Plain Language Summary of Publication The use of lumbar puncture and safety recommendations in Alzheimer’s disease: a plain language summary Harald Hampel1, Aya Elhage1, Leslie M Shaw2, Paul Aisen3, Christopher Chen4, Alberto Lleó5,6, Takeshi Iwatsubo7, Atsushi Iwata8, Masahito Yamada9,10,11, Takeshi Ikeuchi12, Jianping Jia13, Huali Wang14, Charlotte E Teunissen15, Elaine Peskind16, Kaj Blennow17,18, Jeffrey Cummings19 & Andrea Vergallo1 1 Eisai Inc., Neurology Business Group, Nutley, New Jersey, USA; 2Perelman School of Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; 3USC Alzheimer’s Therapeutic Research Institute, San Diego, California, USA; 4Memory Aging and Cognition Centre, Departments of Pharmacology and Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 5Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau–Biomedical Research Institute Sant Pau–Universitat Autònoma de Barcelona, Barcelona, Spain; 6Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; 7Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; 8Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan; 9Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan; 10Division of Neurology, Department of Internal Medicine, Kudanzaka Hospital, Tokyo, Japan; 11Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan; 12 Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan; 13Innovation Center for Neurological Disorders, Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China; 14Dementia Care and Research Center, Peking University Institute of Mental Health (Sixth Hospital), Beijing Dementia Key Lab, National Clinical Research Center for Mental Disorders, Beijing, China; 15Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands; 16VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA; 17Institute of Neruoscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; 18Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden; 19Chambers- Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas (UNLV), Las Vegas, Nevada, USA First draft submitted: 30 July 2021; Accepted for publication: 30 September 2021; Published online: 22 July 2022 Summary What is this summary about? How to say (double-click on the icon This is a plain language summary of an article published in Alzheimer’s & Dementia. to play sound)… It looks at a type of test called a lumbar puncture (also known as spinal tap) • Alzheimer’s: ahlts-hahy-merz used in people suspected of having Alzheimer’s disease or some other form of • Lumbar puncture: luhm-buh puhngk-chuh dementia. This summary focuses on how to do a lumbar puncture safely. • Cerebrospinal fluid: suh-ree-brow-spai-nuhl floo-uhd Why is this important? Alzheimer’s disease is a progressive condition, which means it gets worse over time. This leads to difficulties with thinking and memory. People with Alzheimer’s disease show a build up of proteins called amyloid-β and tau in the brain. This is followed by a gradual loss of brain cells and brain function. The changes in the brain are thought to occur years before symptoms appear. Lumbar puncture is a medical procedure during which samples of cerebrospinal fluid are collected. In Alzheimer’s disease, it is used to examine cerebrospinal fluid biomarkers that can help diagnose disease. Lumbar puncture is traditionally considered as a painful and invasive procedure with frequent side effects. However, multiple studies indicate that a lumbar puncture can be performed safely. Side effects are typically mild and do not require specialist intervention. What are the key takeaways? Despite the low risk of serious complications associated with a lumbar puncture, physicians and their patients may be reluctant to recommend or undergo this procedure. Patient education, specialist training, as well as new methods concerning patient safety are important factors to support the widespread use of lumbar puncture in Alzheimer’s disease. Who is this summary for? • This summary may be suitable for physicians and practitioners who diagnose and treat Alzheimer’s disease. • It may also be relevant to people who experience memory and thinking difficulties associated with Alzheimer’s disease, as well as their families or caregivers. part of 10.2217/nmt-2022-0012 © The Authors Neurodegen. Dis. Manag. (2022) 12(5), 221–229 ISSN 1479-6694 221 Plain Language Summary of Publication Hampel, Elhage, Shaw and co-authors Who sponsored this publication? This publication was sponsored by Eisai Inc. Eisai and the authors would like to thank all the people who contributed to this publication. What is the purpose of this summary? • This summary is a review of the scientific literature published to educate physicians, practitioners, and people about a lumbar puncture. It describes the safety profile of performing this procedure in people