Tag: Neurology

Nutrition’s crucial role in Alzheimer’s progression revealed
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In a recent cross-sectional study published in the journal Frontiers in Nutrition, researchers used data from 266 participants along the cognitive impairment spectrum to investigate the association between nutrition and cognitive decline. Their study reveals that nutrition-related variables such as body composition and dietary patterns are significantly associated with the onset and progression of Alzheimer’s disease (AD), with malnutrition substantially increasing AD risk. Since malnutrition presents an easily adjustable, safe, and non-invasive health behavior, the early identification of at-risk populations and dietary interventions therein may substantially reduce the future global burden of AD and similar cognitive disabilities.

Study: An investigation into the potential association between nutrition and Alzheimer’s disease. Image Credit: Adisak Riwkratok / Shutterstock

Diet and cognitive health

One of humanity’s crowning achievements is longevity – modern medicine’s lengthening of natural human lifespans. An unfortunate side-effect of this achievement, however, is a slowly aging world, with more senior citizens alive today than ever before and a corresponding explosion in the incidence and prevalence of chronic, age-associated conditions such as cardiovascular diseases, cognitive declines, and some cancers. While initially presenting a ‘safer’ (lower mortality) pathology than cancers and cardiovascular diseases, cognitive declines are alarmingly debilitating conditions, resulting in substantial economic and mental trauma for patients and their families, even before accounting for their potentially lethal comorbidities.

Alzheimer’s disease (AD) is the most common cognitive disorder associated with old age. It is a chronic, progressive disease characterized by initial mild memory loss, which eventually declines into severely debilitating dementia. It is caused by the deposition of specific proteins, which results in the loss of neural connections. Despite substantial research in the field, a cure for the condition remains elusive, with clinical interventions focused on symptom management and progression delay.

Recently, studies have suggested a link between malnutrition and dementia. The European Society for Clinical Nutrition and Metabolism (ESPEN) has further classified malnutrition as the most common AD-associated comorbidity. Unfortunately, research has failed to establish an association between specific nutritional components and their impacts on the different stages of AD progression. Understanding the holistic relationship between multiple nutritional indices and their implications on various stages of AD would allow clinicians and dieticians the information needed to curb the prevalence of these cognitive disorders.

About the study

The present study aimed to investigate the relationship between various commonly used nutritional indices and their respective contributions to AD risk and progression. The sample cohort was recruited from the Center for Cognitive Neurology, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University.

Between April 2019 and April 202, 946 participants with mild cognitive impairment (MCI due to AD – ‘AD-MCI’) or dementia due to AD (‘AD-D’) without other neurological conditions relating to cognition (e.g., Parkinson’s disease) and non-diet-based malnutrition (prevalence of hematological tumors, liver cirrhosis) were enrolled. Of these, 266 participants presented completed demographic and medical information and were included in the final analyses. These comprised 73 controls (normal cognition – ‘NC’), 72 AD-MCI, and 121 AD-D samples.

Subject body composition metrics were measured using the Global Leadership Initiative on Malnutrition (GLIM) criteria. These included ‘reduced food intake,’ ‘non-volatile weight loss,’ ‘muscle mass,’ and ‘body mass index (BMI).’ Additionally, subjects’ dietary patterns (e.g., Mediterranean diet and Mediterranean-DASH diet intervention for neurodegenerative delay [MIND]) were recorded, and the nutritional composition of these diets was separately investigated.

Venous blood samples were used for the estimations of fasting blood glucose (FBG), hemoglobin A1c (HbA1c), blood urea nitrogen (BUN), hemoglobin, creatinine, total calcium, albumin, globulin, albumin/globulin (A/G), and other nutritional status determinants.

Study findings

The present study comprised 266 participants, 57.14% of whom were female, with a mean age of 64.89 years. Medical data revealed that 36.84% of participants carried the APOE ε4 allele, a common culprit in AD pathology. Body composition metrics showed that AD-D patients had, on average, substantially lower arm, waist, calf, and hip circumferences and lower BMIs compared to AD-MCI and NC cohorts. Surprisingly, all participants were found to follow some interpretation of either Mediterranean or MIND dietary patterns, which did not differ in their nutritional scores.

“…a smaller waist circumference was linked to lower level of β amyloid protein (Aβ) and higher levels of phosphorylated tau (P-tau) and total tau (T-tau) in the cerebrospinal fluid of AD patients. This phenomenon may be attributed to the utilization of skeletal muscle mass as a nutritional reservoir in response to a prolonged state of negative energy balance during disease. Consequently, the muscle mass of AD patients gradually decreases as the disease progresses in AD.”

Nutritional assessment scales present that the AD-D cohort fared worse than the NC and AD-MCI groups. Study data analyses show that BMI and AD occurrence are independently associated, validating previous research.

Investigations into specific nutritional variables revealed that body composition, nutritional assessment scales, and blood-based nutritional laboratory variables were significantly associated with the occurrence and progression of AD. Malnutrition was found to be most prevalent in the AD-D cohort, but prevalence in even the AD-MCI was shown to be substantially higher than in the NC group.

