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Tag: Neurology

  • WHO calls for urgent action on rising neurological conditions worldwide

    WHO calls for urgent action on rising neurological conditions worldwide

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    A major new study released by The Lancet Neurology shows that, in 2021, more than 3 billion people worldwide were living with a neurological condition. The World Health Organization (WHO) contributed to the analysis of the Global Burden of Disease, Injuries, and Risk Factor Study (GBD) 2021 data.

    Neurological conditions are now the leading cause of ill health and disability worldwide. The overall amount of disability, illness and premature death (known as disability-adjusted life years, DALYs) caused by neurological conditions has increased by 18% since 1990.

    Over 80% of neurological deaths and health loss occur in low- and middle-income countries, and access to treatment varies widely: high-income countries have up to 70 times more neurological professionals per 100 000 people than low- and middle-income countries.

    Neurological conditions cause great suffering to the individuals and families they affect, and rob communities and economies of human capital. This study should serve as an urgent call to action to scale up targeted interventions to allow the growing number of people living with neurological conditions to access the quality care, treatment and rehabilitation they need. It is more important than ever to ensure brain health is better understood, valued and protected, from early childhood to later life.”


    Dr. Tedros Adhanom Ghebreyesus, WHO Director-General

    The top ten neurological conditions contributing to loss of health in 2021 were stroke, neonatal encephalopathy (brain injury), migraine, dementia, diabetic neuropathy (nerve damage), meningitis, epilepsy, neurological complications from preterm birth, autism spectrum disorder, and nervous system cancers.

    Overall, neurological conditions cause more disability and health loss in men compared to women, but there are some conditions like migraine or dementia where women are disproportionately affected.

    Since 1990, the absolute number of individuals living with, or dying from, neurological conditions has increased, while age-standardized DALY rates have dropped. This means that increases in absolute numbers are mainly driven by demographic change and people living longer.

    Diabetic neuropathy was the fastest growing neurological condition. The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million cases in 2021. This increase is in line with the worldwide increase in diabetes. Other conditions such as neurological complications from COVID-19 (for example, cognitive impairment and Guillain-Barré syndrome) did previously not exist and now account for over 23 million cases.

    At the same time, neurological burden and health loss due to other conditions decreased by 25% or more since 1990 as a result of improved prevention (including vaccines), care and research: tetanus, rabies, meningitis, neural tube defects, stroke, neurocysticercosis (parasitic infection that affects the central nervous system), encephalitis (inflammation of the brain), and neonatal encephalopathy (brain injury).

    The study also examined 20 modifiable risk factors for potentially preventable neurological conditions such as stroke, dementia and idiopathic intellectual disability.

    Eliminating key risk factors – most importantly, high systolic blood pressure and ambient and household air pollution – could prevent up to 84% of stroke DALYs. Similarly, preventing exposure to lead could reduce the burden of idiopathic intellectual disability by 63.1%, and reducing high fasting plasma glucose levels could reduce the burden of dementia by 14.6%. Smoking significantly contributed to stroke, dementia and multiple sclerosis risk.

    More investments needed to improve treatment, care and quality of life

    At the World Health Assembly in 2022, Member States adopted the Intersectoral global action plan on epilepsy and other neurological disorders 2022–2031 (IGAP) with an ambitious scope to address the long standing neglect of neurological disorders.

    “The Intersectoral Global Action Plan 2022–2031 sets out a roadmap for countries to improve prevention, early identification, treatment and rehabilitation of neurological disorders. To achieve equity and access to quality care, we also need to invest in more research on risks to brain health, improved support for the healthcare workforce and adequate services,” said Dévora Kestel, Director, WHO Department of Mental Health and Substance Use.

    IGAP sets out strategic objectives and targets to improve access to treatment, care and support for people with neurological disorders; implement strategies for brain health promotion and disease prevention; strengthen research and data; and emphasize a public health approach to epilepsy and other neurological disorders.

    Source:

    The World Health Organization

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  • GPT-4 shows promise in locating brain lesions after stroke

    GPT-4 shows promise in locating brain lesions after stroke

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    Artificial intelligence (AI) may serve as a future tool for neurologists to help locate where in the brain a stroke occurred. In a new study, AI processed text from health histories and neurologic examinations to locate lesions in the brain. The study, which looked specifically at the large language model called generative pre-trained transformer 4 (GPT-4), is published in the March 27, 2024, online issue of Neurology® Clinical Practice, an official journal of the American Academy of Neurology.

    A stroke can cause long-term disability or even death. Knowing where a stroke has occurred in the brain helps predict long-term effects such as problems with speech and language or a person’s ability to move part of their body. It can also help determine the best treatment and a person’s overall prognosis.

    Damage to the brain tissue from a stroke is called a lesion. A neurologic exam can help locate lesions, when paired with a review of a person’s health history. The exam involves symptom evaluation and thinking and memory tests. People with stroke often have brain scans to locate lesions.

    Not everyone with stroke has access to brain scans or neurologists, so we wanted to determine whether GPT-4 could accurately locate brain lesions after stroke based on a person’s health history and a neurologic exam.”


