Received: 29 December 2020 Revised: 24 February 2021 Accepted: 12 April 2021 DOI: 10.1002/alz.12372 REVIEW ARTICLE State-of-the-art of lumbar puncture and its place in the journey of patients with Alzheimer’s disease Harald Hampel1 Leslie M. Shaw2 Paul Aisen3 Christopher Chen4 Alberto Lleó5,6 Takeshi Iwatsubo7 Atsushi Iwata8 Masahito Yamada9 Takeshi Ikeuchi10 Jianping Jia11 Huali Wang12 Charlotte E. Teunissen13 Elaine Peskind14 Kaj Blennow15,16 Jeffrey Cummings17 Andrea Vergallo1 1 Eisai Inc., Neurology Business Group, Woodcliff Lake, New Jersey, USA 2 Perelman School of Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 3 USC Alzheimer’s Therapeutic Research Institute, San Diego, California, USA 4 Memory Aging and Cognition Centre, Departments of Pharmacology and Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 5 Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau–Biomedical Research Institute Sant Pau–Universitat Autònoma de Barcelona, Barcelona, Spain 6 Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain 7 Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 8 Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaecho, Itabashi-ku, Tokyo, Japan 9 Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan 10 Department of Molecular Genetics, Brain Research Institute, Niigata University, Asahimachi, Niigata, Japan 11 Innovation Center for Neurological Disorders, Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China 12 Dementia 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 13 Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands 14 VA 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 15 Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden 16 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden 17 Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas (UNLV), Las Vegas, Nevada, USA Correspondence Harald Hampel, Eisai Inc. Neurology Business Abstract Group, 100 Tice Blvd, Woodcliff Lake, NJ 07677, USA. Recent advances in developing disease-modifying therapies (DMT) for Alzheimer’s E-mail: harald_hampel@eisai.com disease (AD), and the recognition that AD pathophysiology emerges decades before clinical symptoms, necessitate a paradigm shift of health-care systems toward Funding information NIH, Grant/Award Number: AG024904; biomarker-guided early detection, diagnosis, and therapeutic decision-making. Appro- Michael J. Fox Foundation for Parkinson’s priate incorporation of cerebrospinal fluid biomarker analysis in clinical practice is an Research, Grant/Award Number: MJFF- 005441; National Medical Research Coun- essential step toward system readiness for accommodating the demand of AD diagno- cil of Singapore; National Natural Science sis and proper use of DMTs—once they become available. However, the use of lumbar This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2021 Eisai, Inc. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association. Alzheimer’s Dement. 2022;18:159–177. wileyonlinelibrary.com/journal/alz 159 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 160 HAMPEL ET AL . Foundation of China, Grant/Award Num- ber: 81530036; National Key Scientific puncture (LP) in individuals with suspected neurodegenerative diseases such as AD Instrument and Equipment Development Project, Grant/Award Number: 31627803; is inconsistent, and the perception of its utility and safety differs considerably among Beijing Municipal Science & Technology medical specialties as well as among regions and countries. This review describes the Commission, Grant/Award Numbers: Z201100005520016, Z201100005520017; state-of-the-art evidence concerning the safety profile of LP in older adults, discusses Beijing Municipal Commission of Health the risk factors for LP-associated adverse events, and provides recommendations and Family Planning, Grant/Award Num- ber: PXM2019_026283_000003; National and an outlook for optimized use and global implementation of LP in individuals with Key Research and Development Project, suspected AD. Grant/Award Number: 2017YFC1311100; Keep Memory Alive; National Institute of KEYWORDS General Medical Sciences, Grant/Award Number: P20GM109025; National Insti- Alzheimer’s disease, biomarker, cerebrospinal fluid, diagnosis, evidence-based guidelines, lumbar tute of Neurological Disorders and Stroke, puncture, system readiness Grant/Award Number: U01NS093334; National Institute on Aging, Grant/Award Number: R01AG053798; European Commis- sion; Health Holland; Selfridges Group Foun- dation; Japan Agency for Medical Research and Development, Grant/Award Numbers: JP20dm0207073, JP20dm0107143; Ministry of Health, Labour and Welfare, Grant/Award Numbers: 19192257, 20316440; ZonMw; Alzheimer’s Association 1 INTRODUCTION 1.1 The challenges facing systems preparedness for AD-modifying therapies Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease that results from complex interactions among genetic, biological, and If a therapeutic approach with a demonstrated effectiveness in slowing environmental factors. Most AD cases are sporadic, and disease risk the biological and clinical progression of AD were to become available, increases with age. Epidemiological projections indicate that AD is a at least 20 million people in the European Union8 and 15 million in the global and fast-growing public health epidemic. Worldwide, the pro- United States9 would require timely and systematic biological screen- portion of people aged 65 years or older is growing rapidly, and it is ing and diagnostic work-up. Beyond diagnosis, biomarkers will play a estimated that by 2060, this age group will account for ≈24% to 29% key role for prognostic evaluation and screening, which are essential of the population in Western Europe and the United States, and 29% for both pharmacological clinical trials and future medical practice.10 to 40% of the population in Asian countries (including China, Japan, In the clinical trial setting, biomarkers are used for patient selection, Singapore, South Korea, and Taiwan).1 With the increase in longevity target engagement, dose adjustment, and long-term identification and and aging populations, the population burden of age-related neurode- monitoring of biological effects.7,11 generative diseases such as AD will rise significantly. Worldwide, an Extensive evidence indicates that prevention and early intervention estimated 46.8 million people were living with all forms of dementia is the most effective way to combat dementia and preserve brain in 2015, and this number is expected to reach 131.5 million in 2050 health at the highest functional level.12,13 It is estimated that the US (Figure 1).2 health-care system could save $7.9 trillion if all AD were diagnosed AD is the most common cause of dementia, accounting for ≈60% early during the MCI stage rather than at the late, full-blown dementia to 80% of cases.3 From a biological standpoint, roughly 30% of clin- stage.3 To prepare health-care systems for disease-modifying ther- ically normal individuals 65 years of age and older have biomarker apies (DMTs) for AD, building capacities for systematic assessment evidence of amyloid accumulation, placing them on the AD biological of AD pathophysiological biomarkers, such as those in the evolving continuum.4–6 With the progress in understanding AD pathophysiol- amyloid/tau/neurodegeneration (AT[N]) system,7 is imperative. ogy and the current definition of AD as a clinical biological framework,7 a number of candidate drugs targeting distinct molecular pathways such as the amyloid beta (Aβ) pathway have shown putative disease- 1.2 The utility of cerebrospinal fluid biomarkers modifying effects and have reached late stages of clinical development for future clinical practice for the treatment of patients in early stages of the AD clinical contin- uum, including the mild cognitive impairment (MCI) stage (i.e., prodro- Two well-validated modalities, cerebrospinal fluid (CSF) biomarkers mal AD), as well as for secondary prevention of cognitive impairment and positron emission tomography (PET), have been widely used to and dementia in patients with preclinical AD. assess AD pathophysiology in vivo.14–16 Blood-based biomarkers 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License HAMPEL ET AL . 161 represent a promising direction of AD biomarker research and hold enormous potential to transform clinical practice, because blood RESEARCH IN CONTEXTS tests are globally accessible and cost-, resource-, and time-effective. 