“Since malnutrition is a risk factor that can be intervened, early identification and intervention of individuals with nutritional risk or malnutrition are significantly beneficial for reducing the risk, development, and progression of AD.”
Journal reference:

He, M., Lian, T., Liu, Z., Li, J., Qi, J., Li, J., Guo, P., Zhang, Y., Luo, D., Guan, H., Zhang, W., Zheng, Z., Yue, H., Zhang, W., Wang, R., Zhang, F., & Zhang, W. (2024). An investigation into the potential association between nutrition and Alzheimer’s disease. In Frontiers in Nutrition (Vol. 11). Frontiers Media SA, DOI – 10.3389/fnut.2024.1306226, https://www.frontiersin.org/articles/10.3389/fnut.2024.1306226/full
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March 11, 2024
A Journey into Women’s Brain Health Research

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In this special International Women’s Day interview on the evolution of neurology with a special focus on women’s brain health, we dive into the work of Cheryl Carcel. With a unique perspective shaped by experiences in both low-middle-income and high-income countries, the conversation sheds light on the critical disparities in neurological care and outcomes between genders.

Please could you share with us the journey that led you to focus on neurology and, more specifically, on women’s brain health?

As a medical student from a low-middle-income country (the Philippines), I was fascinated by neurology, where by taking a person’s medical history and performing physical examinations, it was possible to diagnose with good accuracy a person’s neurological disease. This is crucial in a country with few resources, such as diagnostic imaging.

During my neurology training, I noticed that women were usually more disabled or likely to die after a stroke, but I did not realize that this was a global issue. It wasn’t until I started my Ph.D. at the University of Sydney and analyzed some of the stroke clinical trials at The George Institute and found evidence that women indeed had worse outcomes including worse quality of life after stroke compared to men.

These trials were run internationally, so not only was it happening in the Philippines, where I had first-hand experience with my patients, but also around the globe and even in high-income countries.

In your research on sex and gender differences within neurology, what have been some of the most surprising or enlightening findings regarding how neurological disorders affect men and women differently?

It still surprises me that in 2024, women and men still experience these differences. There are two things I want to highlight:

We know about biological differences in women and men and that these may affect how we respond to diseases like stroke. For example, younger women are more likely to have a stroke than younger men, and this is probably due (to some extent) to hypertensive disorders of pregnancy and gestational hypertension.

But the gender aspects are more difficult to explain because they may involve the role a woman plays in society – she may not immediately present to the hospital after a stroke (and thereby receive time-dependent life-saving medications) because she has caregiving responsibilities, or she may be older, living alone with no one to call the ambulance. Aside from the role women play in society, there may be differences in the way women and men are treated, or there may be implicit bias from healthcare professionals.

Participants enrolled in stroke clinical trials are not often representative of the population experiencing the disease in the community. Women, people of color, and individuals from culturally and linguistically diverse backgrounds (CALD) are under-enrolled relative to their burden of disease in stroke. Treatment effect estimates of many medical therapies, including stroke, have been largely derived from trial evidence generated from a Caucasian male population, limiting the generalisability of the safety and efficacy evidence.

Given the clear differences in how neurological conditions can manifest and impact men and women, how do you believe these insights should influence the development of treatments, patient care, and support systems in neurology?

Work in this field (mine and many others) suggests that in order to overcome these differences, we need to consider the collection, analysis, and reporting of sex and gender health data and include more diverse populations in our clinical trials in order to provide reliable evidence on how safe and effective new medications and devices are for everyone. There has also been evidence to suggest that when women lead clinical trials, the trial population is more inclusive, and data is more likely to be disaggregated by sex.

Image Credit: Tunatura/Shutterstock.com

What are some of the most significant challenges you face in researching women’s brain health, and how do you propose the scientific community addresses these challenges to ensure more inclusive health outcomes?

If you had asked me the same question 4 years ago, I would have said that the biggest challenge at that time was convincing the medical and research community that sex and gender differences in stroke/cardiovascular disease is a real problem.

Now that all these mounting evidence cannot be ignored, the next challenge is to find strategies to narrow this health gap. One of the best ways of doing this is working with end-users—the people with lived experiences, health care professionals, advocacy groups, government, etc to find a solution that works for the people involved.

You advocate for the disaggregation of data by sex in medical research. Can you explain how this approach has influenced your research outcomes and why it’s crucial for achieving gender equity in health care?

Gender equality is one of the UN Sustainable Development Goals (Sustainable Development Goal 5). Clinically meaningful sex and gender differences in screening, risk factor prevalence, health-seeking behavior, treatment, and prognosis are increasingly recognized across a range of non-communicable diseases, which confer the greatest health burden.

Why women and men’s experiences and treatment differ for the same diseases, and how this links to socially embedded gender structures, is under-appreciated in medical research and clinical practice. By disaggregating data by sex and, where possible, gender, we are not only doing good science (Prof Londa Schiebinger’s wise words Gendered Innovations | Stanford University), but we are expanding our knowledge of these differences into the health care system to improve clinical practice, medical research, health systems design, policy, and public health.

Your trial in Nigeria and Peru focuses on essential acute stroke care in low-resource settings. How do you see this work contributing to a more inclusive approach to global health, especially concerning women’s health care in these regions?

This trial is funded by the World Heart Federation, and our intention was two-fold: to improve acute stroke care in low-resource settings and to build research capacity in the area. The COVID pandemic has impacted this project, and it is currently on hold as we work through logistical issues. If this trial has a positive outcome, then having clear guidelines on essential acute stroke treatments has the potential to eliminate implicit and explicit gender bias.

I am also working on another project that aims to improve the participation of women in stroke clinical trials. Ensuring that clinical trials include a balanced proportion of women and men and that key findings are interpreted separately by sex is crucial.

