How the brain benefits from stress, a newly approved MS drug, and the neurological implications of…owning a cat?

Scientists have long thought that schizophrenia may be associated with the zoonotic parasite Toxoplasma gondii. While evidence for that hypothesis remains elusive, this week we’re bringing you a study that’s found evidence of bloodstream Bartonella infection in patients with schizophrenia—which suggests cats and schizophrenia may really be linked after all. In this issue, you’ll also find a study indicating stress may bring cognitive benefits, research that suggests the ubiquitin-like protein FAT10 may be a target for Parkinson’s treatments, and more. 

Neuro Flashback

In 1936, Walter J. Freeman II performed the first lobotomy in US history. At the peak of his career, Freeman was a celebrated physician and scientist. He served as the first chairman of the Department of Neurology at George Washington University, and he was a tireless advocate of surgical treatments for mental illness. His eccentric appearance, engaging personality during interviews, and theatrical demonstrations of his surgical techniques earned him popularity with local and national media—and, he performed more than 3,000 prefrontal and transorbital lobotomies between 1930 and 1960.

We can all guess how this ended, though. Poor patient outcomes, critical portrayals in media, and increased regulatory scrutiny contributed to the lobotomy’s decline in popularity. The development of antipsychotic medications eventually relegated the lobotomy to the medical dustbin, and Freeman’s reputation deteriorated. Today, despite significant advancements in technique, oversight, and ethical scrutiny, neurosurgical treatment of mental illness still carries social stigma.

In the News

Stress is a killer, but could it lead to better cognitive function? We all feel stressed sometimes, and past research has linked excessive stress to a litany of negative outcomes, like chronic illness and poor emotional well-being. However, while those who experience very little or no stress are more likely to experience better daily well-being and fewer chronic health conditions, a recent study showed they are more likely to have lower cognitive function.

The study, published in Emotion, used data from 2,711 participants who completed a short cognition test. The participants were then interviewed on 8 consecutive days, answering questions on their mood, any chronic conditions they may have, physical symptoms like headaches, coughs, or sore throats, and what they did during that day. Researchers found that roughly 10% of participants reported experiencing no stressors throughout the study, and those individuals were less likely to have chronic health conditions and more likely to experience better moods. These same participants, however, performed lower on the cognition test, with the difference equaling more than 8 years of aging. Researchers concluded that daily stressors, though inconvenient, may actually benefit the brain, possibly by requiring the brain to exercise to find solutions. 

A stay in prison could spell dementia. America’s incarcerated population is aging. By 2030, it’s estimated that adults over 50 years of age will account for one-third of all prisoners. Given that evidence indicates that incarceration accelerates the aging process, the findings of a new study on dementia should come as no surprise: There was a high occurrence of dementia in older adults returning to their communities from prison, suggesting that the detection of those with mild cognitive impairment during incarceration should be a priority. 

The study, published in the American Journal of Geriatric Psychiatry, examined 28,267 individuals aged 50 years or older who were Medicare beneficiaries and re-entered the community from incarceration between October 1, 2007 and December 31, 2017. Researchers examined the prevalence of dementia among this cohort before comparing it to 141,335 never-incarcerated controls. They found that the reentry cohort had, on average, a 32% higher 10-year prevalence of Alzheimer’s and mild cognitive impairment (MCI) diagnoses compared to the control group, with the most significant differences observed among those aged 65-74 years. The findings point to the importance of identifying those with MCI during incarceration, so re-entry care services can be implemented to slow the progression of cognitive decline.

Brain cell death-drive mechanisms may actually protect against Alzheimer’s. Every once in a while, a piece of research is published that flips the script entirely. A new study has done just that, showing that mechanisms in brain cells—which were previously thought to be associated with cell death in Alzheimer’s—may provide a protection by resisting Alzheimer’s disease cell death and potentially prolonging progression of the disease.