    Jung-Hyun Lee, MD, study author of State University of New York (SUNY) Downstate Health Sciences University in Brooklyn and member of the American Academy of Neurology

    The study used 46 published cases of people who had stroke. Researchers gathered text from participants’ health histories and neurologic exams. The raw text was fed into GPT-4. Researchers asked it to answer three questions: whether a participant had one or more lesions; on which side of the brain lesions were located; and in which region of the brain the lesions were found. They repeated these questions for each participant three times. Results from GPT-4 were then compared to brain scans for each participant.

    Researchers found that GPT-4 processed the text from the health histories and neurologic exams to locate lesions in many participants’ brains, identifying which side of the brain the lesion was on, as well as the specific brain region, with the exception of lesions in the cerebellum and spinal cord.

    For the majority of people, GPT-4 was able to identify on which side of the brain lesions were found with a sensitivity of 74% and a specificity of 87%. Sensitivity is the percentage of actual positives that are correctly identified as positive. Specificity is the percentage of negatives that are correctly identified. It also identified the brain region with a sensitivity of 85% and a specificity of 94%.

    When looking at how often the three tests had the same result for each participant, GPT-4 was consistent for 76% of participants regarding the number of brain lesions. It was consistent for 83% of participants for the side of the brain, and for 87% of participants regarding the brain regions.

    However, when combining its responses to all three questions across all three times, GPT-4 provided accurate answers for 41% of participants.

    “While not yet ready for use in the clinic, large language models such as generative pre-trained transformers have the potential not only to assist in locating lesions after stroke, they may also reduce health care disparities because they can function across different languages,” said Lee. “The potential for use is encouraging, especially due to the great need for improved health care in underserved areas across multiple countries where access to neurologic care is limited.”

    A limitation of the study is that the accuracy of GPT-4 depends on the quality of the information it is provided. While researchers had detailed health histories and neurologic exam information for each participant, such information is not always available for everyone who has a stroke.

    Source:

    American Academy of Neurology

    Journal reference:

    Lee, J-H., et al. (2024) GPT-4 Performance for Neurologic Localization. Neurology Clinical Practice. doi.org/10.1212/CPJ.0000000000200293.

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  • Evolving brain sizes from 1930 to 1970 could signal decreased dementia risk, researchers say

    Evolving brain sizes from 1930 to 1970 could signal decreased dementia risk, researchers say

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    The development and upkeep of the human brain are influenced by both genetic factors and environmental conditions, which may subsequently impact the risk of dementia later in life. Thus, a recent study published in JAMA Neurology assessed whether there were changes in skull and brain size, as well as the thickness of the cortex, across individuals born between the years 1930 and 1970.

    Study: Trends in Intracranial and Cerebral Volumes of Framingham Heart Study Participants Born 1930 to 1970. Image Credit: Gorodenkoff/Shutterstock.comStudy: Trends in Intracranial and Cerebral Volumes of Framingham Heart Study Participants Born 1930 to 1970. Image Credit: Gorodenkoff/Shutterstock.com

    Background

    The health of the American populace has improved significantly due to advancements in healthcare diagnostics and treatment strategies, resulting in an extended average lifespan. However, this increase in longevity also brings a higher likelihood of encountering Alzheimer’s disease and other forms of dementia, as well as various conditions prevalent in older age.

    Fortunately, the dementia incidence is decreasing, perhaps in part because of more education and better preventive measures for cardiovascular risk. Another important contributor may be the early environment.

    The Framingham Heart Study cohort (FHS) includes many generations of people, followed up over decades. The difference between the earliest and latest subjects to be enrolled in the cohort spans over 80 years.

    This led the researchers in the current study to draw their cohort from this study group, examining trends in cardiovascular and brain health in successive generations.

    The aim was to look for a predicted increase in brain development in the US population due to changing early life environment trends. This would reflect in larger brain volumes.

    About the study

    All participants were born between 1925 and 1968. None had been diagnosed with dementia or stroke, and all had undergone magnetic resonance imaging (MRI) between 1999 and 2019. The mean age at MRI varied with the decade of birth but with overlap between decades.

    What were the findings?

    There were over 3,200 participants, the mean age at MRI being 58 years. The images revealed that multiple brain volume measurements showed an upward trajectory with the later birth cohorts.

    The investigators measured intracranial volume (ICV), hippocampal volume (HV), cortical surface area (CSA), cortical gray matter volume (CGMV), and white matter volume (WMV). Females were observed to be 5.5 inches shorter on average, with lower HV, CGMV, and WMV.

    The difference in hippocampal volume was by -0.64 mL, while males had ~54 mL and 63 mL greater volumes for gray and white matter, respectively.

    The 1930s birth cohort had a mean height of 66 inches vs 68 inches for the 1970s birth cohort. The average ICV increased by over 6%, at 1321 mL in the 1970s vs 1234 mL in the 1930s cohort, respectively.  This was after compensating for confounding factors like age, sex, and height.

    Regional measures also varied with the birth cohort, showing a definite trend. Both HV and WMV went up with the decade of birth. So did the CSA, while the cortical thickness decreased, implying cortical atrophy.