When women are under-represented in trials, there is a threat that treatment is not safe or effective and introduces the potential for unequal access to treatments. Our ongoing efforts will develop and evaluate inclusive and innovative recruitment strategies to improve the representation of women in stroke trials, making stroke treatment more accessible to all people.

As women, we need to be brave. Speak up and let your voice be heard and counted when you have something to say. You are important, and your voice matters.

Based on your experience and research findings, what policies or actions do you believe are essential to advance the inclusion of women’s health needs in both national and international health agendas?

An important program of work at The George Institute for Global Health in collaboration with the Australian Human Rights Institute at the University of New South Wales in Sydney is an Australia-wide Call to Action to embed sex and gender analysis into medical research. This work has led to the formation of The Sex and Gender Sensitive Research Call to Action Group, which includes 11 universities across Australia, the UK, and the United States committing to analysing and reporting health data by sex.

A philanthropic group is currently funding a larger project aimed at translating the Call to Action paper. Some key wins of this project so far include mapping the key stakeholder organizations in Australia engaged in sex and gender research advocated for policy changes with the National Health and Medical Research Council and Medical Research Future Fund (the main health funding bodies in Australia) and through a co-design workshop with our group, the Association of Australian Medical Research Institutes (AAMRI), the peak body for medical research institutes across Australia, has produced a set of sex and gender policy recommendations for health and medical research.

Through these policy changes in different stakeholder groups, we hope that we will achieve critical mass in Australia to make the collection, analysis, and reporting of sex and gender health data the norm and not just nice to do.

This month, we will be launching Australia’s new National Centre for Sex and Gender Equity in Health and Medicine, which will bring together researchers, policymakers, healthcare professionals, and consumer stakeholders with an interest in addressing the effects of biological sex and gender identify on health outcomes, enabling greater learning, collaboration, and impact. This Centre is a partnership between The George Institute for Global Health, the Australian Human Rights Institute at UNSW Sydney and Deakin University.

The center aims to develop effective strategies to prevent and treat the leading causes of death and disability for everyone; we need health and medical research that is inclusive and looks at how sex and gender affect different conditions.

Reflecting on this year’s theme for International Women’s Day, what does “Inspire Inclusion” mean to you personally and professionally, and how do you envision its implementation in the realm of brain health and beyond?

This year, the UN’s theme is Count Her In: Invest in Women. Accelerate Progress. It talks a bit about economic empowerment but also provides equal opportunities to earn, learn, and lead. This is very relevant to our work on improving the participation of women in clinical trials. We want to be able to count women in by ensuring their health and medical data are captured; and are safe and effective.

Where can readers find more information?

About Cheryl Carcel

A/Prof Cheryl Carcel is a neurologist and the Head of the Brain Health Program at The George Institute for Global Health in Sydney, Australia. She is a conjoint associate professor at University of New South Wales in Australia. She was selected as a World Heart Federation (WHF) Emerging Leader and a Stroke Society of Australasia Emerging Stroke Clinician and Scientist. Her most important life roles are being a mother of two young and active children and wife.

Career highlights:
•   Recent promotion to Associate Professor at University of New South Wales and Head of the Brain Health Program at The George Institute.
•   Appointed as acting director of the Centre for Sex and Gender Equity in Health and Medicine- a national centre in Australia that will address sex and gender inequities through world-class research that considers how sex and gender impact health and medicine.
•   Invited to be one of the keynote speakers in the European Stroke Organisation’s Stroke Science Workshop last year. This is an important achievement as this workshop is a meeting on clinical and translational research aspects of stroke with a limited number of well-known stroke specialists as well as junior scientists. My invitation as a keynote speaker to this meeting signals that sex and gender differences should be considered front and centre in stroke.

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March 7, 2024
Essential tremor associated with increased risk of dementia

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Dementia may be three times more common among people with essential tremor, a movement disorder that causes involuntary shaking, than the general population, according to research released today, March 6, 2024. The study will be presented at the American Academy of Neurology’s 76^th Annual Meeting taking place April 13–18, 2024, in person in Denver and online.

Essential tremor is the most common tremor disorder, more common than Parkinson’s disease. In addition to arm and hand tremors, people may also develop involuntary shaking of the head, jaw and voice.

While many people living with essential tremor experience mild tremor, in some individuals, the tremor can be quite severe. Not only do tremors affect a person’s ability to complete daily tasks such writing and eating, our study suggests that people with essential tremor also have an increased risk of developing dementia.”

Elan D. Louis, MD, MSc, Study Author at University of Texas Southwestern Medical Center in Dallas and a Fellow of the American Academy of Neurology

The study involved 222 people with essential tremor who had an average age of 79 at the start of the study. They took thinking and memory tests to determine whether they had normal cognitive skills, mild cognitive impairment or dementia at the start of the study.

Participants then had follow-up exams every 1.5 years for an average of five years.

Of this group, 168 people had normal cognitive skills, 35 had mild cognitive impairment and 19 had dementia at the start of the study.

During the study, 59 developed mild cognitive impairment and 41 developed dementia.

Researchers then compared the rate at which people developed mild cognitive impairment and dementia, as well as the prevalence of these conditions, to the rates and prevalence for the general population. They also compared participants to the rates and prevalence for people with Parkinson’s disease.

Researchers found 19% of participants had or developed dementia during the study, and each year an average of 12% of people diagnosed with mild cognitive impairment went on to develop dementia. These rates were three times higher than the rates in the general population. However, the rates were lower than those seen in people with Parkinson’s disease, a population for which dementia is more prevalent.