suspected of having Alzheimer’s disease or some other form of dementia. • This summary highlights the importance of education and specialist training to minimize the side effects that may be associated with this procedure. What is Alzheimer’s disease? • Alzheimer’s disease is the most common cause of dementia. Around 6 in 10 people in the world suffer from dementia due to Alzheimer’s disease. The disease mostly affects people over the age of 65 years. Alzheimer’s disease is increasingly recognized as a process that begins years before symptoms of dementia appear. • It is a long-term and progressive brain disorder that slowly affects the ability to learn, think, remember, and reason. With advancing disease, people with Alzheimer’s disease are no longer able to independently perform everyday activities. This negatively affects their overall quality of life. Confusion Language Behavioral Inability to Increased deficits changes independently dependence Difficulty perform daily on care in learning activities partners new things Memory loss • Brains of people affected with Alzheimer’s disease have a build up of toxic clusters of proteins called amyloid-β and tau. These proteins may contribute to significant brain shrinkage and damage to brain cells. This particularly occurs in the areas of the brain related to memory and thinking. • Researchers do not completely understand what causes Alzheimer’s disease. Current research efforts are ongoing to fill the gaps in our understanding of the disease. • New treatments targeting key proteins of the disease process in Alzheimer’s disease are emerging. 222 Neurodegen. Dis. Manag. (2022) 12(5) future science group Lumbar puncture and safety in Alzheimer’s disease Plain Language Summary of Publication What is the estimated number of global cases of dementia? • Since the average life expectancy has increased, the number of people with age-related brain diseases such as Alzheimer’s disease will rise significantly. • Worldwide, an estimated 46.8 million people were living with all forms of dementia in 2015. This number is expected to reach 131.5 million in 2050. Estimated growth in dementia relative to size of the aged 60+ population by region East Asian & Asia Pacific people with dementia North American 270.4 13.4 M 2015 million people with dementia 36.5 M 2050 European 74.9 4.8 M 2015 people with dementia million 11.7 M 2050 176.6 10.5 M 2015 million 18.7 M 2050 South & Southeast Asian people with dementia Central & South American 201.6 8.7 M 2015 million people with dementia African 28.7 M 2050 people with dementia 72.6 87.2 4.0 M 2015 Australasian & Oceanian million 4.7 M 2015 million people with dementia 18.1 M 2050 15.8 M 2050 6.4 0.4 M 2015 million 1.1 M 2050 What is a biomarker? • Biomarkers (short for biological markers), are measures that reflect what is happening inside the body at any given moment. They can be an indicator for early signs of disease or disease progress. • Biomarkers can be measured by scanning the body or analyzed in body fluids such as blood, urine, saliva, or cerebrospinal fluid. Some diseases can be detected even before people experience symptoms. • Biomarkers can provide detailed information on abnormal changes in the brain. This can help guide timely diagnosis, prognosis, and treatment decisions to ensure the most accurate approach to care for people with Alzheimer’s disease. • Biomarkers may play a key role in selecting people for clinical studies. In the future, they may help in choosing people most likely to benefit from a treatment. • Biomarkers can potentially help monitor the effectiveness and side effects of new and existing treatments. What is the importance of biomarkers in Alzheimer’s disease? • Biomarkers can help confirm diagnosis of Alzheimer’s disease. They play an increasingly important role in various steps along the journey of people with the disease. • Currently, diagnosis is often made by observing symptoms using mental status tests that asseses a person’s thinking and memory skills; a physical exam to assess a person’s coordination, reflexes, and physical ability; blood tests; or brain imaging tests. There is wide evidence supporting the value of biomarkers in the early diagnosis of Alzheimer’s disease. • However, biomarkers are not yet used routinely in many centers. future science group www.futuremedicine.com 223 Plain Language Summary of Publication Hampel, Elhage, Shaw and co-authors What are the current biomarkers associated with Alzheimer’s disease and the AT(N) system? • In people with Alzheimer’s disease, proteins known as amyloid-β and tau cluster together to form amyloid plaques and tau tangles. This is accompanied by abnormal brain function and loss of brain cells, known as neurodegeneration. Amyloid plaques, tau tangles, and neurodegeneration