as markers of damage from vascular disease. Participants with hypertension and reverse dipping had more than two times the number of white-matter hyperintensities compared with others and averaged more than 6 cm3 of periventricular white matter changes, compared with an average of 2.5 cm3 or less.  More bad news: Hypertensives with reverse dipping also scored lower on memory tests, with an average score of about 33 compared with 40 in other participants. More studies are needed to tease out the true relationship between reverse dipping, white matter changes, and memory problems. Stay tuned.

Communications breakdown. We all know that stress is not good for your body. But did you know that stress can actually remodel your brain, making efficient communications—the raison d’être of brain cells—difficult if not impossible? Really, stress just seems to cause one long chain of hard knocks to the brain’s communication systems. In a mouse model, researchers have found that just one stressful event can cause quick and long-lasting changes in the astrocytes of the brain by causing them to shrink away from synapses.

This not only effects the astrocytes’ ability to clean up neurotransmitters after they’ve shuttled info between the nerve cells, but makes the synapses jump over larger distances to transmit info. This can result in the disruption of communications. And, norepinephrine—the stress hormone—can suppress the pathway that leads to production of GluA1, a protein that allows nerves cells and astrocytes to “talk.”  But take heart. The good news here is that by identifying the involvement of GluA1, researchers now have a new therapeutic target to focus on, to possibly prevent or even reverse stress-induced damage, and treat the common neuropsychiatric disorders related to stress caused by traumatic events like anxiety, depression, and drug addiction. How’s that for looking on the bright side?

Neuro Trivia

What is photoptarmosis?

More commonly known as “sun sneezing,” photoptarmosis is a common nerve reaction caused by exposure to bright light. It often happens when someone suddenly walks outside into the sun and is stricken with uncontrollable sneezing fits. These fits are not harmful but can be dangerous if they occur while driving a car or piloting a plane, for example.

Novel Diagnostics

Quick, easy, accurate. In a memory clinic, the Brief Assessment of Impaired Cognition (BASIC) and the Brief Assessment of Impaired Cognition Questionnaire (BASIC-Q) were found to be great tools to use to identify patients with mild cognitive impairment (MCI). Even better is that both can be given to patients in 5 minutes or less. Researchers validated these two tests in a study of 163 patients, and found a sensitivity of 86% and a specificity of 89% for the BASIC test, and 88% and 88%, respectively, for the BASIC-Q. These results were impressive, especially compared to the Mini Mental State Exam, which had a low sensitivity (61%) and only moderate specificity (72%). Not only did BASIC and BASIC-Q accurately differentiate mild cognitive impairment from normal, these quick tests also differentiated between mild cognitive impairment and dementia. Researchers are planning to validate these tests in general practice/primary care settings next.

Just a simple MRI. How would you like a test that could tell you the current state of your patients with multiple sclerosis (MS)? It may just be possible, with MRI. Here’s what researchers found: In patients with multiple sclerosis (MS), three basic MRI biomarkers could help clinicians determine current disease severity and disability: gray-matter atrophy, white-matter atrophy, and the number of T1-hypointesnse areas. All are significant indicators of MS. Here’s why: Brain atrophy is frequently seen in MS patients in both the gray and white matter, and adversely affects motor function. T1-hypointense lesions—aka, T1 black holes—are common with MS and in cases of severe CNS damage.

Researchers had 42 patients with MS (mean age at onset: 26.7 years; mean disease duration: 12.4 years) undergo one 3-tesla whole-body MRI scan that included fat-saturated 3D T2-FLAIR and 3D T1-weighted fast field echo sequences. They found a significant correlation between patients’ EDSS scores and the volume of gray and white-matter atrophy and the number of T1-hypointensity areas. They also found that a simple T1-hypointensity count accurately reflected the clinical severity and disease activity in these patients. And this is why the news is even better, say researchers: “Because T1-count can be manually counted without specific volumetric software, this simple information would be quite useful in routine clinical practice to estimate the ongoing disease activity in each MS patient.”

Novel Treatments

Ice, ice baby. Cooling the brain may be a simple, effective way to treat concussions someday. Engineers at the University of Wisconsin-Madison found that cooling brain cells in a dish could mitigate damage. When you consider that in the United States, nearly 3.8 million sports-related concussions occur annually, along with 1.7 million new cases of traumatic brain injury, there is a real need for treatments. These engineers created a network of neurons in a dish that were mechanically stimulated to induce injury and cell damage like that seen with concussions. Cooling the cells to 33° C (91.4° F) was the most protective at 24- and 48-hours post-injury. But, a caveat is in order—there was a sweet spot. Thirty-one degrees Celsius was actually bad for the cells. And, importantly, cooling needed to start within 4 hours of the injury and go on for at least 6 hours. Researchers concluded that too little or too much cooling and waiting too long after injury are no-no’s.  How does it work? Cooling the cells actually turns off damaging biochemical pathways in the cells. Despite the injury, the cooled cells stayed healthy and normal. After 6 hours, the cells were brought back up to normal body temps and voila! The molecular switches were still shut off. More studies are needed, but wouldn’t it be “cool” if cooling was an effective treatment for concussion?