    Comparing the 1930s to the 1970s cohort, the largest increase was for CSA, which increased by 15%. The WMV and HV increased by 8% and 6%, respectively, but CGMV by 2%. The cortical thickness declined by over a fifth, from 2.3 mm to 1.9 mm, respectively. There was no significant difference between the sexes.

    Even after limiting the analysis to only those born in the 1940s and aged 55 to 65 years, the same trends were observed, though the differences were attenuated. For instance, the increase in WMV and CGMV were only 0.2% and 0.1%, respectively.

    What are the implications?

    The study results indicate that later generations are experiencing increased brain volume, both overall and regional. The difference was greatest for ICV, WMV, and HV, when the 1930s and 1940s cohorts were compared.

    “We hypothesize that larger brain volumes indicate larger brain development and potentially greater “brain reserve” that could explain the declining incidence of dementia.”

    The ICV reflects normal brain development and does not go down with aging or diseases affecting the volume. In fact, the adult ICV predicts cognitive levels in old age and provides a reliable and consistent biomarker for brain size.

    HV loss may occur early in neurodegenerative conditions, including Alzheimer’s,

    The larger cortical WMV in later cohorts might be the result of greater gyrification, leading to larger CSA. The increased WMV indicates higher neuronal connectivity while reducing the effects of brain tissue loss with aging. The increase in CSA with a reduction in cortical thickness supports this explanation.

    The presence of gyri in the brain increases the brain CSA by 1,700 times compared to the brain of a shrew but limits the increase in cortical thickness to six times. Genes regulate different brain regions differently to develop gyri to various extents.

    The increase in larger brain structures is due to changes in early life experiences, including better education, social environment, and health status. The better preventive measures for cardiovascular disease may be responsible as well. Thus, modifying these factors could also improve resistance to late-life dementia.

    At the population level, these effects may be very important, helping to optimize brain development and building cognitive resilience over the decades.

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  • Xenotransplantation model used for studying microglial response to Alzheimer’s disease

    Xenotransplantation model used for studying microglial response to Alzheimer’s disease

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    Microglia are specialized immune cells in the brain. While they normally protect our brains, they can also contribute to neurodegenerative diseases such as Alzheimer’s. The exact mechanism behind this contribution is not yet fully understood due to the complexities involved in studying them in human brain samples. Now, a research team led by Prof. Bart De Strooper (UK-DRI@UCL and VIB-KU Leuven) and Prof. Renzo Mancuso (VIB-UAntwerp) made a xenotransplantation model – mice with stem-cell-derived human microglia in their brains to observe how human microglia respond to the disease environment. Their findings, published in Nature Neuroscience, will help scientists better understand the complex mechanisms involved in Alzheimer’s disease.

    Alzheimer’s disease (AD) is a complex, progressive neurodegenerative disorder that affects millions of people worldwide. The World Health Organization predicts a tripling of cases by 2050, highlighting the urgent need for new treatments.

    Microglia, our brain’s immune cells, are responsible for clearing debris and responding to inflammation in the brain. Scientists have been studying these cells in AD, as they play a central role in the disease, especially in the building-up of and early response to amyloid-β plaques, a hallmark of the disease. The microglia react to the plaques as they are perceived as foreign to the brain, making them the main drivers of the neuroinflammation that characterizes AD. Studying these cells in human brain samples post-mortem can be challenging because of genetic differences between people, the time between death and examination, and the presence of other brain disorders. Indeed, studies in human postmortem brain samples have shown mixed results regarding the reaction of microglia. It’s also not possible to test the effects of medication on post-mortem brains.

    That is why the first authors of the study, Dr. Nicola Fattorelli and Dr. Anna Martinez Muriana, together with their colleagues at the VIB-KU Leuven Center for Brain & Disease Research, the VIB-UAntwerp Center for Molecular Neurology and the UK Dementia Research Institute, developed a unique mouse model. This xenotransplantation model is genetically engineered to mimic the amyloid-β plaque accumulations seen in humans with AD and can be transplanted stem-cell-derived human microglia. Previously, a similar model was able to show how transplanted human neurons die in AD. Now, this approach allowed the researchers to investigate how human microglia respond to amyloid plaques during the course of the disease.

    Microglial responses to AD

    The scientists found that human microglia showed a much more complex immune response to amyloid-β than their rodent counterparts. Human microglia also displayed a different genetic transition from the normal to the reactive state of the cells.

    This could have implications for the development of treatments. Researchers need to be cautious when using mouse models to study AD in preclinical systems for potential therapeutic targeting of microglia because the responses of human and mouse microglia may not be the same.”

    Professor Renzo Mancuso, first author of the study and group leader at the VIB-UAntwerp Center for Molecular Neurology

    Genetics and early intervention

    The study also revealed that different genetic risk factors for AD influence how human microglia respond to the disease. Moreover, the genetic risk of AD was spread over the different reactive states of the microglia, further demonstrating the importance of microglia in the disease process. This suggests that future microglia-targeted therapies need to be implemented with care as genetic factors might differentially affect their cell states and modify the disease course in unpredictable ways.

    Furthermore, the data hinted at a possible interaction between microglia and soluble forms of amyloid-β, which appear early in the disease process, well before plaques form. This interaction might occur in the very early stages of Alzheimer’s and could potentially influence how the disease progresses. The question remains as to whether this microglial response affects neurons or other brain cells, inducing the cellular responses in AD that ultimately result in neurodegeneration, and what this means for possible treatments. In the meantime, this model provides a unique possibility to test novel drugs against human microglia for the treatment of AD.