Researchers also found that 27% of participants had or developed mild cognitive impairment during the study, a rate almost double that of the rate of 14.5% for the general population, but less than the rate of 40% for people with Parkinson’s disease.

“While the majority of people with essential tremor will not develop dementia, our findings provide the basis for physicians to educate people with essential tremor and their families about the heightened risk, and any potential life changes likely to accompany this diagnosis,” Louis said.

A limitation of the study was that the comparison data for the general population was published prior to the start of the study.

The study was supported by the National Institutes of Health.

Source:

American Academy of Neurology

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March 7, 2024
Study reveals safety of MS drugs during breastfeeding in child’s early years of life

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Certain medications for multiple sclerosis (MS) called monoclonal antibodies, taken while breastfeeding, may not affect the development of a child during the first three years of life, according to a preliminary study released today, March 4, 2024. The study will be presented at the American Academy of Neurology’s 76^th Annual Meeting taking place April 13–18, 2024, in person in Denver and online. The study examined four monoclonal antibodies for MS: natalizumab, ocrelizumab, rituximab and ofatumumab.

MS is a disease in which the body’s immune system attacks myelin, the fatty white substance that insulates and protects the nerves. Symptoms may include fatigue, numbness, tingling or difficulty walking.

Most monoclonal antibody medications for multiple sclerosis are not currently approved for use while a mother is breastfeeding. Yet MS can develop during the childbearing years of life. Since the risk of MS relapses increases after giving birth, some mothers may need or want to restart these therapies, so it is important to determine whether these medications, through breast milk, have a negative impact on a child’s development.”

Kerstin Hellwig, MD, study author of Ruhr University in Bochum, Germany

For the study, researchers used the German MS and Pregnancy Registry to identify 183 infants born to mothers taking monoclonal antibodies while breastfeeding. Of this group, 180 had mothers with MS and the three had mothers with neuromyelitis optica spectrum disease (NMOSD). NMOSD is also a demyelinating disease, but it is rare and specifically affects the optic nerve, spinal cord or brain.

The infants were compared to another 183 infants, matched for exposure to MS medications shortly before or during pregnancy, born to mothers with the same diseases who did not take monoclonal antibodies while breastfeeding.

Of those exposed to MS medications, 125 were exposed to natalizumab, 34 to ocrelizumab, 11 to rituximab and 10 to ofatumumab. Two infants were first exposed to natalizumab and then ocrelizumab. One infant was exposed to rituximab and then ocrelizumab.

The first exposures to the medications through breastfeeding ranged from the day a child was born to the ninth month of life. Infants were breastfed for an average of five-and-a-half months while their mothers took these medications.

For all infants, researchers then examined the number of hospital stays, antibiotic use, developmental delays such as problems with social and fine motor skills and delayed speech development, and the infants’ weight at follow-up visits during the first three years of life.

After comparing infants exposed to the medications to infants not exposed, researchers found no differences in their health or development.

“Our data show infants exposed to these medications through breastfeeding experienced no negative effects on health or development within the first three years of life,” Hellwig said.

A limitation of the study was that only about a third of the infants were followed for the full three years. Therefore, Hellwig said, the results for the third year of life are less meaningful than for years one and two.

Source:

American Academy of Neurology

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March 5, 2024
Is posttraumatic epilepsy associated with long-term dementia risk?

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In a recent study published in JAMA Neurology, researchers assessed the associations between post-traumatic epilepsy (PTE) and the risk of dementia.

Study: Posttraumatic Epilepsy and Dementia Risk. Image Credit: Orawan Pattarawimonchai/Shutterstock.com

Background

PTE is the occurrence of unprovoked seizures more than a week after a traumatic brain injury, and it accounts for up to 20% of acquired epilepsies.

Research suggests that PTE is associated with poor short-term psychosocial, cognitive, and functional outcomes; however, less is known about the long-term impact of PTE.

Moreover, epilepsy and traumatic brain injury are independently associated with the risk of dementia. Growing evidence implicates neurodegenerative mechanisms in PTE pathophysiology.

As such, individuals with PTE may likely have adverse cognitive outcomes compared to those with epilepsy or brain injury alone.

About the study

In the present study, researchers examined the associations between PTE and dementia risk using data from the atherosclerosis risk in communities (ARIC) study.

The ARIC study enrolled people aged 45–64 during 1987-89. Participants completed subsequent in-person visits and follow-up telephone calls. Subjects were asked about hospitalizations during telephone calls; reported hospitalization records were obtained.

ARIC study data were linked to the United States (US) Centers for Medicare and Medicaid Services (CMS). Follow-up for the present analysis continued until the diagnosis of dementia, death, discontinuation, or administrative censoring.

Head injury was defined using data from questionnaires, International Classification of Diseases, ninth and tenth revisions (ICD-9/10) codes from ARIC study hospitalization records, and ICD-9/10 codes from linked CMS records.

Epilepsy/seizure was defined using seizure- or epilepsy related ICD-9/10 codes from ARIC and CMS records. PTE was defined as epilepsy/seizure occurring ≥ seven days after (diagnosis of) head injury.

The researchers stratified participants into exposure groups – 1) reference (no epilepsy/seizure and no head injury), 2) head injury, 3) epilepsy/seizure, and 4) PTE. The associations between exposure variables and dementia risk were examined using Cox proportional hazard models.

