A cure for Alzheimer’s dementia, controversial stroke research gets a second look, and detecting Alzheimer’s before symptoms appear

We’re kicking off the new year with some great news about smells. While the overcast winter weather isn’t always much to look at, it can be a feast for the olfactory senses. The smells of fragrant burning logs and seasonal cooking waft right in. Along those lines, we’ve got some news about a treatment that stimulates olfactory regions to help alleviate or suppress the progression of Alzheimer’s disease. We also cover a new type of cell that could represent a breakthrough in Alzheimer’s research, findings on chronic kidney disease as a risk factor for nerve damage, and what small vessel disease means for risk of stroke.

Neuro Flashback

In 2006, the Nobel Assembly at Karolinska Institute awarded the Nobel Prize in Physiology/Medicine jointly to Andrew Fire and Craig Mello for their discovery of RNA interference, which is gene silencing triggered by double-stranded RNA. RNA interference is one of the fundamental mechanisms for controlling the flow of genetic information in cells. The win prompted an enormous level of hype and investment in research, but a series of clinical failures and safety issues led large drugmakers to abandon the approach. However, determination has paid off for some. Ionis Pharmaceuticals and Biogen collaborated on Spinraza, a so-called antisense drug that became the first effective treatment for spinal muscular atrophy. It was approved in late 2016. Moderna Therapeutics also rode a wave of promising messenger RNA-based medicines to the most lucrative biotechnology initial public offering of all time in 2018. While it still has some way to go, recent studies have shown that RNA-based medicines show promise as a treatment for various neurological disorders.

In the News

Cell discovery could lead to AD diagnosis breakthrough. Can you picture a world in which Alzheimer’s disease (AD) could be detected long before the emergence of symptoms? In as little as 5 years, that could be reality. The recently announced discovery of vector trace cells might lead to the development of a test that can diagnose AD before symptoms appear.

Vector trace cells operate sort of like the brain’s GPS system. They help us store information about the distance and direction of objects or places, and we use them to recall locations. These cells also live in the area of the brain that’s the first to start deteriorating due to AD. The discovery of these cells—details of which were published in Nature Neuroscience—could lead to methods that facilitate earlier diagnosis of the disease, and possibly even more effective treatment.

Scientist vindicated for controversial research on stroke. For years, Anne Abbott, PhD, was spurned by the scientific and medical community for her views that lifestyle changes and medications alone can protect against stroke, without the need for surgical interventions. Dr. Abbott, however, was recently vindicated after receiving the John Maddox prize.

She had spent years railing against the medical establishment, members of which have tended to press for things like carotid surgery and stents as the primary preventative measure against stroke. Instead, Dr. Abbott said, large numbers of strokes can be prevented simply with medication and lifestyle changes, like anti-cholesterol drugs and more exercise. The associate professor of neuroscience at Monash University in Melbourne told The Guardian that for years she was told to not publish her findings on the matter. Now, not only has she been recognized with the same prize that Anthony Fauci, MD, earned this year, but a growing number of doctors have adopted her line of thinking and are accepting her research.

‘Super-ager’ genes may offer clues for AD prevention. No, they’re not a new team of elderly crime-fighters, although that would be pretty cool. “Super-agers” are those individuals who exhibit exceptionally high cognitive function well into old age. And a new study indicates that their genes may be the reason why they have lower levels of tau protein tangles and beta-amyloid protein plaques in their brains.

The study, which was published in JAMA Network Open, looked at the brain images of 94 participants, all older than 80 years, and found that some had brains that looked similar to those who were far younger and healthier. These super-agers tended to have a genetic mutation that may help protect them from damaging the protein build-up in the brain that characterizes AD and other forms of dementia. Because the study didn’t take into account lifestyle factors, which likely play a role in protecting from AD, more research is crucial. But the study does indicate that genetics do, to some extent, determine Alzheimer’s risk. Could this lead to better therapeutic options?

Neurological problems lead to higher risk of dying from COVID-19. As the pandemic continues, a growing body of research suggests that certain individuals are at a higher risk of dying from COVID-19. A new study finds that those hospitalized with COVID-19 and neurological problems, including stroke and confusion, have a higher risk of dying than other COVID-19 patients.

The study, published in Neurology, looked at data from more than 4,700 COVID-19 patients admitted to the Montefiore Health System during a 6-week period between March 1, 2020 and April 16, 2020. Of those patients, 12% had neurological problems severe enough to prompt brain imaging. This group was then compared to COVID-19 patients of a similar age and disease severity but with no neurological problems who were admitted during the same period. Researchers found that individuals with stroke were twice as likely to die (49% mortality) compared with the control group (24% mortality). Similarly, people with confusion had a 40% mortality rate compared with 33% within the control group. These findings could help physicians to identify and focus treatment efforts on individuals most at risk and could ultimately lead to a decrease in COVID-19 deaths.