1. Systematic review: In this review, we critically analyze However, at the current stage, blood-based biomarkers are still under the most recent and relevant evidence about the safety development, and both analytical validation and standardization profile of lumbar puncture (LP) when applied to indi- efforts as well as much more research is needed to establish their viduals with neurodegenerative diseases, particularly in utility in clinical trials and clinical practice. Comparing the two more groups most likely to be investigated and treated for established modalities, while PET offers unique insights into the Alzheimer’s disease (AD), based on data from >6000 par- spatial and temporal evolution of AD pathophysiology, CSF analysis ticipants in observational studies and/or attending mem- is more cost-effective, is less resource-intense, provides evidence on ory clinics. In addition, we review the evidence-based several pathophysiological processes, and is more accessible globally clinical guidance and recommendations for optimized use compared to PET brain imaging.8,9 The number of PET scanners and of LP in individuals with suspected AD pathophysiology. cyclotrons is limited, and existing scanners likely have limited time- Furthermore, we highlight new and emerging techniques slots to accommodate additional patients who need Aβ and/or tau of LP that hold the potential to further increase the PET assessments. More importantly, one single CSF analysis with fully operability, time-effectiveness, and eventually safety of automated assays can allow simultaneous investigation of all of the the procedure. The authors reviewed the literature using AT(N) biomarkers (Table 1), thus dramatically accelerating diagnostic, PubMed, Google Scholar, and other sources. prognostic, and therapeutic decision-making.17–21 2. Interpretation: Available evidence from large patient After decades of development and optimization, several well- populations shows that LP is a generally safe procedure validated CSF biomarkers show strong and consistent association with that can be readily incorporated into clinical research AD, and thus have been integrated into the research diagnostic criteria and practice. By aligning the appropriate use of LP in for AD.7,16 A comprehensive summary of the diagnostic and prognostic the diagnostic work-up of AD to international LP con- value of CSF biomarkers is beyond the scope of the current article, and sensus guidelines—with attention to both minimization of can be found in recent reviews.22–24 procedural risk factors and enabling patient stratification according to individual risk of adverse events (AEs)—very low rates of clinically significant AEs related to LP can be 1.3 Factors that limit the widespread use of achieved. The requirement for LP should not, therefore, lumbar puncture and CSF biomarker assessment in constitute a barrier to widespread use of cerebrospinal AD diagnosis fluid (CSF) biomarkers in both clinical trials and medical practice for AD. Despite these advantages, CSF biomarker analysis in the context of 3. Future directions: The review also contains an in- AD—especially its application at suspected preclinical or prodromal depth discussion about the challenges and barriers in stages—has in many countries been hampered partially by low rates of global and regional health-care systems that need to be recommendation and performance of lumbar puncture (LP; also called overcome along the path toward incorporating LP and spinal tap), the medical procedure for CSF collection.25,26 Regional dif- CSF biomarker analysis in the diagnostic journey for ferences in medical practice, insurance coverage, and clinical guidelines patients with AD. Identifying and implementing solutions influence the number of LPs performed each year in individuals with to address such barriers would be an important next suspected AD pathophysiology. Scandinavian and several other Euro- step toward optimizing the next-generation AD patient pean countries have relatively high rates of performance of LP for AD journey. diagnostics in clinical practice, whereas in North America, the use of LP is largely limited to academic clinical and research settings.27 The over- all landscape analysis indicates a considerable hesitation in requesting LP for AD. This is highlighted by a recent analysis of nationwide health- diagnosis is not that important in the absence of an effective treatment, care insurance claims data in Germany, which reported that <1% of are all likely to play a role in limiting the use of this procedure. patients with MCI or overt dementia underwent LP and CSF analysis.28 To examine the incidence and prevalence of AEs occurring during Such hesitation may be attributable to the perceived invasiveness of and after LP performed in the context of an MCI or dementia syndrome, the LP procedure and potential adverse events (AEs), especially when international research frameworks and workgroups have conducted serial procedures are required, and with limited utility of early diagno- prospective studies, as well as systematic registry- and literature- sis and limited improvement from currently available AD therapies. The based reviews and meta-analyses.25,26,28–34 While these studies have concerns about safety are particularly important in the case of prodro- not been double-blinded, or even blinded for the patient, this effort has mal stages of AD (and in the future also for preclinical stages of AD). generated evidence-based medical guidance that supports and informs Last but not least, physicians’ lack of confidence and experience in per- the more widespread use of LP in AD clinical practice and clinical forming LP and CSF biomarker analysis, as well as the perception that trial settings.31–33 In addition, informative videos to demonstrate the 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 162 HAMPEL ET AL . F I G U R E 1 Estimated growth in dementia relative to the size of the aged 60+ population by region. Global incidence and projected growth in numbers of people living with dementia2 TA B L E 1 The amyloid/tau/neurodegeneration (AT[N]) research framework for AD7 Cognitively unimpaired Mild cognitive impairment Dementia A − T− N − Normal AD biomarkers, cognitively unimpaired Normal biomarkers with MCI Normal AD biomarkers with dementia A + T− N − Preclinical AD pathological change AD pathological change with MCI AD pathological change with dementia + + − A T N Preclinical AD AD with MCI (prodromal AD) AD with dementia A + T+ N + A + T− N + AD and concomitant suspected non-AD AD and concomitant suspected non-AD AD and concomitant suspected non-AD pathological change, cognitively unimpaired pathological change with MCI pathological change with dementia A − T+ N + Non-AD pathological change, cognitively Non-AD pathological change with MCI Non-AD pathological change with A − T− N + unimpaired dementia A − T+ N + Abbreviations: A/T/N, amyloid beta deposition, pathologic tau, and neurodegeneration; AD, Alzheimer’s disease; MCI, mild cognitive impairment. +, positive for biomarker based on dichotomous cutoff value. −, negative for biomarker based on dichotomous cutoff value. procedure to physicians and to inform patients, based on the interna- to be overcome to facilitate implementing large-scale, CSF-based tional consensus guidelines, have been developed and are published diagnostic and therapeutic decision-making paradigms, which would with open access.35,36 ultimately enable timely management of AD on a global scale. Here we provide a state-of-the-art review of the most recent and relevant evidence about the safety and tolerability of contemporary LP when applied to neurodegenerative diseases, particularly in the 2 SAFETY OF LP IN SUBJECTIVE COGNITIVE groups most likely to be investigated and treated for AD. In addition, DECLINE, MCI, AND AD we review the evidence-based clinical guidance and recommendations for the optimized use of LP in individuals with suspected AD patho- 2.1 An overview of the most relevant clinical physiology. We highlight new and emerging techniques that hold the evidence potential to significantly improve the safety and feasibility of LP by tailoring the performance of the procedure to the patient’s anatomical The currently available medical evidence shows that LP is a safe pro- and medical profiles. Finally, we review some of the main challenges cedure in older adults with or without cognitive impairment.31 The 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License HAMPEL ET AL . 163 safety profile of LP has been comprehensively documented in studies traction on intracranial veins, eventually triggering meningeal nocicep- leveraging clinical trial data, involving >7000 patients, as well as in rou- tive terminals.39,40 tine clinical practice, involving >30,000 patients with a variety of neu- While mild cases of headache can be treated with caffeine or parac- rological disorders.33 In the context of AD, multiple retrospective and etamol/caffeine, the management of severe and persistent headache prospective studies indicate that LP can be performed safely with low usually involves the use of an epidural blood patch,31 a procedure, complication rates in patients with suspected AD (<1% of serious com- although rarely used in older individuals, that has been shown to be plaints requiring specialist treatment).25,26,29,31–34 Details of key stud- effective (leading to complete recovery) and well-tolerated in all age ies discussed below are summarized in Table 2. ranges, including patients over 65 years old.41 The clinical spectrum of headache after an LP procedure may vary, and besides the typical post- LP headache, some patients may experience non-typical tension-like 2.2 Rates of adverse events headache.38 Other possible post-LP AEs include lower-back discomfort/pain, The largest prospective multicenter feasibility study in the population short-term numbness of the legs, nausea, vomiting, and dizziness; in of interest involved 3868 patients who attended memory clinics, rare cases, vasovagal symptoms such as hypotension or syncope have of whom 3558 underwent LP, and of whom 3456 were available been reported.26,29,31,32 In the multicenter feasibility study conducted for follow-up assessment. In the total study population, 20% of in a pooled cohort of 3868 patients, back pain was reported by 17% participants had subjective cognitive decline, 25% had MCI, 40% of patients; nausea, vomiting, or both by 2.5%; dizziness by 1.3%; and were diagnosed with dementia, and the remaining individuals were vasovagal episode by 0.5%.29 Another feasibility study involving 689 diagnosed with other neurological or psychiatric diseases.29 The mean patients (mean [SD] age 62.4 [9.1] years) reported a similar incidence of (standard deviation [SD]) age was 66 (11) years, and the mean (SD) back pain after LP (16.1%).25 Other studies performed in smaller pop- Mini-Mental State Examination score was 25 (5). This study population ulations reported a lower incidence of non-headache AEs compared to was representative of a real-world hospital or outpatient practice. One large-scale studies.25,26,32 thousand sixty-five participants (31%) reported post-LP complaints, A similar safety profile has been reported in a multicenter study and