The study, published in the Proceedings of the National Academy of Sciences, used a method called fluorescent ubiquitination-based cell cycle indicator (FUCCI), which allows for the live monitoring of the cell cycle via temporal expression of fluorescence markers of G0/1 or S/G2/M cell cycle phases. It’s commonly used in cancer and developmental biology research, but it has never been used to study neurons in the context of neurodegenerative diseases, until now. Researchers found that the process formerly thought to drive the disease appears to be protecting the neurons from Alzheimer’s cell death. The findings pave the way for a significant rethink on how researchers investigate treatments for the disease.

Star-shaped brain cells may dictate how deeply we sleep. For decades, researchers have been examining neurons to figure out why some people sleep longer and more deeply than others, and why we all appear to need different amounts of sleep to feel well-rested. Now, new research has taken a step forward in this field by examining a brain cell type that has received little attention. The study has confirmed that astrocytes can influence how long and how deeply animals sleep. The findings could open new avenues for treating sleep disorders and enhance our understanding of brain diseases linked to sleep disturbances, like Alzheimer’s.

Past research has indicated that astrocytes may help trigger the slow-wave activity observed in the brain during sleep. In the new study, published in Elife, researchers tracked changes in slow-wave brain activity of sleeping mice while manipulating astrocytes using a drug that can switch the cells on in genetically engineered animals. By activating astrocytes, they could induce more slow-wave activity, and therefore more sleep, in the mice. Additionally, researchers found that two receptor molecules on the astrocytes—called the Gi and Gq receptors—appear to control two different aspects of sleep. Activating Gq receptors made the mice sleep longer, while engaging Gi receptors induced a much deeper sleep without affecting sleep duration. The findings pave the way for higher quality, higher quantity snoozing for all.

Neuro Trivia

Question: How much does the brain shrink as we age?

Answer: The volume and/or weight of the brain declines at a rate of around 5% per decade after age 40. A healthy lifestyle can offset some of the adverse shrinkage effects.

Novel Diagnostics

Pilot study links schizophrenia to Bartonella. Researchers have been exploring the relationship between infections and neuropsychiatric disease for years. For example, past research has suggested that cat ownership is associated with schizophrenia due to the zoonotic parasite Toxoplasma gondii, even though conclusive evidence remains elusive. Now, however, researchers appear to have identified a neurological link to another cat-associated infectious agent after they found Bartonella spp in the blood of people with schizophrenia and schizoaffective disorder. 

Bartonella is associated with cat-scratch disease, which until recently, was thought to be a short-lived infection. In the new study, published in Vector Borne and Zoonotic Diseases, researchers used a cohort of 17 people with stable, medically managed schizophrenia or schizoaffective disorder, and a control group of 13 healthy adults. Participants answered questionnaires detailing the severity of their symptoms and were then tested for Bartonella. The samples were cultured, and both cultured and whole blood samples underwent qPCR and droplet digital, or ddPCR testing—a new diagnostic technology. Researchers found that 12 of the participants with schizophrenia had Bartonella, when compared with just one of the controls. DdPCR provides a more sensitive molecular test than was previously possible. According to researchers, they would not have found Bartonella DNA in any of the participants without it. The researchers are now planning a larger study to test these preliminary results.

Funding granted for AI tool that can discern Parkinson’s. Three distinct neurodegenerative disorders—Parkinson’s disease, multiple system atrophy Parkinsonian variant (MSAp), and progressive supranuclear palsy (PSP)—often share overlapping motor and non-motor symptoms, including changes in gait. This can make it tricky for physicians to distinguish between Parkinson’s and the other two distinct Parkinson’s-like syndromes. But researchers at the University of Florida are hoping to solve this problem. They recently received a $5 million grant from NIH to test a new artificial intelligence tool, which aims to distinguish the precise diagnosis for patients with early Parkinson’s disease, MSAp, or PSP.