    “Overall, this research is an important step toward understanding the mechanisms behind AD. The study provides new insights into the complex ways human microglia respond to AD, which could help researchers develop better treatments for the disease,” concludes Professor De Strooper. “Our findings validate this xenograft model as a powerful tool to investigate the genetics underlying microglial response in Alzheimer’s.”

    Source:

    Vlaams Instituut voor Biotechnologie

    Journal reference:

    Mancuso, R., et al. (2024). Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease-related amyloid-β pathology. Nature Neuroscience. doi.org/10.1038/s41593-024-01600-y.

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  • Skin biopsy for α-synuclein detection proves effective

    Skin biopsy for α-synuclein detection proves effective

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    In a recent study published in JAMA, researchers evaluated the positivity rate of cutaneous phosphorylated alpha-synuclein protein (P-SYN) deposition among individuals with dementia with Lewy body presence (DLB), Parkinson’s disease (PD), pure autonomic failure (PAF), and multiple system atrophy (MSA).

    Study: Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies. Image Credit: BLACKDAY/Shutterstock.comStudy: Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies. Image Credit: BLACKDAY/Shutterstock.com

    Background

    Synucleinopathies are neurodegenerative illnesses that cause P-SYN accumulation in the peripheral and central nervous systems. They include PD, MSA, DLB, and PAF. These illnesses share clinical characteristics, including progressive impairment and neurodegeneration.

    Current pharmacology lacks disease-modifying medication for these illnesses, and many individuals diagnosed with synucleinopathies face diagnostic delays or misdiagnoses.

    A reliable biomarker for identifying synucleinopathies, such as immunohistochemistry of cutaneous phosphorylated α-synuclein, is urgently needed. This test might be sensitive and specific.

    About the study

    In the present prospective, multicenter, cross-sectional study, researchers investigated whether skin biopsy could detect P-SYN in PD, MSA, DLB, and PAF patients.

    The researchers enrolled clinically confirmed cases of DLB, PD, PAF, or MSA recruited from 19 community-based and 11 academic neurology practices between February 2021 and March 2023, aged between 40 and 99 years.

    Individuals without history or clinical features indicative of a synucleinopathy (such as constipation, hyposmia, dementia, rapid-eye movement [REM] sleep disorder, or mild cognitive impairments) or neurodegenerative disorders comprised the control group.

    The researchers excluded individuals with biopsy-associated risks and synucleinopathy-mimicking diseases. They also excluded those with missing data from questionnaires and clinical examinations. The study exposure was a cutaneous biopsy for P-SYN detection.

    The primary outcome was cutaneous P-SYN detection frequency among individuals with MSA, PD, PAF, or DLB and controls.

    The researchers obtained skin biopsy specimens from the posterior cervical area, 3.0 cm from the spinous process of C-7, and the distal aspects of the leg at a distance of 10 cm from the lateral malleolus, and the thigh 10 cm from the lateral knee.

    The team examined the participants using the Hoehn and Yahr scale, the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS), the Montreal Cognitive Assessment, and orthostatic blood pressure.

    The participants filled out questionnaires such as the 39-component Parkinson’s Disease Questionnaire, the European Quality of Life questionnaires (EQ-VAS and EQ-5D), the MSA Quality of Life assessment Questionnaire, the rapid eye movement (REM) sleep disorder questionnaire, and the Orthostatic Hypotension Questionnaire.

    The researchers obtained disease symptom and duration data from participant medical records. The referral physician, who evaluated the individual, provided a clinical diagnosis.

    The participant history, examination scores, medical records, and ancillary test results were transmitted to two disease specialists for central review to validate the diagnosis of the particular synucleinopathy based on specified consensus and eligibility criteria for diagnoses or controls.

    Results

    Out of 428 patients (277 with synucleinopathy and 151 controls), 343 were included in the primary analysis [mean age, 70 years; 175 (51%) men]; 223 fulfilled the consensus criteria for synucleinopathy, and 120 met the criterion as controls following expert panel evaluation.

    Among those with synucleinopathy, 96 (28%) were diagnosed with Parkinson’s disease, 50 (15%) with Lewy body dementia, 55 (16%) with multiple system atrophy, and 22 (6.4%) with complete autonomic failure.

    The proportion of participants with P-SYN in their skin was 93% (n = 89) with Parkinson’s disease, 98% (n=54) with multiple system atrophy, 96% (n=48) with Lewy body dementia, and 100% (n=22) with complete autonomic failure; 3.30% (n=4) of controls had cutaneous phosphorylated-SYN deposition.

    P-SYN detection in the subepidermal plexus varied by synucleinopathy subtype, with MSA (49%, n=27) having a higher prevalence than Parkinson’s disease (3.1%, n=3), DLB (10%, n=5), or PAF (9.1%, n=2). There were no infections or significant problems.

    The length-dependent small fiber neuropathy varies amongst synucleinopathy subtypes. Neuropathy was most prevalent in DLB patients (78%, n=39), followed by those with Parkinson’s disease (63%, n = 60), PAF (46%, n=10), and MSA (22%, n=12).