Neuro Trivia

How often do people die from stroke in the United States?

In the United States, one person has a stroke every 40 seconds, and a stroke results in death every 4 minutes.

Novel Diagnostics

Depression could be a sign of worse things to come. It may seem natural to expect patients to experience a downturn in mood after spending time in the ICU. But according to a new study, depression may predict long-term cognitive impairment (LTCI) in survivors of critical illness.

The study, published in the Journal of Trauma and Acute Care Surgery, followed up with more than 500 ICU survivors at 3 and 12 months following discharge from the hospital. Researchers sought to investigate whether depression and post-traumatic stress disorder are independently related to long-term cognitive impairment. Their primary outcome was global cognition using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Trail Making Test, Part B, a test of executive functioning. Researchers found that patients experiencing depression at 3 months had lower RBANS and lower Trail B scores at both intervals. The findings indicate an independent association of early post-ICU depression, but not of PTSD, with coexisting LTCI, even when controlling for past ICU delirium. This suggests that treatment for depression could be a novel intervention area for LTCI prevention in ICU survivors. So, don’t discount cases of ICU blues. They could be a sign of other latent conditions.

Feeling anxious? That may indicate the progression of PD. Parkinson’s disease often comes with neuropsychiatric symptoms, like depression, psychosis, and anxiety. But could these symptoms be a marker of the progression of the disease? According to a new study, there appears to be a correlation between symptoms like these and brainstem pathologies in Parkinson’s patients.

The study, published in the American Journal of Geriatric Psychiatry, looked at whether there’s a link between neuropsychiatric symptoms and the severity of neuropathology in the substantia nigra and locus coeruleus. Researchers looked at the brains of 175 participants with a primary pathological diagnosis of Parkinson’s disease to establish the burden of neuronal loss and gliosis and Lewy body pathology within the locus coeruleus and substantia nigra. They then monitored each patient for any of the aforementioned symptoms. The findings indicate that psychosis and depression in those with Parkinson’s disease are associated with the underlying neurodegenerative process and demonstrate that cell loss and gliosis may be a better marker of neuropsychiatric symptoms than Lewy body pathology.

Cerebrospinal fluid biomarkers get top marks for accuracy. Diagnosing Alzheimer’s can be tricky business, but new research brings a consistent flow of new tools and methods. Now, the findings of a longitudinal data analysis has found a high degree of accuracy in several emerging CSF biomarkers for the progression of Alzheimer’s disease, which stands to improve diagnostic capabilities.

The study, published in the European Journal of Neurology, looked at the diagnostic accuracy of recently emerged CSF markers for Alzheimer’s disease (AD) in reference to brain amyloid positron emission tomography (PET). Researchers also sought to determine if these biomarkers can help distinguish AD from other dementias. They looked at 319 individuals, monitoring their levels of amyloid‐β (Aβ) 1–42, total tau (t‐tau), phosphorylated tau, Aβ40, Aβ38, beta‐site amyloid precursor protein cleaving enzyme 1 (BACE‐1), neurogranin (ng), phosphorylated neurofilament heavy‐chain, and α‐synuclein (α‐syn) in CSF. Fifty-seven of the participants also underwent a PET scan. The findings suggest that emerging CSF markers, especially ng/BACE‐1 ratio and their combinations with core AD CSF markers (all AUCs > 0.85), have a high degree of accuracy in discriminating amyloid PET positivity.

Chronic kidney disease touches a nerve. The sensory and motor nerve deficits that are common in older adults are often associated with loss of functional independence. A new longitudinal study has discovered that chronic kidney disease appears to be a risk factor for peripheral nerve impairment in older adults.

The study, published in PLoS Neglected Tropical Diseases, used data from the Health, Aging and Body Composition Study, which looked at 1,121 people from 2000-2008. Researchers analyzed individuals who initially had non-impaired nerve function, with a median age of 75 years. The findings showed that, over the 7-year study period, community-dwelling older adults who had pre-existing CKD experienced new and worsening sensorimotor nerve impairments. CKD patients had 2.37 higher adjusted odds of worsening monofilament insensitivity, though not with development of new monofilament insensitivity.