The three conditions have key differences in pathology and prognosis, which means accurately diagnosing patients is critical for determining treatment options and developing more effective therapies. Past research has indicated that diagnostic accuracy for Parkinson’s may be as low as 58%, and more than half of those misdiagnosed with the disease have either MSAp or PSP. Researchers will use the funding to create a new AI tool, which they’ll test using MRI images from 315 patients. The tool involves a novel, noninvasive biomarker technique using diffusion-weighted MRI, which can measure how water molecules diffuse in the brain and identify where neurodegeneration occurs. Researchers hope that the tool will lead to the development of improved treatments for all three conditions.

Assessment of dementia symptoms leaves a lot to be desired. Clinical management of dementia depends heavily on nurses’ ability to assess and document neuropsychiatric symptoms. A lack of standardization, as well as inadequate documentation, can result in poor symptom management, prolonged hospitalization, or even the denial of admission to a care facility following patient discharge. But a new quality improvement project sought to address this. Researchers found that by implementing an evidence-based protocol using the Neuropsychiatric Inventory-Questionnaire (NPI-Q), they were able to improve the assessment and documentation of neuropsychiatric symptoms among dementia patients, which could lead to better clinical management. 

In the study, published in the American Journal of Geriatric Psychiatry, researchers examined a 14-bed inpatient behavioral health unit over a 12-week period, during which time eight patients with dementia were admitted. A group of nine nurses were trained in proper NPI-Q administration, which they conducted at admission, discharge, and three times weekly. Around 70% of patients who received both admission and discharge NPI-Qs had improved NPI-Q scores at discharge. Researchers found that the use of a structured, validated instrument was found to be likely to improve nursing assessment and documentation of neuropsychiatric symptoms among dementia patients. While the cohort was small, researchers concluded that the practice change was well-accepted by nurses, was sustainable, and may even improve care quality, as evidenced by improved NPI-Q scores from admission to discharge.

Flaw found in autism screening method. The 10-item Autism Spectrum Quotient (AQ10) is used across the globe to screen for Autism Spectrum Disorder. But several researchers recently pointed out that this widely used method for autism screening is being misused, which may have prevented many people from receiving an ASD diagnosis over the past decade.

A statement, published in The Lancet Psychiatry, illuminated a discrepancy between the clinical cutoff recommended by the National Institute for Health and Care Excellence (NICE) guidelines and the research informing this guidance. NICE incorrectly recommends that a score above 6 (ie, 7 or higher) should result in a referral for specialist diagnostic assessment. However, the researchers point out that the NICE Guideline Development Group recommended a 6 or higher value, which suggests that NICE guidelines have erroneously recommended the higher cutoff. This has likely resulted in patients not receiving referrals and missed opportunities for interventions. The researchers recommended that the NICE guidance on autism be revised, emphasising the correct 6 or higher AQ10 cutoff, so that patients are provided with appropriate diagnoses.

Novel Treatments

FDA approves Johnson & Johnson MS drug. Following its development of a vaccine for COVID-19, Johnson & Johnson is receiving more good news. The US Food and Drug Administration has approved the drugmaker’s daily oral drug ponesimod for treatment of relapsing forms of multiple sclerosis.

Ponesimod is an oral selective sphingosine-1-phosphate receptor 1 modulator that is taken once daily. The approval comes after the firm produced data from a 2-year late-stage study where ponesimod 20 mg was shown to be effective in significantly reducing annual MS relapses by roughly 30% compared to teriflunomide. Additionally, nine of the 10 ponesimod-treated patients demonstrated no deterioration of disability over 3 months. In previously conducted studies that took place over a 10-year period, the drug showed a proven safety profile and was generally well-tolerated. According to the studies, if treatment with ponesimod is stopped, it leaves the blood within 1 week and stops affecting the immune system at 1 to 2 weeks in a majority of patients. Meanwhile, the European Medicines Agency is still reviewing ponesimod’s marketing authorization.