    The overall P-SYN for all research participants corresponded with their exam results and surveys. P-SYN deposition by the study participants was associated with the period since MSA, PAF, and PD diagnosis.

    Conclusions

    The study findings showed that skin biopsy may identify phosphorylated alpha-synuclein among individuals with DLB, PD, PAF, and MSA. The findings demonstrated that cutaneous P-SYN in >92% of participants, with skin biopsies, was tolerated well with minor side effects.

    However, there were 21% of misdiagnosed cases. Accurate diagnosis is critical for patient and family counseling, starting symptomatic treatment, and conducting clinical studies of possible disease-modifying medications.

    Cognitive neurology experts recommend skin biopsy as a novel method for movement problems. The findings might speed up medication development for synucleinopathies by enhancing patient homogeneity in clinical trials.

    More studies are needed to confirm the findings and better understand the potential relevance of skin biopsy detection in clinical treatment.

    Journal reference:

    • Christopher H. Gibbons, MD, MMSc, et al., (2024) Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies, JAMA 2024, doi: 10.1001/jama.2024.0792.

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  • Novel treatment approach to halt epilepsy progression identified

    Novel treatment approach to halt epilepsy progression identified

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    Only a very small percentage of neurons show changes after an epileptic seizure in mice, but these alterations can be permanent and trigger future seizures that can affect the whole brain and lead to impaired cognition, like memory and learning, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The researchers identified an experimental treatment that, if provided within the first 48 hours after the first seizure, can prevent these long-term changes. The findings, which were published recently in The Journal of Clinical Investigation, suggest a promising target for developing treatments for epilepsy and preventing downstream effects of seizures.

    Epilepsy is characterized by excessive activity of brain cells – neurons – which generate seizures. Research is increasingly showing that the development of epilepsy involves changes of synapses, which are structures that connect one neuron to another. While an estimated 3.4 million people in the United States live with some form of epilepsy, it is still unknown what causes it, and there is no cure. Further, half of individuals with epilepsy experience cognitive impairment, such as problems with memory, or with emotional regulation, but it remains unclear why or how epilepsy changes brain cells to cause this. What’s more, epilepsy is common in children with autism and individuals with dementia. 

    It is clear that there is some connection between an epileptic brain, impaired memory and trouble controlling emotions and how we act on those feelings, but we don’t understand the underlying mechanisms. Existing treatments for epilepsy only help manage seizures. This research gives us a promising starting point for developing therapies that prevent them from happening.”


    Frances E. Jensen, MD, chair of the Department of Neurology, and senior author of the study

    In this study, the researchers used a method that “tagged” neurons in the hippocampus-;an area commonly affected by epilepsy, and critical for memory-;of mice that were activated by epileptic activity. The researchers were able to monitor those activated neurons over time and observe how they responded to subsequent seizures. They found that only about twenty percent of neurons in the hippocampus were activated by seizures. Over time, the overactivity of these neurons diminished their ability to make connections with other neurons, called synapses, which is necessary for learning.

    “The overactive neurons lose their ability to build the strong synapses necessary for learning, which may explain why some people with epilepsy have trouble with learning and with memory,” said Jensen. “If we can stop these neurons from undergoing changes after being activated by seizures, our hope is that we can also prevent not only the progression of epilepsy, but also avoid these cognitive deficits individuals experience long-term.”

    To see if they could prevent neurons from becoming permanently epileptic, the researchers used an experimental glutamate receptor-blocker, called IEM-1460, which has been shown to reduce neuron hyperexcitability in models of mice with epilepsy. They found when they treated mice with this blocker in the first 48 hours after their very first seizure the neurons did not become permanently activated, and the subjects did not experience future seizures or the associated effects, like impaired cognition and trouble learning.

    “Now that we have identified the subgroup of neurons that are impacted by epilepsy, we can investigate what makes these cells vulnerable to becoming epileptic, and whether that is something we can develop a therapy to stop,” said Jensen. “We are also eager to determine whether there is a glutamate receptor-blocker that works similarly to IEM-1460 in humans, which could be given to people after their first seizure, and prevent the lifelong struggles associated with epilepsy.”

    Source:

    University of Pennsylvania School of Medicine

    Journal reference:

    Xing, B., et al. (2024). Reversible synaptic adaptations in a subpopulation of murine hippocampal neurons following early-life seizures. The Journal of Clinical Investigation. doi.org/10.1172/JCI175167.

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  • Innovative Levodopa infusion pump trial shows promise for reducing Parkinson’s symptoms

    Innovative Levodopa infusion pump trial shows promise for reducing Parkinson’s symptoms

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    An international, multisite phase 3 trial co-led by a University of Cincinnati researcher found Parkinson’s disease medication delivered through an infusion pump is safe and effective at reducing symptoms for longer periods of time.

    These results, published March 15 in the Lancet Neurology journal, could lead to additional treatment options for patients with the condition. 

    Parkinson’s symptoms such as tremors, slowness and stiffness are caused by low levels of dopamine in the body. For decades, doctors have treated Parkinson’s by giving patients levodopa, the inactive substance in the brain that once converted makes dopamine. 