Model 1 was adjusted for sex, age, education, race, military veteran status, and center. Model 2 was additionally adjusted for smoking/alcohol status, hypertension, and diabetes.

Model 3 was further adjusted for the apolipoprotein E ε4 genotype. Besides, Fine and Gray proportional hazard models accounted for the competing mortality risks individually and with stroke.

Findings

The team included 12,558 participants from the ARIC study for analysis. They were aged 54.3, on average, at baseline. Most participants (57.7%) were female, and 28.2% were Black.

The team categorized 1,811, 640, and 145 participants as having a head injury, epilepsy/seizure, and PTE, respectively, over a median follow-up of 25.4 years.

The median time from baseline to first head injury, epilepsy/seizure, or PTE was 15.1, 13.8, or 3.1 years, respectively. Overall, 2,498 cases of dementia occurred over a follow-up of 250,372 person-years. Notably, individuals with PTE had the lowest cumulative dementia-free survival.

In the first model, PTE was associated with 4.85 times the risk of dementia compared to the reference group.

In contrast, epilepsy/seizure and head injury were associated with 2.81- and 1.64-fold higher dementia risk, respectively. In models (2 and 3) with additional adjustments (for vascular and genetic risk factors), the elevated dementia risk associated with PTE was marginally attenuated.

Nevertheless, this (PTE-associated) increased dementia risk was still significantly higher than that associated with epilepsy/seizure or head injury alone.

PTE was associated with a three-fold increased risk of dementia in models that accounted for the competing risks of death individually and with stroke.

Further, younger participants consistently showed stronger associations between PTE and dementia risk than older subjects across all models. There was no evidence of multiplicative interaction by race or sex.

Conclusions

In sum, the study demonstrated that subjects with PTE had about a 4.5-fold increased risk of dementia relative to those without epilepsy/seizure and head injury.

After accounting for the competing risks of death and stroke, there was approximately three-fold higher dementia risk associated with PTE.

Moreover, dementia risk was significantly higher with PTE than with epilepsy/seizure or head injury alone. Notably, the study population comprised older adults without prior head injury at baseline; thus, the findings may not be generalized to those who sustain a head injury early in life.

The study could not account for physical functioning and frailty, which might confound the observed associations.

Besides, the researchers did not have access to details of injury mechanisms, acute imaging findings, and clinical characteristics.

Taken together, the findings reveal increased dementia risk among people with PTE that was significantly higher than in individuals with head injury or epilepsy/seizure alone.

These results highlight the significance of prevention of not only head injuries but also PTE following these injuries.

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February 29, 2024
Study demonstrates the deleterious effects of chronic cocaine use on functional brain networks

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A collaborative research endeavor by scientists in the Departments of Radiology, Neurology, and Psychology and Neuroscience at the UNC School of Medicine have demonstrated the deleterious effects of chronic cocaine use on the functional networks in the brain.

Their study titled “Network Connectivity Changes Following Long-Term Cocaine Use and Abstinence”, was highlighted by the editor of Journal of Neuroscience in “This Week in The Journal.” The findings show that continued cocaine use affects how crucial neural networks communicate with one another in the brain, including the default mode network (DMN), the salience network (SN), and the lateral cortical network (LCN).

The disrupted communication between the DMN and SN can make it harder to focus, control impulses, or feel motivated without the drug. Essentially, these changes can impact how well they respond to everyday situations, making recovery and resisting cravings more challenging.”

Li-Ming Hsu, PhD, assistant professor of radiology and lead author on the study

Hsu led this project during his postdoctoral tenure at the Center for Animal MRI in the Biomedical Research Imaging Center and the Department of Neurology. The work provides new insights into the brain processes that underlie cocaine addiction and creates opportunities for the development of therapeutic approaches and the identification of an imaging marker for cocaine use disorders.

The brain operates like an orchestra, where each instrumentalist has a special role crucial for creating a coherent piece of music. Specific parts of the brain need to work together to complete a task. The DMN is active during daydreams and reflections, the SN is crucial for attentiveness, and the CEN, much like a musical conductor, plays a role in our decision-making and problem-solving.

The research was motivated by observations from human functional brain imaging studies suggesting chronic cocaine use alters connectivity within and between the major brain networks. Researchers needed a longitudinal animal model to understand the relationship between brain connectivity and the development of cocaine dependence, as well as changes during abstinence.

Researchers employed a rat model to mimic human addiction patterns, allowing the models to self-dose by nose poke. Paired with advanced neuroimaging techniques, the behavioral approach enables a deeper understanding of the brain’s adaptation to prolonged drug use and highlights how addictive substances can alter the functioning of critical brain networks.

Hsu’s research team used functional MRI scans to explore the changes in brain network dynamics on models that self-administrated cocaine. Over a period of 10 days followed by abstinence, researchers observed significant alterations in network communication, particularly between the DMN and SN.

These changes were more pronounced with increased cocaine intake over the 10 days of self-administration, suggesting a potential target for reducing cocaine cravings and aiding those in recovery. The changes in these networks’ communication could also serve as useful imaging biomarkers for cocaine addiction.

The study also offered novel insights into the anterior insular cortex (AI) and retrosplenial cortex (RSC). The former is responsible for emotional and social processing; whereas, the latter controls episodic memory, navigation, and imagining future events. Researchers noted that there was a difference in coactivity between these two regions before and after cocaine intake. This circuit could be a potential target for modulating associated behavioral changes in cocaine use disorders.