Researchers find a way to “reverse” effects of childhood trauma. Early-life stress and childhood trauma are linked with depression later in life, but the mechanisms behind this have not been well understooduntil now. A new study has found that early-life stress in mice induces epigenetic changes in a particular type of neuron, which in turn makes the animals prone to stress later in life. After administration of a drug that inhibits an enzyme that adds epigenetic marks to histones, the researchers also found that the latent effects of early-life stress can be reversed.

The study, published in Nature Neuroscience, was based on how early-life stress results in modifications to the genome that influences gene expression, including in the nucleus accumbens, which regulates motivation- and reward-linked behaviors. Researchers explored whether early-life stress results in histone modification, which means chemical groups are added to or removed from histones, the proteins that DNA winds around. They tested this hypothesis using mouse models by separating them from their mothers and giving them limited bedding. Not only did the mice exhibit depression-like behaviors, but they also had histone modifications. Additionally, researchers tested the effects of pinometostat, a small molecule inhibitor, and found that they could reverse the effects of the early-life stress. While this may be just one of many effects that early-life stress may have on the brain, the findings indicate that a treatment for childhood trauma could be feasible.

FAT10: A new target for Parkinson’s treatments. Parkinson’s disease is the second most common age-related neurodegenerative disease, but there is still no treatment that targets the root cause of the disease, which remains unclear. That may soon change, however, after a team of researchers found that the ubiquitin-like protein FAT10 inhibits the molecular defense mechanisms protecting the brain from Parkinson’s disease, suggesting that FAT10 could be a target for a future treatment for Parkinson’s.

Parkinson’s disease develops when nerve cells die off in the mesencephalon as a result of the faulty disposal of damaged mitochondria and the subsequent development of oxygen radicals. The new study, published in Cell Reports, focused on FAT10, which is a signalling substance that marks other molecules for disposal. In cases of Parkinson’s disease, FAT10 marks the enzyme Parkin for disposal. This enzyme is responsible for assisting in the proper disposal of damaged mitochondria, which means it protects against Parkinson’s. The more Parkin enzymes are disposed of, the worse the disease becomes. Researchers hope that these findings will provide a new framework for the effective treatment of Parkinson’s, in the form of a FAT10 inhibitor.

Study pinpoints brain protein as target for seizure treatment. There are no FDA-approved anti-seizure medications that target G-protein-coupled receptors (GCPRs) for patients with epilepsy, but newly published research suggests that some FDA-approved medications may have benefits as novel anti-epileptic drugs. The research comes in the form of an analysis of brain samples from epilepsy patients and controls, which revealed differences in expression of hundreds of proteins in the hippocampus and other brain regions, and identified G-protein Subunit Beta 1 (GNB1) as a promising treatment target.

In the study, published in Brain Communications, researchers used mass spectrometry to study the hippocampal Cornu Ammonis 1-3 region (CA1-3), frontal cortex, and dentate gyrus microdissected from 14 brain samples. Of the 939 significantly altered proteins in both the hippocampus and frontal cortex, 20 were encoded by genes with mutations that cause epilepsy. Specifically, researchers observed that GNB1 is involved in 28 pathways that are significantly impacted in the hippocampus of those with epilepsy, and 15 of these pathways include GPCRs with an FDA-approved drug for non-epilepsy-related indications. Tests are now being conducted on some candidate drugs that target GPCRs, with the hope that they might prove to be effective treatments.

New in Patient Management

A dementia diagnosis can push some to the edge. Following a dementia diagnosis, many patients experience loss, anger, and uncertainty. In the United States, both dementia cases and suicide rates among older adults are increasing, which has prompted researchers to look into suicide risk among newly diagnosed dementia patients. In an effort to gain a better understanding of this phenomenon, a new study has found that adults aged 65 to 74 years who recieve a dementia diagnosis have an increased risk of suicide mortality, especially within the first 90 days of diagnosis.