    “Levodopa is a replacement strategy. We all make levodopa, but Parkinson’s patients make less of it,” said Espay, co-principal investigator of the trial, James J. and Joan A. Gardner Family Center for Parkinson’s Disease Research Endowed Chair in UC’s Department of Neurology and Rehabilitation Medicine and a physician at the UC Gardner Neuroscience Institute. 

    Espay said oral levodopa is effective and typically helps people regain normal motor function, but its benefits tend to last less than a few hours after a few years, requiring increases in doses or its frequency. 

    Levodopa is most commonly administered orally, but this trial tested continuous, 24-hour levodopa delivery through a subcutaneous infusion pump. A total of 381 patients with Parkinson’s disease in 16 countries enrolled in the trial and were randomized to receive levodopa through the infusion pump or through traditional oral medication.

    The researchers found levodopa delivered through the infusion pump was safe and led to almost two hours of day (1.72) of additional “on time,” or the time when the medication is working and symptoms are lessened, compared to taking levodopa orally.

    Espay said the results of this trial pave the way for this specific infusion pump delivery system to be approved by the Food and Drug Administration and other countries’ respective governing bodies.

    Once approved, this will become an important treatment strategy to consider for patients with Parkinson’s disease experiencing motor fluctuations not adequately controlled with medication. Future studies will need to determine the durability of the long-term benefits and whether any safety issues could emerge, as well as how it might compare with deep brain stimulation.”


    Prof Alberto J Espay, James J and Joan A Gardner Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati

    Two additional subcutaneous delivery systems are also expected to be approved this year, Espay said, and researchers are continuing to study how to improve levodopa formulations and delivery to optimize its effect for patients.

    “Levodopa delivery systems are expected to continue to improve over time,” he said. “This is a thriving area of research for the benefits of our patients.”

    Source:

    Journal reference:

    Espay, A. J., et al. (2024). Safety and efficacy of continuous subcutaneous levodopa–carbidopa infusion (ND0612) for Parkinson’s disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial. The Lancet Neurology. doi.org/10.1016/s1474-4422(24)00052-8

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  • Study highlights growing burden of neurological disorders worldwide

    Study highlights growing burden of neurological disorders worldwide

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    Globally, the number of people living with, or dying from, neurological conditions such as stroke, Alzheimer’s disease and other dementias, and meningitis has risen substantially over the past 30 years due to the growth and aging of the global population as well as increased exposure to environmental, metabolic, and lifestyle risk factors. In 2021, 3.4 billion people experienced a nervous system condition, according to a major new analysis from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, published in The Lancet Neurology journal.

    The analysis suggests that worldwide, the overall amount of disability, illness, and premature death-;a measurement known as disability-adjusted life years (DALYs)-;caused by neurological conditions increased by 18% over the past 31 years, rising from around 375 million years of healthy life lost in 1990 to 443 million years in 2021.

    The absolute number of DALYs is increasing in large part due to aging and growing populations worldwide. However, if the impact of demographics is removed through age-standardization, rates of DALYs and deaths caused by neurological conditions have declined by around a third (27% and 34% respectively) worldwide since 1990-;largely due to better awareness, vaccination, and global prevention efforts for some conditions such as tetanus (93% decrease in age-standardized rates of DALYs), meningitis (62% decrease), and stroke (39% decrease). 

    The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy (brain injury), migraine, Alzheimer’s disease and other dementias, diabetic neuropathy (nerve damage), meningitis, epilepsy, neurological complications from preterm birth, autism spectrum disorder, and nervous system cancers. Neurological consequences of COVID-19 (cognitive impairment and Guillain-Barré syndrome) ranked 20th, accounting for 2.48 million years of healthy life lost in 2021. 

    The most prevalent neurological disorders in 2021 were tension-type headaches (around 2 billion cases) and migraines (about 1.1 billion cases). Diabetic neuropathy is the fastest-growing of all neurological conditions.

    The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes.”


    Dr Liane Ong, co-senior author from the Institute for Health Metrics and Evaluation (IHME), University of Washington, USA

    The current study builds on previous GBD analyses [2] to provide the largest and most comprehensive analysis to compare the prevalence and burden (illness and death) of nervous system disorders between countries on a global scale between 1990 and 2021-;expanding the number of studied neurological conditions from 15 to 37 that span from birth to later life.

    To better reflect that neurological disorders can occur at any stage of life, for the first time the GBD 2021 Nervous System Disorders Collaborators studied neurodevelopmental disorders and neurological conditions in children, and found that they were responsible for almost a fifth (18%) of all DALYs in 2021, accounting for 80 million years of healthy life lost worldwide. 

    “Every country now has estimates of their neurological burden based on the best available evidence,” said lead author Dr Jaimie Steinmetz from IHME. “As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies.”

    The study, conducted to inform ongoing advocacy and awareness efforts, will support the WHO’s Intersectoral Global Action Plan on epilepsy and other neurological disorders 2022–2031 (IGAP) that aims to reduce the impact and burden of neurological disorders and improve the quality of life of people with neurological disorders as well as their caregivers and families.