are the hallmarks of Alzheimer’s disease. • The current system for classifying brain changes in Alzheimer’s disease consists of detecting three main biomarkers: amyloid (A), tau (T), and neurodegeneration (N). This is known as the AT(N) system. • These biomarkers are useful in accurately diagnosing people with Alzheimer’s disease. They can be detected in blood, cerebrospinal fluid, or with brain scans. Shrunken brain Healthy with Alzheimer's brain size disease Biomarkers Brain scans Amyloid Amyloid PET Amyloid PET scanning makes the amyloid plaques Amyloid light up on the scan. The bright colored areas indicate plaque increased build up of amyloid plaques in the brain. This is one of the earliest changes observed in the brains of people with Alzheimer's disease Tau Tau PET Tau Tau PET scanning makes the tau tangles light up on tangles the scan. The bright colored areas show increased accumulation of tau tangles in the brains of people with Alzheimer's disease Neurodegeneration Neurodegeneration Metabolic PET MRI Metabolic PET scanning makes brain MRI scanning shows the areas that have abnormally low brain size and structure of the activity light up. The low metabolic activity brain. The darker regions is suggestive of damage to brain cells. This indicate thinning and shrinkage is a common finding in the brains of people of the brains affected with affected with Alzheimer's disease Alzheimer's disease PET: Positron emission tomography; MRI: Magnetic resonance imaging. 224 Neurodegen. Dis. Manag. (2022) 12(5) future science group Lumbar puncture and safety in Alzheimer’s disease Plain Language Summary of Publication What is a lumbar puncture? • Lumbar puncture, sometimes referred to as spinal tap, is a medical procedure that involves inserting a needle into the lower spine (also known as lumbar region) to collect a sample of cerebrospinal fluid. This fluid surrounds the brain and spinal cord. The needle is placed well below the end of the spinal cord and cannot injure the spinal cord. • Lumbar puncture is used to diagnose and treat different health conditions. It can be used to measure biomarkers associated with Alzheimer’s disease in the cerebrospinal fluid, which can help guide timely diagnosis and treatment. People can have a lumbar puncture in either a sitting or lying down position Sitting position Lying position Lumbar puncture (spinal tap) During the procedure, a needle is inserted between the bones of the lower back to collect the spinal fluid What are the steps involved when using lumbar puncture for diagnosis of Alzheimer’s disease? The following diagram shows the steps involved in the lumbar puncture procedure 1. Consultation with a physician after experiencing 2. Diagnostic test: 3. Analysis of 4. Result and symptoms lumbar puncture cerebrospinal fluid diagnosis Evidence for abnormal Lumbar puncture Collect a sample of levels of: Memory in lying or cerebrospinal fluid • Amyloid concerns sitting position for automated analysis • Tau • Neurodegeneration future science group www.futuremedicine.com 225 Plain Language Summary of Publication Hampel, Elhage, Shaw and co-authors What are the benefits of using lumbar puncture compared with brain imaging techniques for diagnosing Alzheimer’s disease? Cost-effective Short sampling times Benefits of the procedure More globally accessible Less resource-intense What are the current barriers to widespread use? People-related Physician and practitioner-related Anxiety Concern • Due to little or no prior experience • Due to lack of confidence and experience of of having the procedure performing the procedure • Due to not having seen a video/visual • Due to the invasiveness of the procedure and demonstrationof the procedure associated side effects Lack of awareness Lack of education and training • On the importance of early diagnosis • On the principles of performing the procedure safely • On the importance of biomarkers • On how to interpret biomarker test results for early diagnosis • On the importance of biomarkers for early diagnosis Hesitancy Perception that diagnosis is not important • Due to lack of understanding on the • Due to lack of available clinical guidelines importance of early diagnosis • Recommendations for optimal practice • To get a diagnosis of Alzheimer's disease since a diagnosis is thought to be of limited value in the absence of an effective treatment Health system infrastructure- related barriers • Insurance coverage conditions • Resource and time constraints 226 Neurodegen. Dis. Manag. (2022) 12(5) future science group Lumbar puncture and safety in Alzheimer’s disease Plain Language Summary of Publication What are the adverse events? • Adverse events are side effects that can cause harm to the body. Adverse events associated with lumbar puncture are uncommon. Multiple