“Prior studies have demonstrated functional connectivity changes with cocaine exposure; however, the detailed longitudinal analysis of specific brain network changes, especially between the anterior insular cortex (AI) and retrosplenial cortex (RSC), before and after cocaine self-administration, and following extended abstinence, provides new insights,” said Hsu.

Source:

University of North Carolina Health Care

Journal reference:

Hsu, L.-M., et al. (2024). Intrinsic functional connectivity between the anterior insular and retrosplenial cortex as a moderator and consequence of cocaine self-administration in rats. The Journal of Neuroscience. doi.org/10.1523/jneurosci.1452-23.2023.

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February 29, 2024
Study reveals pivotal insights into the progression of Parkinson’s disease

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Parkinson’s disease, the second most common type of progressive dementia after Alzheimer’s disease, affects nearly 1 million people in the U.S. and an estimated 10 million individuals worldwide. Each year, close to 90,000 new cases of Parkinson’s disease are diagnosed in the U.S.

In a new study, Jeffrey Kordower, director of the ASU-Banner Neurodegenerative Disease Research Center, and his colleagues unveil pivotal insights into the progression of Parkinson’s disease, presenting new hope for patients battling the severely debilitating disorder.

The research highlights the role of a critical protein called tau in the early stages of the disease. The results suggest that aggregates of the tau protein may jump-start processes of neuronal damage and death characteristics of the disease.

The findings challenge the conventional view of Parkinson’s disease pathology, which typically focuses on the protein alpha-synuclein as the classic diagnostic hallmark of the disease. The new study illustrates how tau pathology could be actively involved in the degeneration of dopamine-producing neurons in the brain, independent of alpha-synuclein. This revelation could shift the focus of Parkinson’s disease research, diagnosis and treatment.

Currently, a protein called alpha-synuclein is believed to be the main player in Parkinson’s disease pathogenesis. This study highlights that misfolded tau may be the first player in causing the cardinal motor symptoms in the disease.”

Jeffrey Kordower, Professor, ASU’s School of Life Sciences

The study appears in the current issue of the journal Brain.

Shattering progression

The progression of Parkinson’s disease involves distinct stages, and the timeline can vary significantly among individuals. The typical stages of Parkinson’s, as outlined by the Parkinson’s Foundation, can help patients understand the changes as they occur.

The disease impacts people in different ways, and not everyone will experience all the symptoms or experience them in the same order or intensity. Some may experience the changes over 20 years or more; for others, the disease advances rapidly.

The progression of the disease is influenced by a combination of genetic and environmental factors. Following a diagnosis, many individuals experience a good response to medications such as levodopa, and this optimal time frame can last for many years. Over time, however, modifications to medication are often needed and symptoms may intensify.

The prevalence of Parkinson’s has doubled in the past 25 years, which may be related to population growth, aging, genetic predisposition, lifestyle changes and environmental pollution.

A fresh perspective

The tau protein accumulates in two regions: the substantia nigra and putamen, both part of the basal ganglia in the brain. The substantia nigra is responsible for the production of dopamine, which is critical for modulating movement, cognitive executive functions and emotional limbic activity.

The putamen, a component of the dorsal striatum, is involved in movement initiation, selection and decision-making, as well as learning, memory, language and emotion. Dysfunction in the putamen can contribute to various disorders, particularly those related to motor function.

A wide range of physical and mental symptoms characterize Parkinson’s disease. These include: rhythmic tremors, often beginning in a limb, such as the hand or fingers; slowness of movement, which can lead to difficulty in performing simple tasks; muscle stiffness or rigidity; and difficulties with balance.

In addition to these physical symptoms, Parkinson’s disease can also cause various mental and emotional changes, including depression and anxiety, sleep disorders, memory difficulties, fatigue and emotional changes.

Brain traces of disease

The scientists conducted the study using postmortem brain tissue from older adults who had experienced different degrees of motor impairment. The research analyzed brain tissues from individuals with no motor deficits, mild motor deficits with and without Lewy pathology in the nigral region of the brain, and from individuals clinically diagnosed with Parkinson’s disease.

Lewy bodies are abnormal aggregates of the protein alpha-synuclein that accumulate in the brain, and they are a hallmark of several neurodegenerative disorders, including Parkinson’s and dementia with Lewy bodies.

In the case of Parkinson’s, Lewy bodies are primarily found in the substantia nigra, a region of the brain that is crucial for movement control, which leads to characteristic motor symptoms such as rigidity, tremors and bradykinesia (slow movement).

The study focused on a cohort of subjects with mild motor impairments -; not pronounced enough to diagnose Parkinson’s, but still significant. Dividing these subjects based on the presence or absence of α-synuclein, researchers found that tau pathology was a common denominator.

The researchers observed that the brain tissue associated with minimal motor deficit demonstrated similar accumulations of tau to those with advanced Parkinson’s, suggesting that tau’s role occurs early in the disease’s evolution. These findings open doors to earlier diagnosis and intervention, potentially slowing or altering the disease’s progression.

The research also sheds light on parkinsonism, a condition that mimics Parkinson’s disease symptoms but is distinct in its underlying mechanisms. The study suggests that tau pathology in the nigrostriatal region of the brain is a shared characteristic, offering a new lens through which to view and treat various forms of parkinsonism.

The findings also underscore the potential of targeting tau pathology as a therapeutic approach in Parkinson’s disease. Because tau aggregation correlates with motor deficits and degeneration of dopamine-producing regions of the brain, interventions aimed at reducing tau accumulation could offer new hope for altering the disease’s trajectory.