Novel Treatments

Could copper be the key to an AD cure? Alzheimer’s disease is characterized by the presence of amyloid plaques in the patient’s brain. These plaques gather copper, leading to an AD patient’s brain containing roughly 5 times as much as the brain of a healthy individual. Recently, a team of scientists announced that a newly developed molecule that regulates the circulation of copper in the brain could serve as an effective treatment for AD.

The molecule, developed by CNRS scientists from the Guangdong University of Technology and Shenzhen University in China, extracts copper that’s trapped in amyloid plaques. The copper is then reintroduced into the brain’s normal enzymatic circuit, which needs copper to function. So far, the molecule has been tested on mice and has been found to inhibit memory loss after oral administration. These promising results have led scientists, who have patented the molecule, to start seeking a pharmaceutical partner to develop preclinical trials for a possible drug. It could prove a copper-bottomed treatment for AD.

That’s the smell of a promising treatment! Olfactory nerves have terminals deep within regions of the brain that influence things like memory. This may be why the olfactory system often becomes dysfunctional during the early stages of Alzheimer’s and Parkinson’s diseases—as well as why olfactory function can play a key role in regaining consciousness after brain injuries. All of this prompted a research team at the University of Otago in New Zealand to look into whether stimulating a person’s sense of smell could help prevent conditions like Alzheimer’s disease.

The research is now focused on the development of a non-invasive, wearable electrical stimulation system to target the olfactory regions. The contraption produces small electrical pulses on the skin to stimulate the olfactory nervous system. The idea is that areas of the brain that tend to be impacted by the likes of Alzheimer’s and Parkinson’s could be jump-started to help alleviate symptoms or even suppress the progression of those conditions. It also has the potential to help with things like coma recovery. The wearable simulator is due to undergo clinical tests soon. Hopefully, we’ll all be able to say “smell ya later” to AD.

New drug may help PD symptoms. The symptoms of Parkinson’s disease can be debilitating, but new treatments to help mitigate them are being developed all the time. Recently an open-label study has shown promise for the drug zuranolone. The study indicates general good tolerability, as well as efficacy in improving tremor symptoms, in patients with Parkinson’s who were on stable doses of concurrent dopaminergic agents.

Zuranolone (SAGE-217) is an investigational oral neuroactive steroid (NAS) gamma-aminobutyric acid A (GABA A) receptor–positive allosteric modulator (PAM). Researchers involved in the phase 2 study on the drug focused mainly on its impacts on tremor symptoms. The study involved 14 elderly PD patients who received zuranolone capsules (20-30 mg) for 7 days. By the end of the treatment period, patients reported an improvement of 40% measured on the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II/III Tremor Score. Researchers saw improvements in the motor score, the nonmotor experiences of daily living, and motor experiences of daily living scores (MDS-UPDRS Parts I and II, respectively). Beyond this, patients did not exhibit any serious adverse events — and none of the patients opted to discontinue treatment. The findings suggest that NAS GABA A receptor PAMs could be effective as a supplementary treatment for PD.

CGRP receptor antagonist might fight migraines. There’s been yet another possible breakthrough in the seemingly endless quest to find an effective treatment for migraines. A recently published phase 2 study found that rimegepant, the first calcitonin gene-related peptide receptor antagonist approved in the United States for the acute treatment of migraine, may help prevent migraine headaches as well.

The study—published in The Lancet—looked at 747 adults with episodic and chronic migraine. Participants were randomly given either oral rimegepant 75 mg every other day or matching placebo over the course of 12 weeks. Researchers found that, during the final 3 weeks of the study period, treatment with rimegepant resulted in 4.3 fewer migraine days per month, compared with 3.5 fewer monthly migraine days with placebo, on average (mean difference, –0.8 days; 95% CI, –1.46 to –0.20; P=0.0099). Beyond this, roughly half of those taking rimegepant experienced at least a 50% reduction in the average number of moderate-to-severe migraine days per month, compared to 41% in the placebo group. And who wouldn’t want to celebrate a headache-free day?

New in Patient Management

Montelukast may give you nightmares. The various possible side effects of montelukast for asthma are well established. But a new study has found that, for children with asthma, neuropsychiatric adverse drug reactions for montelukast are far more common than previously thought, and they can lead to an impairment in quality of life.

The study, published in the Journal of Asthma, looked at 125 patients with asthma aged 3 to 18 years. Researchers sought to detect the neuropsychiatric adverse drug reactions (ADRs) that occurred in real time and to analyze the impact of these ADRs on quality of life. Patients and their parents were given a neuropsychiatric complaint assessment questionnaire at the beginning of the study and at the end of the second week of treatment. The KINDL QoL scale was also administered to patients during this period. Researchers found that neuropsychiatric ADRs occurred in 78 (62.4%) of the 125 patients. These patients recovered when the drug was withdrawn. Compared with pretreatment, temperamental behavior, nightmares, and sleep disorders occurred significantly more often in patients using montelukast. Researchers concluded that neuropsychiatric ADRs induced by montelukast are far more common than recorded in the literature and negatively affect the quality of life of children.