far fewer individuals required medical intervention. Specifically, investigating the feasibility of LP in the biological diagnosis of neurode- 11 patients (0.3%) received an epidural blood patch, and 23 patients generative diseases including Parkinson’s disease.42 The study enrolled (0.7%) required hospitalization for medical monitoring. All patients 683 participants and reported an overall incidence of AEs after LP had complete recovery after treatment. Based on these findings, of 23%: more than two-thirds of events (68%) were rated as mild, the authors concluded that LP can be performed safely in patients while only 5.6% were rated as severe. The most common AEs were undergoing a diagnostic work-up for suspected AD, and that the headache (13%) and lower-back pain (6.5%). Interestingly, both AEs knowledge of risk factors can be leveraged to reduce the prevalence proved to be significantly more frequent in healthy control individuals of complaints. In the Japanese Alzheimer’s Disease Neuroimaging and patients with other neurological disorders than those with Parkin- Initiative study, 198 of the total 537 individuals (36.9%) across the mild son’s disease.42 Similar findings were reported in the multicenter fea- AD, late MCI, and cognitive normal groups had LP, without any serious sibility study, in which MCI or AD diagnosis was associated with lower AEs reported.37 risk of headache or back pain than for controls, after LP.29 Very rare (in <1 in 10,000 patients) but potentially disabling or fatal complications after LP include infection, cerebral or spinal hem- 2.3 Adverse events profiles after LP orrhage, spinal epidural or subdural cerebral hematoma, and cerebral venous thrombosis.31 The risk of hemorrhage or thrombosis can be LPs may be associated with specific AEs, which are generally mild reduced by normalizing hemostatic factors such as platelet counts and and manageable. Headache and back pain are the most commonly coagulation parameters, including the international normalized ratio reported post-LP AEs. According to The International Classification (INR) and/or the prothrombin time (PT). Anticoagulant medication of Headache Disorders third edition, post-dural puncture headache (dicoumarol, warfarin, novel oral anticoagulants [NOACs] or low is described as headache occurring within 5 days of a LP, believed to molecular weight heparin) should be reviewed before the procedure. be caused by CSF leakage through the dural puncture.38 Typically, it Other diagnostic alternatives (i.e., PET) should be preferred over develops within 3 days of the procedure and manifests as an ortho- LP in a patient on antithrombotics. A temporary discontinuation static or postural, usually frontal, headache, precipitated by moving may be considered case-by-case and performed only when there is from a supine to an upright position and resolving within 20 seconds good benefit/risk ratio, that is, lower risk of thrombosis during the of recumbence.31,34 The incidence of typical post-LP headache ranges discontinuation window. In addition, tight and regular monitoring of from 0.9% to 9.0%.26,29,32,34 More than 85% of post-LP headaches INR and/or PT changes, which generally fall or increase more slowly in resolve without treatment. While the pathophysiological dynamics of older people than young adults, should be de deployed.31,43 The overall post-LP headache are not fully elucidated, in-human data indicate management of antithrombotics in the case of LP for suspected neu- that the leakage of CSF leads to transient intracranial hypotension rodegenerative disease follows the guiding principles of the elective (increased by standing), which causes dilation of as well as pressure and (not in life-threatening conditions) procedure. For instance, the timing 164 TA B L E 2 Key studies of LP safety in patients treated in memory clinics, or healthy volunteers Study Participants Procedural details AE profile Comments BIOMARKAPD 3868 patients attending 23 memory Needle type: Any AE: n = 1065 (30.8%) ∙ 513/649 headaches (79.0%) were mild (patient multicenter clinics: – Cutting edge: n = 2956 (83.1%) Headache: n = 649 (18.8%) functioning normally) or moderate (impaired LP feasibility – Female: n = 3855 (49.9%) – Atraumatic: n = 560 (15.7%) – Typical PLPH: n = 296 (8.6%) functioning, but hospitalization not required) in study29 – Mean (SD) age: 66 (11) years Needle diameter: – Non-specific headache: n = 353 (10.2%) severity – Mean (SD) MMSE: 25 (5) – ≤25 G: n = 982 (27.6%) Back pain: n = 589 (17.0%) ∙ 498/649 headaches (76.7%) resolved within ≤4 Diagnosis: – 23‒24 G: n = 212 (6.0%) – Mild: n = 462 (13.3%) days; 165 (25.4%) resolved within <1 day – Healthy individuals (SCI): n = 754 – 22 G: n = 1,129 (31.7%) – Moderate or persistent (lasting several ∙ 248/649 headaches (38.2%) required no treatment; (19.5%) – 21 G: n = 309 (8.7%) days): n = 127 (3.7%) 379 (58.4%) resolved with analgesic medication – MCI: n = 946 (24.5%) – 19‒20 G: n = 899 (25.3%) Nausea and/or vomiting: n = 86 (2.5%) ∙ Factors associated with reduced risk of typical – AD: 1052 (n = 27.2%) Patient position: Dizziness: n = 45 (1.3%) post-LP headache were: – Other dementia: n = 478 (12.4%) – Lying: n = 1779 (50.0%) Vasovagal collapse: n = 16 (0.5%) – Age >65 years (OR 0.68; 95% CI, 0.46–1.00) – Psychiatric disorders: n = 167 (4.3%) – Sitting: n = 1754 (49.4%) Severe complications: – Dementia (OR 0.84; 95% CI, 0.55–0.80) – Neurological disorders: n = 215 CSF collection: – Blood patch needed: n = 11 (0.3%) – Use of atraumatic needle (OR 0.39; 95% CI, (5.6%) – Free flow/dripping: n = 2749 (77.3%) – Hospitalization needed: n = 23 (0.7%) 0.20–0.75) – Other/unclear: n = 256 (6.6%) – Active withdrawal: n = 661 (18.6%) – Emergency department visit, without ∙ Factors associated with reduced risk of back pain Volume of CSF collected: hospitalization: n = 3 (0.1%) were: – <5 mL: n = 450 (12.6%) – Death: n = 1a – Age >65 years (OR 0.56; 95% CI, 0.48–0.65) – 5–12 mL: n = 1761 (49.5%) – MCI (OR 0.72; 95% CI, 0.54–0.97) – >12 mL: n = 1214 (34.1%) – Dementia (OR 0.74; 95% CI, 0.56–0.99) Spanish 689 patients attending three memory Needle type: Any AE: n = 248 (36.0%) ∙ Risk of headache reduced with age (OR 0.95; 95% CI, multicenter clinics in Spain: – Cutting edge: n = 449 (65.2%) Headache: n = 171 (24.8%) 0.93–0.97) per year study25 – Female: n = 361 (52.4%) – Atraumatic: n = 240 (34.8%) – Typical PLPH: n = 140 (20.3%) ∙ Fear of procedure associated with increased risks of – Mean (SD) age: 62.4 (9.1) years Needle diameter: – Non-specific headache: n = 31 (4.5%) PLPH (OR 2.02; 95% CI, 1.31–3.12) and back pain Diagnosis: – 20 G: n = 169 (24.5%) Back pain: n = 111 (16.1%) (OR 1.809; 95% CI, 1.17–2.78) – Healthy controls: n = 239 (35.3%) – 22 G: n = 520 (75.5%) Dizziness or nausea: n = 27 (3.9%) ∙ Incidence of back pain higher in women than in men – SCI: n = 142 (20.9%) Patient position: (OR 1.95; 95% CI, 1.25–3.04) – MCI: n = 127 (18.7%) – Lateral decubitus: n = 481 (69.8%) ∙ Use of atraumatic needles associated with: – AD: n = 105 (15.5%) – Sitting: n = 208 (30.2%) – Lower incidence of AEs (OR 0.35; 95% CI, – Other: n = 65 (9.6%) CSF collected by gravity dripping at all 0.17–0.37) centers – Lower incidence of PLPH (OR 0.28; 95% CI, Mean (SD) volume of CSF: 9.8 (1.9) mL 0.17–0.47) – Lower incidence of back pain (OR 0.38; 95% CI, 0.23–0.64) ∙ Sitting position associated with increased risk of severe headache (OR 4.70; 95% CI, 1.68–13.1) (Continues) HAMPEL ET AL . 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License TA B L E 2 (Continued) Study Participants Procedural details AE profile Comments HAMPEL ET AL . Peskind et al. Participants enrolled in studies of CSF All punctures performed with 24 G Any AE: n = 47 (11.0%) ∙ Risk of PLPH unrelated to age, sex, position during 200532 biomarkers: atraumatic needle Clinically significant AEs:b n = 17 (4.0%) LP, volume of CSF collected, or duration of rest after – Cognitively normal adults: n = 275 Patient position: Mild headache: n = 19 (4.4%) procedure – Patients with MCI/AD: n = 67 – Lateral decubitus: n = 281 Moderate headache: n = 6 (1.4%) ∙ Incidence of PLPH was significantly lower in – Sitting: n = 147 Severe PLPH: n = 4 (0.9%) participants with MCI/AD than in cognitively normal CSF withdrawn by syringe Mild lower-back soreness: n = 11 (2.6%) individuals (P = .03) 87 participants underwent two LPs Moderate lower-back soreness: n = 2 (0.5%) Vasovagal symptoms:c n = 4 (0.9%) Mild nausea: n = 3 (0.7%) Others:d n = 1 (4.3%) de Almeida et al. 477 research participants (675 LPs) at a All LPs performed using a 22 G PLPH: n = 38 (5.6%) ∙ 32/38 PLPHs resolved after rest, hydration, and 201134 single center atraumatic needle Transient back pain and bleeding (number of over-the-counter analgesics; three required Mean (SD) age: 42 (9) years Median (IQR) volume of CSF collected: cases not reported) prescription analgesics, and one required a blood Prior LPs: 13 mL (12‒14) patch 0: n = 144 (30.2%) ∙ Significant risk factors for PLPH were body mass 1: n = 73 (15.3%) index ≤25 kg/m2 (OR 3.3; 95% CI, 1.5–7.0) and ≤2 2: n = 54 (11.3%) previous LPs (OR 2.1; 95% CI, 1.1–4.1) >2: n = 206 (43.2%) Vilming et al. 239 patients undergoing diagnostic LP All punctures performed using 20 G or PLPH developed in 88/239 patients (36.8%) ∙ PLPH was significantly more common in females 200168 Female: n = 155 (64.9%) 22 G needles than in males (46% vs. 21%, respectively; P = .0003) ∙ Severe PLPH was also more common in females (64% vs. 23%, respectively; P = .02) ∙ Prevalence of PLPH was not related to age, weight, height, or body mass index ∙ PLPH was significantly more common with 20 G needles than with 22 G needles (50% vs. 26%, respectively; P = .0002) Vidoni et al. 525 patients enrolled in ADNI Lumbar puncture performed with either Incidence of PLPH: ∙ Incidence of PLPH was lowest with 24 G atraumatic 2014125 Diagnosis: cutting edge (n = 221) or atraumatic – Non-dementia: n = 3 (2.6%) needles (n = 3; 1.3%) – Non-dementia: n = 114 (n = 304) needles – MCI: n = 21 (6.4%) ∙ No significant difference in PLPH rates between – MCI: n = 311 Needle diameter 18/20 G (n = 61), 22 G – AD: n = 4 (4.0%) punctures using gravity drip or negative pressure to – AD: n = 100 (n = 220), or 24/25 G (n = 244) collect CSF (6.7% vs. 3.7%, respectively) CSF collected by either gravity drip (n = 214) or negative pressure (n = 300) Abbreviations: AD, Alzheimer’s disease; ADNI, Alzheimer’s Disease Neuroimaging Initiative; AE, adverse event; BIOMARKAPD, Biomarkers for Alzheimer’s Disease and Parkinson’s Disease; CI, confidence interval; CSF, cerebrospinal fluid; IQR, interquartile range; LP, lumbar puncture; MCI, mild cognitive impairment; MMSE, Mini-Mental State Evaluation; OR, odds ratio; PLPH, post-lumbar puncture headache; SCI, subjective cognitive impairment; SD, standard deviation. a Caused by intracerebral hemorrhage due to oral anticoagulant treatment 2 days after LP. b Moderate or severe headache, moderate lower-back soreness, vasovagal symptoms, and “other.” c Pallor, diaphoresis, and transient hypotension with or without nausea. d Moderate leg cramps accompanied by nausea. 