    Over 80% of neurological deaths and health loss occur in low- and middle-income countries (LMICs)

    Overall, estimates reveal striking differences in nervous system burden between world regions and national income levels. In high-income Asia Pacific and Australasia – regions with the best neurological health – the rate of DALYs and deaths were under 3,000 and 65 per 100,000 people, respectively in 2021. In these regions, stroke, migraine, dementia, diabetic neuropathy, and autism spectrum disorders accounted for most health loss. 

    In contrast, in the worst-off regions of western and central sub-Saharan Africa, the rate of DALYs and deaths were up to five times higher (over 7,000 and 198 per 100,000 people respectively) in 2021, with stroke, neonatal encephalopathy (brain injury), dementia, and meningitis the biggest contributors to years of healthy life lost.

    “Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” said Dr. Tarun Dua, Unit Head of WHO’s Brain Health unit and one of the co-senior authors of the study. “Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries.”

    The authors highlight that, as of 2017, only a quarter of countries globally had a separate budget for neurological conditions, and only around half had clinical guidelines. What’s more, the medical personnel who care for people with neurological conditions are unevenly distributed around the world, with high-income countries having 70 times more neurological professionals per 100,000 individuals than LMICs.

    Prevention needs to be a top priority

    “Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” said co-lead author Dr Katrin Seeher, Mental Health Specialist at WHO’s Brain Health Unit. 

    The study quantified the proportion of nervous system burden that was potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability. 

    The analysis suggests that modifying 18 risk factors over a person’s lifetime-;most importantly high systolic blood pressure (57% of DALYs)-;could prevent 84% of global DALYs from stroke. 

    Additionally, estimates suggest that controlling lead exposure could reduce the burden of intellectual disability by 63%, while reducing high fasting plasma glucose to normal levels could reduce the burden of dementia by around 15%. 

    “The worldwide neurological burden is growing very fast and will put even more pressure on health systems in the coming decades,” said co-senior author Dr Valery Feigin, Director of Auckland University’s National Institute for Stroke and Applied Neuroscience in New Zealand. “Yet many current strategies for reducing neurological conditions have low effectiveness or are not sufficiently deployed, as is the case with some of the fastest-growing but largely preventable conditions like diabetic neuropathy and neonatal disorders. For many other conditions, there is no cure, underscoring the importance of greater investment and research into novel interventions and potentially modifiable risk factors.”

    “Nervous system conditions include infectious and vector-borne diseases and injuries as well as non-communicable diseases and injuries, demanding different strategies for prevention and treatment throughout life,” said Steinmetz “We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world.” 

    Despite these important findings, the authors note several limitations, including that, while they have done their best to capture all nervous system health loss, some conditions were left out because they could not isolate the neurological component, including infections such as HIV, which has a large impact in many parts of the world. And while the study uses the best available evidence, estimates are constrained by the quantity and quality of data, especially in LMICs.

    Writing in a linked Comment, Professor Wolfgang Grisold, President of the World Federation of Neurology, London, UK (who was not involved in the study) says, “This important new GBD report highlights that the burden of neurological conditions is greater than previously thought. In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging, because the effects on the individuals vary substantially.”

    Source:

    Journal reference:

    GBD 2021 Nervous System Disorders Collaborators. (2024). Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet Neurology. doi.org/10.1016/s1474-4422(24)00038-3.

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  • Concussion from explosive blasts may induce Alzheimer’s biomarkers in middle-aged veterans

    Concussion from explosive blasts may induce Alzheimer’s biomarkers in middle-aged veterans

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    Middle-age veterans who experienced concussions due to blasts from explosive devices may have biomarkers in their spinal fluid similar to people who develop Alzheimer’s disease, according to a new study published in the March 13, 2024, online issue of Neurology®, the medical journal of the American Academy of Neurology.

    Traumatic brain injury (TBI) is caused by a bump, blow or jolt to the head or by an injury to the head caused by falls, motor vehicle crashes, assaults or in military personnel, blast and impact injuries.

    Mild TBI, also known as a concussion, is when a person may lose or have an alteration of consciousness. A loss of consciousness is brief, lasting anywhere from moments to up to 30 minutes.

    Previous research has shown that moderate to severe traumatic brain injuries may increase a person’s risk of Alzheimer’s disease. What is lesser known is whether mild traumatic brain injuries from military training and combat may also increase a person’s risk. Our study found that these concussions may indeed increase a person’s risk of Alzheimer’s disease.”


    Elaine Peskind, MD, study senior author of the Northwest Mental Illness Research, Education and Clinical Center at the VA Puget Sound Health Care System and the University of Washington School of Medicine in Seattle

    The study involved 51 veterans who experienced concussion from at least one war zone blast or a combination of blast and impact injuries. They were compared to 85 veterans and civilians who had never experienced a TBI. Participants had an average age of about 35, and all but one participant were male.

    People in the concussion group experienced an average of 20 blast concussions and an average of two impact concussions each.

    All participants took thinking and memory tests. They also had lumbar punctures to collect cerebrospinal fluid. Researchers measured levels of amyloid-beta and tau in the spinal fluid, biomarkers that can be early signs of Alzheimer’s disease.