Kordower is joined by researchers from Neurodegenerative Diseases Research Unit, Biogen, Cambridge, Massachusetts; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, Maryland; Neurology, School of Medicine, Georgetown University Medical Center, Washington, D.C.; Department of Neurology, University of Alabama at Birmingham; and Pacific Parkinson’s Research Centre and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver.

Source:

Journal reference:

Chu, Y., et al. (2023). Nigrostriatal tau pathology in parkinsonism and Parkinson’s disease. Brain. doi.org/10.1093/brain/awad388.

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February 24, 2024
Using deep brain stimulation to map dysfunctional brain circuits linked to four disorders

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Mass General Brigham researchers identified sets of connections that are disrupted and malfunctioning as a consequence of Parkinson’s disease, dystonia, obsessive compulsive disorder and Tourette’s syndrome.

Fiber bundles associated with symptom improvement following deep brain stimulation in Parkinson’s disease (green), dystonia (yellow), Tourette’s syndrome (blue),and obsessive-compulsive disorder (red). Image Credit: Barbara Hollunder

A new study led by investigators from Mass General Brigham demonstrated the use of deep brain stimulation (DBS) to map a ‘human dysfunctome’ — a collection of dysfunctional brain circuits associated with different disorders. The team identified optimal networks to target in the frontal cortex that could be used for treating Parkinson’s disease, dystonia, obsessive compulsive disorder (OCD) and Tourette’s syndrome. Their results are published in Nature Neuroscience.

“We were able to use brain stimulation to precisely identify and target circuits for the optimal treatment of four different disorders,” said co-corresponding author Andreas Horn, MD, PhD, of the Center for Brain Circuit Therapeutics in the Department of Neurology at Brigham and Women’s Hospital and the Center for Neurotechnology and Neurorecovery at Massachusetts General Hospital. “In simplified terms, when brain circuits become dysfunctional, they may act as brakes for the specific brain functions that the circuit usually carries out. Applying DBS may release the brake and may in part restore functionality.”

Connections between the frontal cortex in the forebrain and basal ganglia, structures located deeper in the brain, are known to control cognitive and motor functions. If brain disorders occur, these circuits may become affected, and their communication may become overactive or malfunction. Previous studies have shown that electrically stimulating the subthalamic nucleus, a small region in the basal ganglia that receives inputs from the entire frontal cortex, can help alleviate symptoms of these disorders.

To understand this relationship better, the authors analyzed data from 534 DBS electrodes in 261 patients from across the globe. Of this cohort, 70 patients were diagnosed with dystonia, 127 with Parkinson’s disease, 50 with OCD and 14 with Tourette’s syndrome. Using software developed by Horn’s team, the researchers mapped the precise location of each electrode and registered results to a common reference atlas to compare locations across patients. The researchers used computer simulations to map tracts that were activated in patients with optimal or suboptimal outcomes.

Using these results, they were able to identify specific brain circuits that had become dysfunctional in each of the four disorders, such as those mapping to sensorimotor cortices in dystonia, the primary motor cortex in Tourette’s, the supplementary motor cortex in Parkinson’s disease and parts of the cingulate cortex in OCD. Notably, the identified circuits partially overlapped, implying that interconnected pathways are disrupted in these disorders.

Further, the investigators were able to apply these findings to fine tune DBS treatments and demonstrate preliminary improved results in three cases, including one at Massachusetts General Hospital, a founding member of Mass General Brigham. This patient, a female in her early 20s, was diagnosed with severe, treatment-resistant OCD involving obsessions about food and water intake, along with compulsive skin picking. Following electrode implantation and targeted stimulation, the researchers were able to show a significant improvement in her symptoms one month after treatment.

Except for the three patients that were tested prospectively, the study was a retrospective analysis of data aggregated from multiple centers. Further studies are needed to validate findings in prospective fashion.

We can take this technique further and finely segregate dysfunctional circuits in order to have greater impact with treatment. For example, with OCD, we can look at isolating circuits for obsessions versus compulsions and so on.”

Barbara Hollunder, MSc, Lead Author, Movement Disorders and Neuromodulation Unit, Department of Neurology, Charité – University Medicine Berlin

Source:

Journal reference:

Hollunder, B., et al. (2024) Mapping Dysfunctional Circuits in the Frontal Cortex Using Deep Brain Stimulation. Nature Neuroscience. doi.org/10.1038/s41593-024-01570-1.

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February 24, 2024
Some stroke patients experience more fatigue and daytime sleep

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Some people feel worse than others after a stroke. Stroke patients with cognitive and emotional problems tend to experience fatigue more often and sleep more during the day, according to recent research.

Approximately 9 000 people are admitted to Norwegian hospitals with stroke each year. About half of these patients feel exhausted afterwards, and many patients sleep more during the day than before the stroke. These after-effects are challenging and significantly affect patients’ everyday life.

However, we still have a limited understanding of which factors lead to increased fatigue and daytime sleep after stroke. Our research group therefore wanted to investigate whether cognitive and emotional complaints are related to increased fatigue and sleep during the day.

Our results were recently published in an article in the journal Frontiers in Neurology.

People with cognitive and emotional disorders struggle

Our analyses show that patients who report poorer memory and concentration three months following stroke have a higher risk of being more fatigued and sleeping more during the day at twelve months.