165 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 166 HAMPEL ET AL . for withholding and resuming varies according to the pharmacological TA B L E 3 Risk factors for headache after LP31 approach adopted to modulate the coagulation activity.27,29,31–35,43 In Patient related Procedure related summary, an LP for the diagnostic work-up of a patient with AD who is ∙ Younger age ∙ Use of a cutting-bevel needle on antithrombotics should be performed only when molecular imaging ∙ Female sex rather than an atraumatic needle is not available and only after individualized and comprehensive ∙ Past history of headache ∙ Use of a large-bore (≤22 gauge) estimation of all the potential risks of therapy discontinuation. ∙ BMI ≤25 kg/m2 needle ∙ Less previous experience ∙ Number of LP attempts of LP ∙ Active rather than passive ∙ Fear of the procedure withdrawal of CSF 2.4 The risk of AEs is not specialist-related ∙ Withdrawal of >30 mL of CSF ∙ Sitting posture during procedure The risk of AEs does not significantly change when the procedure is performed by different health-care professionals. An analysis of 675 Abbreviations: BMI, body mass index; CSF, cerebrospinal fluid; LP, lumbar LPs carried out in prospective research studies reports that ≈95% of puncture. procedures (640/675) were performed by trained and qualified regis- tered nurses (RNs) or nurse practitioners (NPs), and the rest (35/675) in the lumbar region, but not far enough to reach the subarachnoid were performed by physicians.34 The study found that the incidence space. Complications were reported by the volunteers, and evaluated of post-LP headache is similar when the procedure was performed by by another physician, without knowledge of group assignment, and RNs or NPs compared to when the procedure was performed by physi- both led to believe that a standard LP had been performed. The inci- cians (odds ratio [OR] 0.98 [95% confidence interval (CI), 0.23–4.26], dence of headache after the procedure was not statistically different P = .98).34 It is likely that the level of technical training on performing between groups, but post-LP headache was more common for those the LP procedure, rather than the specialty (physician vs. nurse), plays who expressed concern about this complication, suggesting that a major role in the risk of post-LP AEs. This key observation, consis- psychogenic factors play an important role in post-LP headaches.45 tent with experience from other centers that use NPs for LP, supports a Similarly, in the multicenter LP feasibility study,29 anxiety was an more widespread implementation of LP in clinical outpatient practice. independent risk factor for post-LP headache. 2.5 Patients’ perception of the procedure 4 RECOMMENDATIONS FOR REDUCING THE RISK OF POST-LP ADVERSE EVENTS The low rate of request for LP in the AD diagnostic work-up in some countries may be related to patient perception of the procedure. Expert consensus recommendations aimed at reducing the risk of AEs When patients are informed about the safety of the LP procedure, after LP in patients with neurological diseases have been published their perception is generally positive.44 Such patient education can be (Box 1) and are summarized in Figure 2. These recommendations are supported by available informative videos.36 One study enrolling 538 based on a systematic literature review on LP needle characteristics participants aged ≥65 years investigated older adults’ attitudes toward and post-LP complications, data from the multicenter LP feasibility enrolment of non-competent patients with AD (i.e., patients who are study,29 and discussions with participants within the Joint Programme demented and are not competent to provide informed consent) in Neurodegenerative Disease Research Biomarkers for Alzheimer’s Dis- research that does not present potential benefit to patients, such as ease and Parkinson’s Disease and Biomarkers for Multiple Sclerosis exploratory studies on biomarkers; 75% of individuals interviewed consortia.31 declared that they would be willing to be enrolled in AD research using The consensus recommendations address two issues: (1) technical LP even though it does not offer treatment benefit to the patients.30 aspects of the procedure that contribute to a favorable safety pro- file, and (2) strategies for patient stratification based on risk factors for AEs. These recommendations, coupled with compliance with the 3 PSYCHOGENIC FACTORS ON THE INCIDENCE criteria for indications of LP in individuals with suspected AD patho- OF POST-LP COMPLICATIONS physiology, offer three-part guidance for performing LP with maximal clinical confidence in the context of AD diagnostics. The most impor- When discussing the frequencies of AEs such as headache and back tant risk factors for post-LP AEs are reported in Table 3. Below we pain after LP, a possible confounder is that almost all studies were reiterate and expand on some of the key points from the consensus unblinded. They were based on patients in a clinic undergoing LP recommendations.31 as part of the diagnostic assessment, after which the patients were actively asked whether they had any AEs. This study design introduces a risk for bias, with overestimation of the frequencies of complications. 4.1 Technical aspects of the LP procedure that For example, one study used a double-blind design to investigate com- contribute to a favorable safety profile plications after LP.45 The procedure was performed on 100 healthy volunteers; one group of 50 participants had a standard LP, while the Characteristics of needles, such as the design, length, and diameter, are other group had a sham LP with the needle inserted at the same place important technical aspects influencing the safety of LP. In general, the 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License HAMPEL ET AL . 167 F I G U R E 2 Guidance for a safe lumbar puncture. Expert consensus recommendations for reducing the risk of adverse events after lumbar puncture in patients with neurological diseases29,31 associated with conventional and atraumatic needles were 11.0% and BOX 1 4.2%, respectively (relative risk 0.40 [95% CI, 0.34–0.47], P < .0001).46 Based on the consistently favorable safety profile of atraumatic nee- Consensus recommendations to reduce the risk of adverse dles compared to cutting-bevel needles, their use has been recom- events after lumbar puncture for collection of cerebrospinal mended in multiple guidelines addressing neurological practice.47–50 fluid (CSF).29, 31 The main drawback of atraumatic needles is the increased risk of proce- ∙ Evaluate potential contraindications. dure failure in specific categories of patients, such as those with severe ∙ Identify patient-related risk factors. obesity or primary/secondary spine deformity.31,46,51 ∙ Place patient in the lateral recumbent position. Needle diameter (thickness) plays a major role in the risk of ∙ Use an atraumatic narrow-bore (≥22-gauge) needle. post-LP complications. Most studies recommend small-bore needles ∙ Avoid multiple attempts (≤4). (≥24 gauge), which are associated with lower rates of headache, back ∙ Passive rather than active withdrawal of CSF when pain, and discomfort, as well as a lower risk of blood contamination and feasible. CSF leakage.31 Small-bore needles are associated with slower CSF drip ∙ Collect <30 mL of CSF. rate, making the sampling time longer.31 The time of CSF collection, ∙ Communicate effectively to allay patient’s fears and however, is not a risk factor for post-LP AEs, and for diagnostic pur- concerns. poses, <1 millilitre (mL) is needed. The smallest needles (27‒29 gauge) and the large-bore needles (≤22 gauge) are generally not recommended.31,52 choice of the needle for a patient depends on the patient’s age and Standard-length needles (70–90 mm) are used in adults, although weight and the purpose of the procedure. The selection of a specific longer needles may be needed in obese patients.53,54 The use of longer type of needle should aim to minimize discomfort and the risk of com- needles makes the procedure more difficult because such needles are plications (Table 4).31 more flexible and thus have a tendency to divert off track.31,55 This The use of a conventional cutting-bevel needle, rather than an atrau- may necessitate multiple attempts at LP, causing local swelling, bruis- matic (blunt, “bullet” tip) needle, is an important procedure-related risk ing, or muscle spasms, and increasing the risk of back pain.31,55 In factor for post-LP headache. In a meta-analysis of 110 randomized the multicenter feasibility study, compared to individuals for whom