    Researchers found with increasing age, those with blast concussion had lower levels of amyloid beta, both Aβ42 and Aβ40, in the spinal fluid than the group without concussion. At age 50, those with blast concussion had Aβ42 levels an average of 154 picograms per milliliter (pg/mL) lower than the group without concussion; Aβ40 levels in those with blast concussion were 1,864 pg/mL lower than the group without concussion. The results were unchanged with the presence of the APOE-ε4 allele, a genetic risk factor for Alzheimer’s disease. Researchers did not find a difference in spinal fluid tau levels between the two groups.

     Peskind noted, “A reduction in the levels of Aβ42 in the spinal fluid had been shown in other studies to be a marker of amyloid accumulation in the brain, reflecting one of the earliest steps in the development of Alzheimer’s disease. The levels we saw in this study began at around age 45, approximately 20 years earlier than is seen in the general population.”

    Researchers also found that lower levels of spinal fluid amyloid were associated with poorer performance on memory and thinking tests at older ages. At age 50, for a trail-making test where participants connect a series of dots as quickly as possible while remaining accurate, the average time for the group with concussions was 34 seconds longer than the group without concussions. In addition, on a test that measures verbal memory and includes asking people to recall words after a 20-minute delay, those with concussion scored an average 4.2 points lower than those without concussion. Those with concussion scored 8.8 points compared to those without concussion with 13.1 points.

    “Our data show that biomarkers in the spinal fluid associated with concussions from blasts share some properties with the processes that lead to Alzheimer’s disease later in life,” said Peskind. “While our research does not fully address whether veterans who experience these injuries will develop Alzheimer’s disease, it raises the possibility that they may be on a pathway leading to dementia.”

    A limitation of the study was that the study group was young and had a small number of participants older than 45, an age well before the process underlying Alzheimer’s disease typically begin to emerge. Li said longer studies with more participants are needed that incorporate scans that measure amyloid levels in the brain.

    The study was supported by the Department of Veterans Affairs and the University of Washington Friends of Alzheimer’s Research.

    Source:

    American Academy of Neurology

    Journal reference:

    Li, G., et al. (2024) CSF β-Amyloid and Tau Biomarker Changes in Veterans With Mild Traumatic Brain Injury. Neurology. doi.org/10.1212/WNL.0000000000209197.

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  • New method developed for triggering and imaging seizures in epilepsy patients

    New method developed for triggering and imaging seizures in epilepsy patients

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    Researchers have developed a new method for triggering and imaging seizures in epilepsy patients, offering physicians the ability to collect real-time data to tailor epilepsy surgery. In contrast to previous practice, where physicians from neurology and nuclear medicine had to wait for hours to days in hopes of capturing the onset of a seizure, the new method is convenient, spares resources, and is clinically feasible. This research was published in the March issue of The Journal of Nuclear Medicine.

    People with epilepsy and seizures who do not respond to medication are often helped by brain surgery. The goal of the surgical procedure is to remove the epileptic brain tissue and spare the healthy brain tissue to control seizures but avoid neurological deficits. “Precisely delineating the epileptic brain tissue is essential for successful surgeries, and obtaining timely images of seizures may help formulate surgical plans with increased precision” said Sabry L. Barlatey, MD, PhD, resident in the Department of Neurosurgery at University Hospital of Bern in Bern, Switzerland.

    The ictal SPECT method has been used since the 1990s as the sole neuro-imaging technique able to capture an image of an epileptic seizure propagating in the brain. However, due to the growing cost and time constraints in health care, most epilepsy centers abandoned this potentially informative technique.

    In this study, instead of waiting for spontaneous occurrences, we imaged planned seizures that were triggered with targeted electrical stimulation to the brain. To our knowledge, this simple idea had never been tested before.”

    Maxime O. Baud, MD, PhD, Professor of Neurology, Department of Neurology, University Hospital of Bern

    Three adult participants with left temporal epilepsy were included in the case study. Authors identified and used stereotactic electroencephalography (sEEG) leads in targeted cerebral areas to trigger patient-typical seizures. The radiotracer 99mTc-HMPAO was administered within 12 seconds of ictal onset and SPECT images were acquired within 40 minutes.

    Seizures were successfully triggered in each participant, replicating the patient-typical seizure semiology and electrographic pattern on sEEG without any adverse events. Each triggered seizure was patient-specific, and the imaged early seizure propagation was unique. In the first two cases, ictal SPECT offered complementary information to sEEG and revealed early involvement of brain areas lacking electrode coverage. In the third case, sEEG and ictal SPECT provided overlapping information.

    “The finding of this study is of practical nature, as it greatly facilitates the acquisition of the ictal SPECT,” noted Thomas Pyka, MD, Privatdozent in the Department of Nuclear Medicine at the University Hospital of Bern. “This may help obtain images of greater quality and could contribute to the refinement of resection planning, improving seizure and cognitive outcomes in epilepsy surgery.”

    This study was made available online in January 2024.

    Source:

    Society of Nuclear Medicine and Molecular Imaging

    Journal reference:

    Barlatey, S. L., et al. (2024). Triggered Seizures for Ictal SPECT Imaging: A Case Series and Feasibility Study. The Journal of Nuclear Medicine. doi.org/10.2967/jnumed.123.266515.

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