The study, published in the American Journal of Geriatric Psychiatry, looked at a cohort of 2.7 million adults aged > 65 years with newly diagnosed dementia from 2011 through 2016. Researchers found that the suicide rate among the cohort was 26.42 per 100,000 person-years. The findings indicate that the number of observed suicide deaths during the first year after dementia diagnosis is roughly 54% higher than the general geriatric population. Overall, the risk of suicide mortality was particularly elevated within the first 90 days of dementia diagnosis among adults aged 65 to 74 years. Additionally, they observed that rural residence, recent mental health and substance use disorders, and chronic pain conditions were associated with further increased risk.

Can a supplement prevent strokes in patients with rare genetic disorders? Hereditary cystatin C amyloid angiopathy (HCCAA) is part of a group of diseases in which amyloid proteins build up on the walls of blood vessels in the central nervous system. Many HCCAA patients suffer strokes and brain hemorrhages in early adulthood, which often leads to paralysis, dementia, or death. But now, researchers have discovered that a widely used nutritional supplement may significantly reduce the risk of fatal strokes caused by HCCAA.

In the study, published in Nature Communications, researchers created cell lines expressing the disease, and then attempted to disrupt the aggregation of the amyloid-producing proteins. They focused on a supplement called N-acetyl-cysteine (NAC), which is prescribed to break up mucus in lungs and has also been shown to protect against liver damage in cases of acetaminophen overdose. Not only did researchers find that the supplement lowered the risks of fatal stroke, they also found that NAC could be used to block and break up the formation of amyloid plaque deposits. Given that HCCAA can be diagnosed through genetic testing, researchers believe they could administer NAC early in life to potentially stop first-time strokes from happening. 

A daily dose of processed meat could lead to Alzheimer’s. We all know that eating processed meat is bad for us, but new research has illuminated just how unhealthy it may be. The study suggests that consuming a 25 gram serving of processed meat each day—the equivalent to just one rasher of bacon—is associated with a 44% increased risk of dementia. 

The study, published in the American Journal of Clinical Nutrition, used data from a cohort of just under 500,000 people aged 40 to 69 years to explore whether there’s a link between the consumption of meat and development of dementia. Over an 8-year follow-up, researchers identified 2,896 incident cases of all-cause dementia, 1,006 cases of Alzheimer’s disease, and 490 cases of vascular dementia. They found that daily consumption of processed meat substantially increased the risks of dementia, regardless of a genetic predisposition to developing the disease. Additionally, their findings showed that eating some unprocessed red meat could be protective: Those who consumed 50 grams daily were 19% less likely to develop dementia. The lesson? Choose your meat wisely.

Estrogen may ward off dementia. Alzheimer’s disease (AD) impacts more women than men—more than two-thirds of Americans living with AD are female. It’s long been known that reductions in estrogen levels (particularly in menopausal women) affect cognitive function, which often leads to difficulties with memory, attention, and concentration. Estrogen withdrawal can also lead to depressive symptoms. But researchers have never analyzed the relationship between estrogen exposure and cognitive function in older women with depression compared to non-depressed controls—until now. A new study has found that higher cumulative lifetime estrogen exposure is associated with better memory performance among non-depressed women, which suggests that estrogen has a long-term protective role in memory in non-depressed older postmenopausal women.

The study, published in the American Journal of Geriatric Psychiatry, used a cohort of 135 participants aged 60 years and older, 64 of whom were clinically depressed. Using a lifetime estrogen exposure questionnaire, these women were compared with those who were non-depressed. Researchers found that cumulative lifetime estrogen exposure was associated with better performance on a delayed recall test, although this effect was found only among non-depressed participants. Further research is required to determine the role of estrogen in depression, treatment response, and cognitive decline in older women. 

Latest in Journal Summaries

Results from the migraine signature study.

Increased risk of Parkinson’s disease in women after bilateral oophorectomy.

Activation of the basal ganglia and indirect pathway neurons during frontal lobe seizures.

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