controlled trials involving 31,412 patients, rates of post-LP headache the first attempt of LP was successful, the risk of back pain was 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 168 HAMPEL ET AL . TA B L E 4 Characteristics of needles used for LP31 Needle Comparison Advantages Disadvantages Design Cutting bevel ∙ Penetration is felt through skin ∙ Increased complication rates ∙ Requires more use of medications and medical assistance, resulting in higher costs Atraumatic ∙ Reduced complication rates ∙ Decreased flow rates, resulting in longer ∙ Decreased medical health-care costs due to fewer sampling times complications and less need for medical ∙ More attempts and failures assistance and medications ∙ Penetration through skin is difficult to feel ∙ Decreased traumatic taps Length Regular (70–90 mm) ∙ Use in adults ‒ Long (>90 mm) ∙ Use in obese patients ∙ Challenging approach Diameter Small (≥24 gauge) ∙ Reduced complication rates ∙ Decreased flow rates, resulting in longer ∙ Decreased pain and discomfort sampling times ∙ Less risk of blood contamination ∙ More failures ∙ Requires less medical assistance and medications ∙ Requires training and practice Large (≤22 gauge) ∙ Increased flow rates ∙ Increased complication rates ∙ Shorter sampling times ∙ Larger perforations ∙ Fewer failures ∙ Greater risk of contamination Abbreviation: LP, lumbar puncture. approximately doubled when two to four attempts were required (OR 4.2 Patient stratification according to risk of 2.1 [95% CI, 1.7– 2.7]), and increased five-fold when five or more adverse events attempts were needed (OR 5.4 [95% CI, 2.9–10.2]).29 For this reason, it is recommended that no more than four attempts at dural puncture Health-care providers could stratify patients according to individual be made.31,55 risk factors for post-LP AEs or severe complications (Table 3), thereby Active withdrawal of CSF though a syringe reduces the sampling optimizing safety, time, resources, and costs of the procedure. time but is associated with a greater risk of post-LP headache,29 and Younger age appears to be the most important patient-related as such gravity flow removal is recommended compared to active CSF factor affecting the risk of both post-LP headache and lower-back withdrawal.56 The volume of CSF withdrawn (<5 mL vs. >12 mL, tested pain.31 In the multicenter feasibility study, the risk of typical post-LP up to 30 mL) had no significant effect on the risk of post-LP headache headache in patients >65 years of age was 32% lower than in younger or back pain.29,32,34 In an observational AD study, withdrawal of patients (OR 0.68 [95% CI, 0.46–1.00]), and the risk of lower-back pain up to 30 mL of CSF had no adverse effect in terms of complication was 44% lower (OR 0.56 [95% CI, 0.48–0.65]).29 Similar results were rates,57 and this volume is therefore recommended as an acceptable obtained in another feasibility study, involving 689 patients across maximum.31 three memory clinics.25 Increased age was associated with lower LP can be performed with the patient in either a lateral recumbent risks of any headache (OR 0.93 per year [95% CI, 0.91– 0.96]), typical (supine) or sitting position.34,57 The preferred position depends on the post-LP headache (OR 0.94 per year [95% CI, 0.92–0.96]), and severe physician and the patient’s condition.31 There is some evidence sug- headache (OR 0.92 per year [95% CI, 0.87–0.97]).25 The negative gesting that the sitting position during LP might be associated with association between risk of post-LP headache and age is supported a higher risk for severe headache29 or immediate post-procedural by studies conducted in patients with different neurological disease headache.57 and using different protocols.57,60–62 Furthermore, the dementia syn- Evidence suggests that prolonged rest by lying down on a bed drome is associated with an overall reduced risk of post-LP headache. after LP is not associated with lower incidence of AEs compared to In the multicenter feasibility study, individuals with MCI and dementia immediate mobilization.58,59 A systematic review of 24 randomized had lower risks of complications than individuals with normal cognitive controlled trials shows that lying down shortly after the procedure has function (Table 2),29 and similar results have been reported in a longi- no significant effect on the risk of severe post-LP headache compared tudinal study involving 273 participants.61 A low incidence of post-LP to immediate mobilization (relative risk 0.98 [95% CI, 0.68–1.41). A headache (2%) has also been reported in an uncontrolled study of 395 study conducted in 70 patients attending a neurology clinic reports patients with dementia.63 Such findings suggest that the routine use of no significant difference in rates of post-LP headache between LP in older patients with appropriate indications for the evaluation of participants who laid down for 1 or 4 hours after the procedure.58 MCI/dementia should not raise significant safety concerns. 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License HAMPEL ET AL . 169 In terms of sex, several studies reported that post-LP headache terior fossa masses, or Arnold-Chiari malformation. Brain magnetic is more common in women than in men, and especially in women resonance imaging or computed tomography should be carried out ≤40 years of age.48,60,64–67 However, the multicenter feasibility study, in patients with abnormal clinical neurological findings, reduced con- which was a large investigation performed in the aging population sciousness, a relevant history of central nervous system disease, or within memory clinics to define independent risk factors, found no evi- recent seizures. The pre-procedure assessment should include confir- dence of a sex difference in older adults in the incidence of headache or mation of an adequate platelet count (>40 × 109 /L) and coagulation back pain after LP.29 status (international normalized ratio <1.5), and exclusion of coagu- In a review of 675 LPs performed in prospective research studies, lopathies and uncorrected bleeding diathesis.31 the risk of post-LP headache was significantly greater in participants For the use of LP in AD diagnostics specifically, an international with a body mass index (BMI) ≤25.0 kg/m2 than in those with a higher workgroup convened by the US Alzheimer’s Association developed BMI (OR 3.3 [95% CI, 1.5–7.0], P = .001).34 Another study involving 239 recommendations for the appropriate use of LP in the diagnostic work- patients undergoing diagnostic LP found that BMI had no effect on the up of AD, identifying six appropriate and eight inappropriate uses incidence of post-LP headache; however, postural headaches tended to (Table 5).33 The aim of these guidelines is to standardize and optimize develop and resolve more slowly in women with the highest BMIs com- decision-making across general and specialist practitioners. pared to those with lower BMIs.68 Of note, while these recommendations and guidelines are based on Fear of the procedure is an important modifiable risk factor. In the extensive existing data in large patient populations, most studies have multicenter feasibility study, patients were questioned before LP to been conducted in Western countries, and whether the findings can be identify any such fears or a relevant medical history of headache.29 generalized to other populations, such as those in Asia, requires further Compared to patients who reported no concerns, patients who investigation. In addition, currently there are still significant regional described themselves as “very worried” were at significantly higher differences in clinical practice, possibly due to perceptions. For exam- risk of non-specific headache (OR 2.01 [95% CI, 1.39–2.91]) or back ple, physicians in Japan prefer post-LP bed rest for an hour, and they pain (OR 1.41 [95% CI, 1.12–1.78]).29 Similarly, a history of headache hesitate to draw >10 mL CSF. Regional observational studies should was found to be an important risk factor for typical post-LP headache; be performed when necessary to investigate perceptions as well as the the ORs for mild or severe headache in participants with a history of risk factors for LP-associated AEs, which could generate medical evi- headache, compared to those with no such history, were 1.8 (95% CI, dence to inform the diagnostic work-up in specific populations. 1.4–2.6) and 2.7 (95% CI, 1.9–3.7), respectively.29 One study reported that post-LP headache was significantly more common in individuals with limited previous experience of the procedure (≤2 previous proce- 5 EMERGING TECHNIQUES AND INNOVATIONS dures) than in those with more experience (OR 2.1 [95% CI, 1.1–4.1], P IN LP = .03).34 In addition, a prospective study reported that LP is safe when performed in patients with Down syndrome to investigate AD.69 Because the number of attempts is a risk factor for AEs, there is a Identification of such patient-related risk factors can help to iden- clear rationale to optimize the procedure. A growing trend during tify patients at increased risk of post-LP headache and other AEs and the past two decades has been the use of fluoroscopic guidance provides an opportunity to inform and reassure patients and care- to aid LP in patients with particular clinical and anatomical condi- givers before and during the procedure. Careful provision of informa- tions, such as obese patients or those with primary/secondary spinal tion and reassurance of the patient are essential to reduce the risk of deformities.70–72 Intermittent-pulse fluoroscopy can be used to complications.36 Appropriate steps should be taken during the proce- identify the appropriate site for the LP and to monitor the position dure to minimize anxiety and discomfort. of the needle until it reaches the subarachnoid space. This approach can increase success rates and reduce rates