The same applies to patients who report major anxiety and depressive symptoms three months after the stroke.

Cognitive and emotional complaints are thus both important factors for increased daytime sleep and fatigue after a stroke. This finding was also evident when we took into account other factors such as age, sex, the severity of the stroke and quality of sleep at night, as well as their relationship to each other over time.

The study was carried out by collaborating researchers in the Vascular Diseases Research Group (VaD) at the Norwegian University of Science and Technology (NTNU) and researchers from the Department for Health Service Research (HØKH) at Akershus University Hospital.

Ramune Grambaite heads the group at NTNU. She is an associate professor in clinical neuropsychology and clinical manager of the Neuropsychological Outpatient Clinic at NTNU’s Department of Psychology. Elisabeth Kliem is the PhD candidate in the research group and the first author of this article.

We used data from NORSPOT, a study that was carried out at Akershus University Hospital between 2012 and 2013. In that study, stroke patients answered questionnaires three and twelve months after their stroke. The patient sample in our study had relatively mild strokes and had no known cognitive or emotional challenges before the stroke.

Important to follow up patients following stroke

Both cognitive and emotional problems are common after a stroke. Our results show the importance of following up on these complaints in the subacute phase after the stroke.

We can reduce the risk of increased fatigue and need for sleep in the long term if we manage to identify and treat stroke patients who struggle cognitively and emotionally.

More research needed

This study is an important step towards a better understanding of fatigue and increased need for sleep following a stroke. Cognitive and emotional problems after a stroke are often not detected in the routine follow-up, but have the potential to greatly affect the patient’s everyday life.

We therefore hope to see more research undertaken in this field, as it can lead to improved diagnostics and treatment of patients in the long term.

Source:

The Norwegian University of Science and Technology (NTNU)

Journal reference:

Kliem, E., et al. (2022). Self-reported cognitive and psychiatric symptoms at 3 months predict single-item measures of fatigue and daytime sleep 12 months after ischemic stroke. Frontiers in Neurology. doi.org/10.3389/fneur.2022.944586.

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February 24, 2024
Mapping the human dysfunctome with deep brain stimulation

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A new study led by investigators from Mass General Brigham demonstrated the use of deep brain stimulation (DBS) to map a ‘human dysfunctome’ -; a collection of dysfunctional brain circuits associated with different disorders. The team identified optimal networks to target in the frontal cortex that could be used for treating Parkinson’s disease, dystonia, obsessive compulsive disorder (OCD) and Tourette’s syndrome. Their results are published in Nature Neuroscience.

“We were able to use brain stimulation to precisely identify and target circuits for the optimal treatment of four different disorders,” said co-corresponding author Andreas Horn, MD, PhD, of the Center for Brain Circuit Therapeutics in the Department of Neurology at Brigham and Women’s Hospital and the Center for Neurotechnology and Neurorecovery at Massachusetts General Hospital. “In simplified terms, when brain circuits become dysfunctional, they may act as brakes for the specific brain functions that the circuit usually carries out. Applying DBS may release the brake and may in part restore functionality.”

Connections between the frontal cortex in the forebrain and basal ganglia, structures located deeper in the brain, are known to control cognitive and motor functions. If brain disorders occur, these circuits may become affected, and their communication may become overactive or malfunction. Previous studies have shown that electrically stimulating the subthalamic nucleus, a small region in the basal ganglia that receives inputs from the entire frontal cortex, can help alleviate symptoms of these disorders.

To understand this relationship better, the authors analyzed data from 534 DBS electrodes in 261 patients from across the globe. Of this cohort, 70 patients were diagnosed with dystonia, 127 with Parkinson’s disease, 50 with OCD and 14 with Tourette’s syndrome. Using software developed by Horn’s team, the researchers mapped the precise location of each electrode and registered results to a common reference atlas to compare locations across patients. The researchers used computer simulations to map tracts that were activated in patients with optimal or suboptimal outcomes.

Using these results, they were able to identify specific brain circuits that had become dysfunctional in each of the four disorders, such as those mapping to sensorimotor cortices in dystonia, the primary motor cortex in Tourette’s, the supplementary motor cortex in Parkinson’s disease and parts of the cingulate cortex in OCD. Notably, the identified circuits partially overlapped, implying that interconnected pathways are disrupted in these disorders.

Further, the investigators were able to apply these findings to fine tune DBS treatments and demonstrate preliminary improved results in three cases, including one at Massachusetts General Hospital, a founding member of Mass General Brigham. This patient, a female in her early 20s, was diagnosed with severe, treatment-resistant OCD involving obsessions about food and water intake, along with compulsive skin picking. Following electrode implantation and targeted stimulation, the researchers were able to show a significant improvement in her symptoms one month after treatment.

Except for the three patients that were tested prospectively, the study was a retrospective analysis of data aggregated from multiple centers. Further studies are needed to validate findings in prospective fashion.

We can take this technique further and finely segregate dysfunctional circuits in order to have greater impact with treatment. For example, with OCD, we can look at isolating circuits for obsessions versus compulsions and so on.”

Barbara Hollunder, MSc, lead author of the Movement Disorders and Neuromodulation Unit in the Department of Neurology, Charité – University Medicine Berlin

Source:

Journal reference:

Hollunder, B., et al. (2024) Mapping Dysfunctional Circuits in the Frontal Cortex Using Deep Brain Stimulation. Nature Neuroscience. doi.org/10.1038/s41593-024-01570-1.

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February 23, 2024