studies in Alzheimer’s disease indicate that a lumbar puncture can be performed safely with less than 1 in 100 people experiencing serious side effects. • People who experienced serious adverse events recovered completely after treatment. Post-lumbar puncture headache Potentially disabling complications including infection, bleeding in the Back pain brain, and blood clots or soreness (extremely rare; occur in less than 1 in 10,000 people) Fewer than 4 in 10 people Fainting experience side effects Nausea, (vasovagal associated with dizziness, collapse) lumbar puncture or vomiting Potentially serious complications including the need for Hospitalization a blood patch to close needed off spinal fluid (rare; occur in less than 1 in 100 people) What are the risk factors for headache after a lumbar puncture? People-related factors that increase the risk of headache after a lumbar puncture Body mass in the normal or underweight Female sex Younger age range (BMI less than 25 kg/m²) Fear of procedure Past history Lack of and side effects of headaches experience BMI: Body mass index. future science group www.futuremedicine.com 227 Plain Language Summary of Publication Hampel, Elhage, Shaw and co-authors What is the guidance for a safe lumbar puncture? The following points can help trained clinicians and/or trained medical staff to perform lumbar punctures safely Pencil-point (atraumatic) narrow-bore needle that is more than or equal to 22 gauge • Reduces side effects • Decreases pain and discomfort • Lowers the need for medical intervention for side effects • Lowers risk of blood going into the spinal fluid sample • Less risk of spinal fluid leakage Lying down is the preferred position • Sitting position might be associated with a higher risk of severe headache • Short rest by lying down after the procedure is common practice, but prolonged periods are not required for most people Education and training of physicians and practitioners • Educate physicians and practitioners about the importance of an early diagnosis • Procedure can be performed safely and effectively by trained physicians and practitioners • Effective training through goal- and learner-centered video or simulation-based training Communicate effectively with patients and caregivers • Explain medical terminology to overcome misunderstandings and alleviate fears • Show informative videos to reassure people about the procedure • Educate people and caregivers about the importance of an early diagnosis Avoidance of Passive withdrawal No more than repeated attempts of spinal fluid • Stop procedure after four • Do not “pull” cerebrospinal fluid 4 unsuccessful attempts out with a syringe; let it drop attempts from the needle Tube filling volume (less than 30 mL) Aftercare • Do not fill tubes with more than • Caffeine and pain relief tablets can 30 mL of cerebrospinal fluid, help treat mild headache after using the tube specific for the procedure Alzheimer's disease testing 228 Neurodegen. Dis. Manag. (2022) 12(5) future science group Lumbar puncture and safety in Alzheimer’s disease Plain Language Summary of Publication When should a lumbar puncture be performed to diagnose Alzheimer’s disease? Lumbar puncture can be considered for anyone who may have Alzheimer's disease. For example: People with memory problems People with memory problems that are persistent, getting worse, and risk factors for Alzheimer's disease and unexplained People who show a change People with symptoms in behavior suggestive of possible and are being considered for a Alzheimer's disease diagnosis of Alzheimer’s disease People who develop mild cognitive People with no specific impairment or dementia reasons not to have a before the age of 65 years lumbar puncture What are the take-home points from this summary? • Lumbar puncture is a safe method of obtaining cerebrospinal fluid to test for biomarkers associated with Alzheimer’s disease. • With proper training, potential adverse events can be reduced. • Results from a lumbar puncture can provide valuable diagnostic information of all the AT(N) biomarkers. This can be used to confirm or rule out Alzheimer’s disease. Where can readers find more information? The review article discussed in this summary, called ‘State-of-the-art of lumbar puncture and its place in the journey of patients with Alzheimer’s disease’, was published in Alzheimer’s & Dementia in May 2021. It is free to read at: https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 Acknowledgments Medical writing support was provided by Azhaar Ashraf, PhD, on behalf of CMC AFFINITY, a division of IPG Health Medical Communications, and was funded by Eisai Inc. Financial & competing interests disclosure Full author disclosures can be found in the original article. future science group www.futuremedicine.com 229