of traumatic LP.70–72 However, the success rate is still largely operator-dependent.70 For 4.3 Indications for use of CSF biomarkers in the example, in a retrospective review of 1489 bedside procedures and diagnosis of AD and pre-procedure work-up: 723 fluoroscopy-guided procedures, rates of traumatic LP varied from guidelines from international consortia 0% to 24% depending on the operator.73 Several recent studies sug- gest that “phantoms” or virtual simulations can be useful training aids While the safety of the LP procedure is well established, it is criti- to increase confidence in less experienced health-care providers.74–76 cal that the procedure is applied according to guidelines for appro- Such techniques are under development and validation, and hold the priate use and unnecessary or inappropriate procedures are avoided. potential to inform and optimize procedural planning, anatomical The consensus guidelines for LP in patients with neurological dis- guidance, and safety of LP in an individualized fashion. eases emphasized the importance of a detailed work-up to exclude The increase in the use of fluoroscopy-guided LP reflects the evolu- potential contraindications for LP, such as space-occupying lesions tion of fluoroscopy into a sophisticated technology with advanced 3D with mass effects, coagulopathies, congenital spine abnormalities, and imaging.77 3D fluoroscopy can be useful in guiding LP in cases in which skin infections at the puncture site.31 Clinical neurological examina- there are barriers to the bedside attempts.78 Additional technological tions should be performed to exclude space-occupying lesions, pos- advancements are expected to further facilitate the use of fluoroscopy 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 170 HAMPEL ET AL . TA B L E 5 Clinical indications for appropriate use of LP and CSF analysis in the diagnosis of AD33 Appropriate indications for LP Situations in which LP is not indicated ∙ Patients with SCD (cognitively unimpaired based on ∙ Cognitively unimpaired and within normal range functioning for age as established objective testing) who are considered to be at increased by objective testing; no conditions suggesting high risk and no SCD or expressed risk for AD concern about developing AD ∙ MCI that is persistent, progressing, and unexplained ∙ Cognitively unimpaired patient based on objective testing but considered by ∙ Patients with symptoms that suggest possible AD patient, family informant, and/or clinician to be at risk for AD based on family history ∙ MCI or dementia with an onset at an early age (<65 years) ∙ Patients with SCD (cognitively unimpaired based on objective testing) who are not ∙ Meeting core clinical criteria for probable AD with typical considered to be at increased risk for AD age of onset ∙ Symptoms of REM sleep behavior disorder ∙ Patients whose dominant symptom is a change in ∙ Use to determine disease severity in patients who already received a diagnosis of AD behavior (e.g., Capgras syndrome, paranoid delusions, ∙ Individuals who are APOE ε4 carriers with no cognitive impairment unexplained delirium, combative symptoms, and ∙ Use of LP in lieu of genotyping for suspected autosomal-dominant AD-mutation depression) and for whom AD diagnosis is being carriers considered ∙ Autosomal-dominant AD-mutation carriers with or without symptoms Abbreviations: AD, Alzheimer’s disease; APOE ε4, gene apolipoprotein E allele ε4; LP, lumbar puncture; MCI, mild cognitive impairment; SCD, subjective cognitive decline. to guide LP. In particular, the combination of CT with 3D fluoroscopy training aids are effective and can improve operator confidence, an reduces the radiation dose required for fluoroscopy without compro- important finding considering that medical students or junior doctors mising the spatial resolution.79 often report a lack of confidence in performing the procedure,94,95 and To circumvent the X-ray exposure, ultrasonography-based LP operator stress has been associated with reduced patient confidence in techniques are under development.80,81 This technique can provide the operator and an increased risk of post-LP headache in patients.96 additional information to facilitate needle placement that is not Evidence that these benefits can translate into improved performance available from physical examination, particularly in obese patients or in clinical practice comes from a study involving 110 junior doctors with those with spine deformity.81 The clinical utility of ultrasound-based no previous experience performing LPs.97 Participants who received LP techniques has been demonstrated in a number of randomized goal- and learner-centered video training showed better performance controlled trials, and a meta-analysis of these studies reported higher in a simulated ward setting than those who received traditional procedural success rates with ultrasound-guided LPs compared to instruction.97 Effective training may confer an additional safety benefit landmark/palpation-guided LPs (OR 2.1 [95% CI, 0.66–7.44]).82 to the patient because there is evidence that procedure-specific train- Based on the accumulating evidence,83,84 recommendations for ing may increase the use of atraumatic needles by junior doctors.98,99 the use of ultrasonography in adults undergoing LP published by the US Society of Hospital Medicine propose the use of ultrasound for site selection to reduce the number of needle insertion attempts and 6 POTENTIAL CHALLENGES TO ROUTINE LP IN needle redirections.81,85 Ultrasonography has the advantage of being AD CLINICAL PRACTICE applicable at the bedside, avoiding the need for a fluoroscopy suite. A more advanced form of ultrasound-assisted LP is real-time ultra- Given the increasing demand for AD diagnosis, especially in the advent sound using a needle guidance system (NGS).86 In a randomized of a DMT, models and projections based on the current landscape crossover study comparing real-time, NGS-assisted LP with standard indicate that existing health-care systems and related infrastructures pre-procedure ultrasound in a group of 24 medical students learning to available today do not have the capacity to accommodate such a perform the procedure on a gel phantom, NGS guidance was associated demand for large-scale biological diagnostic assessment.8,9 This would with a significantly greater number of successful punctures per par- result in long wait times and create unnecessary delays in therapeutic ticipant compared to pre-procedure ultrasound (5 [interquartile range decision-making that are ultimately detrimental to patient health. (IQR), 3.3–5.0] vs. 3 [IQR, 1.3–4.0], respectively, P = .005). Importantly, As described above, considering the safety, tolerability, and accep- there was also a reduction in performance time (118 seconds vs. 80.6 tance of LP for assessment of CSF AD biomarkers, it is very likely to seconds, respectively, P < .001), and 23 of 24 participants reported that become a key part of the AD patient journey. Besides the necessity they preferred the real-time, NGS-assisted LP.86 of medical education of health-care providers about recommendations Traditionally, physicians have learned to perform LP through and guidelines for optimal practice of LP, resource and time constraints, unstructured observation and supervision during medical training. low reimbursement rates, and provision of proper training are other Training can be improved by leveraging video-based or simulation- challenges hampering the widespread use of LP in AD.29 based training (using either phantoms87 or virtual-reality devices), Time and resource constraints represent major barriers to the use which are increasingly being evaluated and adopted in adult neu- of LP for the diagnosis of early AD because alternative use of health- rology settings.72–76,88–93 Studies have consistently found that such care provider time could be more convenient for a single hospital or 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License HAMPEL ET AL . 171 neurology clinic. This issue is particularly relevant in high-volume cen- health-care providers may have reservations about performing a pro- ters that have competing needs for resources. For example, tertiary cedure that is not without potential AEs and that may not change clini- hospitals are likely to have limited outpatient procedure rooms, and LP cal management significantly. Thus, it is critical to educate patients and is considered a time-consuming procedure. Tertiary hospitals may also health-care providers about the importance of having an early diagno- have a limited number of standard outpatient rooms with enough space sis of AD. to perform LPs as these are designed for 10 to 20 patient consultations Good communication between physicians and patients and their per session. families is needed to overcome terminological misunderstandings and The time-effectiveness of LP may be improved by avoiding or elimi- alleviate anxiety for the procedure. For example, the Japanese term nating procedures that are not proven to generate clinical benefit. For for LP is “youtsui-senshi” and bone marrow aspiration is “kotsuzui- example, optimizing the time of post-LP rest in a hospital or outpa- senshi.” Because of the similarity between the two terms, patients tient setting is essential from a system readiness perspective. If the and their families might misunderstand LP as bone marrow aspira- existing evidence that there is no significant clinical benefit with post- tion, which is typically painful, leading to reluctance to undergo a LP rest was corroborated, the overall time of LP could be drastically LP. Anxiety has been identified as an independent risk factor for cut, thus facilitating patient turnover. Furthermore, with appropriate post LP headache;29 it is therefore conceivable that informing and training, LP can be performed safely and