Cue up the shunt surgery quicker for a better iNPH survival rate. Delaying treatment is never a good idea—and a new study has found this is particularly true for patients with idiopathic normal pressure hydrocephalus. A long‐term follow‐up case‐control study of patients who experienced a delay of treatment found that earlier shunt surgery improves survival.

The study, published in the European Journal of Neurology, looked at the effect of delayed vs early planning of shunt surgery on survival in patients with iNPH via a long‐term follow‐up case‐control study of patients exposed to a severe delay of treatment. Researchers found that an administrative and economic failure between 2010-2011 at a university hospital resulted in an unintentional delay of planning of treatment for a group of iNPH patients, which provided the perfect cohort for a study of this kind. Those 33 patients waited between 6 to 24 months for shunt surgery. Researchers compared these to 69 iNPH patients who received surgery within 3 months. They found that crude 4‐year mortality was 39.4% in the delayed treatment group, compared to 10.1% in the early treatment group.

For signs of Behçet’s, look to the third ventricle. Assessing the progress of a disease is a core tenet of patient management, and biomarkers are often the canary in the coalmine. A recently published longitudinal comparative analysis has found that the width of the third brain ventricle may be a highly sensitive biomarker in chronic progressive neuro-Behçet’s disease (CPNBD).

The study, published in the Journal of Neurological Sciences, saw researchers perform a retrospective, longitudinal comparative analysis of the clinical features and brain MRI in patients with CPNBD. Participants were classified into 3 groups: NBD with acute encephalomeningitis alone (Group A, 8 patients with acute neuro-Behçet’s disease), primary progressive CPNBD (Group B, 3 patients), and a combination of acute encephalomeningitis, and chronic progression (Group C, 2 patients). To assess the progression of CPNBD during treatment, researchers looked at the monthly rate of enlargement of the width of the third ventricle (ΔWTVm) and relative value of ΔWTVm to the transverse cerebral diameter (ΔWTVIm). They found that treatment for CPNBD tended to minimize ΔWTVm and ΔWTVIm in some patients. As such, the width of the third ventricle has emerged as a possible biomarker of high sensitivity for early diagnosis and treatment efficacy in patients with CPNBD.

Small vessels mean higher risk of stroke. When it comes to patient management for stroke survivors, preventing recurrence tops the priority list. New data from a recently published study may help with this goal in certain patients. The data suggest that, for patients treated with anticoagulation for atrial fibrillation after ischemic stroke or transient ischemic attack, small vessel disease is associated with an increased risk of recurrent ischemic stroke during follow-up.

According to an article published in NeurologyLive, researchers looked at data from 1,419 patients, a little over half of whom had SVD. The IS rate during follow-up in patients with any SVD was 2.20 per 100 patient years (95% CI, 1.60–3.02), compared to 0.98 per 100 patient years (95% CI, 0.59–1.62) in patients without SVD. While the findings didn’t demonstrate that baseline SVD is associated with the subtype of recurrent IS, they did show that the absolute rate of recurrent small artery occlusion in patients with baseline SVD was higher than in those without SVD. The researchers pointed to a possible explanation: SVD is associated with risk factors for atherosclerosis, which is a known predictor of stroke recurrence. The findings suggest that oral anticoagulation is not as effective in patients with atrial fibrillation who have SVD as it is in those without. Therefore, this patient group should be a focus for trials of new prevention strategies.

Latest in Journal Summaries

Identifying the distinctive phenotypes in MS.

IV hydrogen therapy with intracisternal magnesium sulfate infusion in severe aneurysmal subarachnoid hemorrhage.

Risk factors for acute stroke-associated pneumonia and prediction of neutrophil-to-lymphocyte ratios.

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Upcoming Medical Meetings

The following meetings are entirely virtual:

International Neuropsychological Society (INS) 2021 Annual Meeting. February 3-6, 2021.

Mayo Clinic Multiple Sclerosis and Autoimmune Neurology Update 2021 – Livestream. February 5-6, 2021.

The following meeting is scheduled to have an in-person and virtual component:

American Academy of Neurology 73rd Annual Meeting (AAN 2021). San Francisco, CA. April 17-23, 2021.

 

 

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