On-again-off-again. For the on-demand rescue of sudden “off” periods in patients with advanced Parkinson disease (PD), researchers are developing a new sublingual film formulation of apomorphine. It improved motor scores at 30 minutes in a multicenter trial of 141 patients with advanced PD.  Compared with placebo, sublingual apomorphine also increased the number of patients who rated themselves at full “on” response within 30 minutes. The most common adverse events were nonserious oropharyngeal events like mucosal edema and tongue pain—almost one-third of patients discontinued treatment due to these. Researchers hope that once this formulation is approved, it will be a more convenient rescue option compared with the subcutaneous apomorphine injections

Giving encephalitis its due. It seems that COVID-19 antibodies aren’t the only ones getting some attention these days. In fact, intravenous immune globulin (IVIG)—a product prepared from a pool of immunoglobulins (antibodies) from the plasma of thousands of healthy donors—may effectively reduce the frequency of seizures, which are common with autoimmune encephalitides. In a small randomized study of only 17 patients who had either anti-leucine-rich glioma inactivate 1 (LGI1) or anti-contactin-associated protein-like 2 (Caspr2) encephalitis and suffered from frequent seizures, IVIG reduced the number of seizures compared with placebo by the fifth week of treatment. Researchers also saw a trend towards improved cognitive outcomes with IVIG. There’s something to be said for a good antibody response!

New in Patient Management

Not what we thought. Benzodiazepines, Z-drugs, and other anxiolytics are commonly used to treat patients with affective disorders, and they are some of the most commonly prescribed drugs in the world. Their cognitive side effects, however, have raised the question of whether these agents may increase the risk of dementia. To study this, Danish researchers conducted a nationwide, nest, case-control study, and found that this was not the case at all. Among the 171,287 patients who had any use of these drugs between 1996 and 2015, benzodiazepines or Z-drugs were not associated with dementia in either the cohort analysis or a nested case-control design. In fact, these agents may even have a slightly protective effect against dementia, they found. In the nested case-control study, there was a slightly higher odds ratio of dementia in patients with the lowest use of benzodiazepines or Z-drugs compared with no lifetime use. And, patients with the highest use had the lowest odds of developing dementia. Sounds like fodder for some more studies!

Migraine-stroke link. Consider that women are three times more likely than men to have migraines. Also consider that high estrogen levels increase the risk of migraine with aura, venous thromboembolism, and stroke. In light of these considerations, it’s no surprise that in a review of the epidemiological evidence of the migraine-stroke relationship, researchers found that migraine with aura was associated with multiple risk factors for stroke, including hypertension, hyperlipidemia, diabetes, atrial fibrillation, patient foramen ovale, and smoking. In women, migraine with aura was also associated with biomarkers of endothelial activation, hormone contraceptive use, pregnancy, and venous thromboembolism. These findings suggest that some auras could be secondary—or caused by ischemia related to microemboli of thrombosis. They also found that ischemic stroke associated with migraine with aura is more common in women less than 45 years old who had a high frequency of migraine attacks, hormonal contraceptive use, pregnancy, and preeclampsia. Finally, they concluded, cardioembolism may play a vital role in cerebral infarctions associated with migraines with aura. Based on their results, researchers recommended diagnostics in women with migraine with aura that are similar to an evaluation for transient ischemic attack, because preventive treatment aimed at the ischemic origin of a secondary aura could prevent both migraine and stroke.

The sunshine vitamin. Clinicians should screen older patients for vitamin D deficiency regularly and treat those with low vitamin D levels. Here’s why: Researchers found that vitamin D deficiency was associated with gait and balance in elderly patients. In a cohort of 370 elderly patients, those with the lowest basal serum 25-hydroxy D vitamin (25[OH]D) levels—less than 10 ng/mL—had lower Basic and Instrumental Activities of Daily Living scores, as well as lower Performance Oriented Mobility Assessment (POMA) scores and lower total scores. After 12 months, POMA balance and total scores improved in patients in this lowest group who had reached a sufficient 25 (OH)D level. After 12 months, they also found that mean POMA balance, gait, and total scores improved in all patients in whom 25(OH)D level was ≥ 20 ng/mL. All in all, pretty good results from a simple vitamin.

An unfortunate coupling. The association between pulse pressures and ischemic stroke is strong, according to researchers in China. They did a retrospective study in 3,315 elderly patients with hypertension (mean age: 71.4 years; 44.5% male). Over a mean follow-up of 5.5. years, there were 206 first ischemic strokes. And when they looked closer, researchers found that per SD mmHg increments in pulse pressures were linked to a 17% increase risk of ischemic stroke. Plus, patients with the highest pulse pressures had the highest risk for ischemic stroke. In a subgroup analysis, the list of what increased the risk of ischemic stroke included ≥ 70 years old, male gender, smoking, drinking alcohol, diabetes at baseline, overweight, uncontrolled blood pressure, and not taking antihypertensives. The message is pretty clear: When it comes to pulse pressures, low is the way to go.

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Upcoming Medical Meetings

The following meeting has been changed to a virtual workshop:

14th Annual Drug Discovery for Neurodegeneration Workshop , in Philadelphia, PA, April 26-28, 2020, has been changed to a virtual workshop that will be hosted online.

The following meetings have been rescheduled:

American Spinal Injury Association (ASIA) 2020 Annual Scientific Meeting, to be held in in New Orleans, LA, May 3-7, 2020, has been rescheduled for October 4-7, 2020, and will remain in New Orleans, LA.

Mid-Atlantic Neurocritical Care Symposium , to be held in Baltimore, MD, May 21-22, 2020, has been rescheduled for 2021.

The following meeting has not yet been rescheduled:

10th Annual Traumatic Brain Injury Conference,  to be held in Arlington, VA, June 1-2, 2020.

View more upcoming Neuro meetings

 

 

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