effectively by nursing staff,100 reassuring patients about the procedure may help to increase the thus reducing the demand for physician time and optimizing time and willingness and preparedness to undergo the procedure as well as resource investment.101 Regardless of specialization, the personnel decrease AEs. Informative videos could help improve the knowl- that perform LP should have sufficient technical training and practice, edge of patients and reduce their fears.36 A recent study involv- and ideally perform the procedure in a frequent and consistent manner, ing 851 individuals who had previously indicated unwillingness to rather than an ad hoc and sporadic manner. be contacted for research involving LP reported that those who From a health-care–system resource perspective, the high medical received gain-framed video education (i.e., emphasizing the propor- costs for patients with AD, compared to cognitively normal individuals tion of individuals free of AEs) had 67% higher odds of changing or those with MCI, are due primarily to high inpatient costs rather their response compared to those who received loss-framed video than the costs of diagnosis.102 Furthermore, several health economic education (i.e., emphasizing the portion experiencing AEs), indicat- studies suggest that CSF biomarker analysis is likely cost-effective. For ing that message framing is important for developing optimal patient example, one study found that the cost-effectiveness of CSF biomarker education.109 analysis depends on the pre-test prevalence of AD; in the scenario of Reimbursement is a critical “system readiness” barrier. While the patients referred to memory clinics with memory impairment who do expenses of performing LP procedures have been covered—to varying not exhibit neuroimaging evidence of medial temporal lobe atrophy, degrees—in the reimbursement frameworks in most countries, overall pre-test prevalence of AD is relatively high (may exceed 15%), and they tend to be low; the expense of CSF biomarker assays is largely not CSF biomarker analysis was deemed cost-effective. As such, the study covered in reimbursement systems. For example, in the United States concluded that biomarker analysis should be considered for adoption in 2020, the physician Medicare payment for a LP is officially listed as in high-prevalence centers.103 Other studies found that detecting AD $143.28, down from $152.09 in 2019.110 In a retrospective analysis of in patients with MCI using CSF biomarkers is cost-effective for dis- 211 LPs performed at a single US center in 2017, the total billable cost ease prediction, progression monitoring, and diagnostic/therapeutic of the procedures was $80,469, but the amount reimbursed was only decision-making.104–106 Furthermore, a study estimated that in the $13,004.111 Moreover, of the 93 cases performed under fluoroscopic UK, although the annual costs of additional amyloid PET scans or CSF guidance for which a separate billing code was added, Medicare paid tests are significant (100,000 extra amyloid PET scans and 100,000 an average of $41. Thus, in some cases, reimbursement does not extra CSF tests at £113 million and £48 million, respectively), they reflect the actual cost of the procedure.111 In Japan, reimbursement are rather modest compared to the likely market price of future for the LP procedure and phospho-tau measurements combined is DMTs or to the costs of inaccurate diagnosis.107 In addition, costs for ≈$90 and physicians often do not believe that this fairly compensates performing LP may have been overestimated in the study, and were, for time and resources. In Europe, obtaining adequate reimbursement for example, based on first-year costs for extensive training (estimated for the costs of CSF analysis can be challenging. A European survey to be 80% of a 1-year salary) plus an additional full-time employment of dementia specialists found that approximately half of the countries of nurses doing two LPs per day and having no other tasks, and may represented did not reimburse the cost of CSF analysis.101 One reason likely be substantially lower in a more streamlined scenario. Health for this may be the lack of expert consensus guidelines on the use systems in different countries/regions vary significantly, and so do of CSF analysis for the diagnostic assessment of dementia, which cost-effectiveness measures, making it necessary to determine the leads to inconsistencies in practice and a lack of standardization of cost-effectiveness in each local system. Nevertheless, it is expected reimbursement.101 In certain Asian countries including Singapore, that the cost-effectiveness associated with CSF biomarkers will patients have limited medical insurance reimbursement for outpatient significantly increase if an effective DMT becomes available.106 procedures. Another barrier is that in the absence of an effective treatment, An overview of factors negatively affecting the widespread use of patients and their families may hesitate to pursue a diagnosis,108 and LP in AD is shown in Figure 3. 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 172 HAMPEL ET AL . F I G U R E 3 Current barriers to widespread use of lumbar puncture (LP) in Alzheimer’s disease (AD) diagnosis. Factors negatively influencing the widespread use of LP in AD diagnosis include patient-related, physician-related, and health system infrastructure-related barriers.8,9,29,101,108 CSF, cerebrospinal fluid 7 CONCLUSIONS biomarkers in both clinical trials and medical practice for AD, as the need for a biopsy is not a barrier to diagnose and treat cancer. Emerging After decades of research and considerable learning from hundreds of techniques and innovations in LP, such as the incorporation of fluo- clinical trials, the field of AD is entering an era of accelerated devel- roscopic guidance and bedside ultrasonography when necessary, can opment whereas a number of promising DMTs are on the near-term further contribute to the safety and feasibility of the procedure in the horizon. In addition, with the increase in longevity and population uncommon scenario in which the regular procedure is not appropriate. aging around the world, the existing health-care systems are facing While CSF biomarker analyses have the potential to become a crit- an unprecedented challenge in timely diagnosis and management of ical component of the globally accessible next-generation AD patient patients with AD. It is imperative for the current health-care systems journey, significant variability has been documented in CSF biomarker to improve and evolve to accommodate the increasing demand for AD measurements, which represents a major hurdle for its widespread diagnosis, and in the advent of DMTs being approved, the timely access, use in clinical decision-making.22,112,113 From a methodological stand- appropriate use, and affordability of costs incurred with DMTs. point, pre-analytical and analytical protocols for CSF collection and Biomarkers are playing an increasingly essential role in guiding handling, assay development, and biomarker analyses in clinical labo- the diagnosis and therapeutic decision-making in AD. Compared to ratories need to be harmonized.22,112,113 other well-validated biomarker modalities, CSF biomarkers represent Pre-analytical workflows and analytical protocols should be har- a cost-, time-, and resource-effective approach with the potential to monized and then standardized at a global scale to reduce inter- improve clinical practice in AD globally. However, their implementation study/inter-site variability and eventually accelerate the biomarker in clinical routine is being delayed by several remediable factors. Avail- development program, that is, discovery, analytical/clinical validation, able evidence from large patient populations shows that LP is a safe and qualification. Pre-analytical factors encompass: different types procedure that can be readily incorporated into clinical research and of tubes, time and temperature before storage, storage temperature practice. By aligning the appropriate use of LP in the diagnostic work- and length, repeated freeze/thaw cycles, among others, and consen- up of AD to international LP consensus guidelines—with attention to sus and harmonized preanalytical protocol for CSF handling have been both minimization of procedural risk factors and enabling patient strat- developed to reduce variability and facilitate reproducibility in CSF ification according to individual risk of AEs—very low rates of clinically biomarker measurements across studies and laboratories.114,115 significant AEs related to LP can be achieved. The requirement for LP In this regard, several international consortia and working groups should not, therefore, constitute a barrier to widespread use of CSF such as The International Federation of Clinical Chemistry and 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License HAMPEL ET AL . 173 Biomedicine Working Group on CSF-Proteins (WG-CSF) and The and CSF biomarker analysis and establish it as an important compo- Alzheimer’s Association International Society to Advance Alzheimer’s nent within the new-generation patient journey, ensuring early disease Research and Treatment (ISTAART), as well as the European Union- detection and timely therapeutic decision-making in AD. North American Clinical Trials in Alzheimer’s Disease Task Force ACKNOWLEDGMENTS (EU/US CTAD Task Force) are intensely supporting the development L. Shaw is supported by NIH grants ADNI U19 AG024904; UPenn of field-wide consensus on the understanding and control for preana- ADRC P30 AG010124; MJFox Foundation for Parkinson’s Research lytical variables on the final biomarker concentrations.22,113 A unified MJFF-005441. C. Chen is supported by the National Medical Research pre-analytical protocol for the core AD CSF biomarkers (Aβ, total tau, Council of Singapore. T. Ikeuchi is supported in part by AMED grants and phosphorylated tau) has recently been devised,116 providing prac- JP20dm0207073 and JP20dm0107143, and MHLW grants 19192257 tical recommendations to overcome the issue of potential variability in and 20316440. J. Jia was supported by the Key Project of the National clinical practice. Natural Science Foundation of China (81530036); the National Key Sci- To follow, the validation steps will be facilitated by (1) widely entific Instrument and Equipment Development Project (31627803); accepted general requirements for the competence of testing and cali- Beijing Scholars Program; Beijing Brain Initiative from Beijing bration laboratories and (2) developing standard operating procedures Municipal Science & Technology Commission (Z201100005520016, (SOPs) stemming from international consensus working groups.117 Z201100005520017); Project for Outstanding Doctor with Combined The ideal assay for large-scale diagnostic practice should fulfil an acceptable balance among the following factors: good accuracy, repro- Ability of Western and Chinese Medicine; and Beijing Municipal Com- ducibility, accessibility, and availability for larger-scale investigations; mission of Health and Family Planning (PXM2019_026283_000003). operability and low expert operator-dependency; and limited demand H. Wang is supported by National Key Research and Development on cost and resource. Project grant 2017YFC1311100. J. Cummings is supported by Keep Memory Alive (KMA); National Institute of General Medical Sciences Different analytical platforms and assays vary in the absolute grant P20GM109025; National Institute of Neurological Disorders levels in the readout, resulting in different cut-offs (i.e., thresholds and Stroke grant U01NS093334; and National Institute on Aging to identify pathology); it is important that investigators who use the grant R01AG053798. Research of C.E. Teunissen is supported by the same platform or assay for CSF analysis work together toward harmo- European Commission (Marie Curie International Training Network, nized analytical protocols and globally accepted cut-offs. The recent Joint Programme – Neurodegenerative Disease), Health Holland, the development of fully automated assays provides the basis for the Dutch Research Council (ZonMw), the Selfridges Group Foundation, development of globally replicable and accepted cut-off points. Fully Alzheimer Netherlands, and the Alzheimer Association. Medical automated assays have already shown good analytical performance, writing support was provided by Paul O’Neill, PhD, of CMC AFFINITY, including limit of quantitation, lot-to-lot comparability, repeatability, McCann Health Medical Communications, and was funded by Eisai. coefficients of variation, and estimated total reproducibility.118–121 These assays have now also been re-calibrated against the available CONFLICTS OF INTEREST certified reference materials (CRMs), to ensure the equivalence H. Hampel is an employee of Eisai Inc. and serves as Senior Associate of results across methods and platforms, and to solve the issue of Editor for the journal Alzheimer’s & Dementia. He has not received any differences in absolute levels.122 fees or honoraria since May 2019. Before May 2019, he was a con- Beyond global methodological standardization, flexible adjustment sultant for, and had received lecture fees from, Servier, Biogen, and of biomarker cut-offs according to relevant biological factors— Roche; research grants from Pfizer Inc., Avid, and MSD Avenir (paid including age, sexual dysmorphism, and apolipoprotein E genotype— to the institution); travel funding from Eisai Inc., Functional Neuro- can improve test accuracy and data interpretation.123,124 In addition, modulation, Axovant, Eli Lilly and Company, Takeda and Zinfandel, GE the range around cutoff values within which there is little change in Healthcare, and Oryzon Genomics; consultancy fees from Qynapse, predictive performance for decline of memory, cognition, and function Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, should be defined.120 GE Healthcare, Oryzon Genomics, and Functional Neuromodulation; The use of LP to enable CSF biomarker analysis in individuals at and participated in the scientific advisory boards of Functional Neu- risk of or with early clinical features of AD offers the opportunity romodulation, Axovant, Eisai Inc., Eli Lilly and Company, Cytox Ltd., to perform a single test and attain the entire AT(N) system profile GE Healthcare, Takeda and Zinfandel, Oryzon Genomics, and Roche of the patient. A CSF-based AT(N) system can be instrumental for Diagnostics. several contexts of use, including diagnosis, prognosis, screening for He is co-inventor in the following patents as a scientific expert and enrolment in clinical trials, and assessment of target engagement and has received no royalties: treatment efficacy. Optimized use of CSF biomarker analysis could enable widespread early detection and management of patients suffer- ∙ In Vitro Multiparameter Determination Method for The Diagnosis ing from AD globally. In this context, a cross-functional collaborative and Early Diagnosis of Neurodegenerative Disorders. Patent Num- effort across academia, the pharmaceutical and biotech industry, the ber: 8916388 health-care community, patient advocacy groups, and regulatory agen- ∙ In Vitro Procedure for Diagnosis and Early Diagnosis of Neurode- cies is essential to construct the appropriate practice paradigm of LP generative Diseases. Patent Number: 8298784 15525279, 2022, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12372 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 174 HAMPEL ET AL . ∙ Neurodegenerative Markers for Psychiatric Conditions. Publication alized management system of neuropsychiatric symptoms (NPSIMS). Number: 20120196300 C.E. Teunissen has a collaboration contract with ADx Neurosciences ∙ In Vitro Multiparameter Determination Method for The Diagnosis and Quanterix, and performed contract research for or received grants and Early Diagnosis of Neurodegenerative Disorders. Publication from Axon Neurosciences, Biogen, Boehringer Ingelheim, Brainstorm Number: 20100062463 Therapeutics, Celgene, EIP Pharma, Eisai inc., Janssen Prevention ∙ In Vitro Method for The Diagnosis and Early Diagnosis of Neurode- Center, Roche, Toyama, and Vivoryon. K. Blennow has served as a con- generative Disorders. Publication Number: 20100035286 sultant, on advisory boards, or data monitoring committees for Abcam, ∙ In Vitro Procedure for Diagnosis and Early Diagnosis of Neurode- Axon Neurosciences, Biogen, JOMDD/Shimadzu, Julius Clinical, Eli generative Diseases. Publication Number: 20090263822 Lilly and Company, MagQu, Novartis, Roche Diagnostics, and Siemens ∙ In Vitro Method for The Diagnosis of Neurodegenerative Diseases. Healthineers, and is a co-founder of Brain Biomarker Solutions in Patent Number: 7547553 Gothenburg AB (BBS), which is part of the GU Ventures Incubator ∙ CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Program. J. Cummings has provided consultation to Acadia, Actinogen, Neuroinflammatory Diseases. Publication Number: 20080206797 Alkahest, Alzheon, Annovis, Avanir, Axsome, Biogen, Cassava, Cerecin, ∙ In Vitro Method for The Diagnosis of Neurodegenerative Diseases. Cerevel, Cortexyme, Cytox, EIP Pharma, Eisai inc., Foresight, GemVax, Publication Number: 20080199966 Genentech, Green Valley, Grifols, Karuna, Merck, Novo Nordisk, ∙ Neurodegenerative Markers for Psychiatric Conditions. Publication Otsuka, Resverlogix, Roche, Samumed, Samus, Signant Health, Suven, Number: 20080131921 and United Neuroscience pharmaceutical and assessment companies. Dr. Cummings has stock options in ADAMAS, AnnovisBio, MedAvante, P. Aisen reports grants from Janssen, Eisai Inc., National Institute and BiOasis. Dr. Cummings owns the copyright of the Neuropsychiatric on Aging, Foundation for the National Institutes of Health, and the Inventory. A. Vergallo is an employee of Eisai Inc. He has not received Alzheimer’s Association; and consulting fees from Merck, Biogen, any fees or honoraria since November 2019. Before November 2019, Roche, Lundbeck, and Immunobrain Checkpoint. C. Chen has provided he had received lecture honoraria from Roche, MagQu LLC, and consultation to Cerecin, Danone, Eisai Inc., Lundbeck, Moleac, and Servier. E. Peskind has provided consultation to Acadia, Avanir, Eli Lilly Senescence. A. Lleó has served as a consultant or on advisory boards and Company, and Takeda. for Fujirebio-Europe, Roche, Biogen, and Nutricia. Dr. Lleó has received funding from the Fondo de Investigaciones Sanitario (FIS), Instituto de AUTHOR CONTRIBUTIONS Salud Carlos III (AC19/00103), and the CIBERNED program (Program Harald Hampel and Andrea Vergallo developed the initial concept 1, Alzheimer Disease) partially funded by Fondo Europeo de Desarrollo and theoretical framework of this article. All authors contributed to Regional, Unión Europea, Una manera de hacer Europa. In addition, researching the literature and data for this article, discussing its con- Dr. Lleó has patent WO2019175379 A1 Markers of synaptopathy tent, and writing and review and/or editing the manuscript. in neurodegenerative disease. A. Iwata has received lecture and consultant fees from Eisai Inc. M. Yamada has received research REFERENCES grants from the Japan Society for the Promotion of Science (JSPS); 1. Population Pyramids of the World from 1950 to 2100 [online]. Avail- the Ministry of Health, Labour and Welfare, Japan (MHLW); and the able at: https://www.populationpyramid.net/world/2060/. Accessed Japan Agency for Medical Research and Development (AMED). He has November 10, 2020. received scholarship grants from Astellas Pharma Inc.; Eisai Co., Ltd.; 2. Prince M, Wimo A, Guerchet M, Ali G, Wu Y, Prina M. 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