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Background: For clinical implementation of Alzheimer's disease (AD) blood-based biomarkers (BBMs), knowledge of short-term variability, is crucial to ensure safe and correct biomarker interpretation, i.e., to capture changes or treatment effects that lie beyond that of expected short-term variability and considered clinically relevant. In this study we investigated short-term intra- and inter-individual variability of AD biomarkers in the intended use population, memory clinic patients., Methods: In a consecutive sample of memory clinic patients (AD n = 27, non-AD n = 20), blood samples were collected on three separate days within a period of 36 days and analysed for plasma Aβ40, Aβ42, p-tau181, p-tau217, p-tau231, T-tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). We measured intra- and inter-individual variability and explored if the variability could be affected by confounding factors. Secondly, we established the minimum change required to detect a difference between two given blood samples that exceeds intra-individual variability and analytical variation (reference change value, RCV). Finally, we tested if classification accuracy varied across the three visits., Results: Intra-individual variability ranged from ~ 3% (Aβ42/40) to ~ 12% (T-tau). Inter-individual variability ranged from ~ 7% (Aβ40) to ~ 39% (NfL). Adjusting the models for time, eGFR, Hba1c, and BMI did not affect the variation. RCV was lowest for Aβ42/Aβ40 (- ~ 15%/ + ~ 17%) and highest in p-tau181 (- ~ 30/ + ~ 42%). No variation in classification accuracies was found across visits., Conclusion: We found low intra-individual variability, robust to various factors, appropriate to capture individual changes in AD BBMs, while moderate inter-individual variability may give rise to caution in diagnostic contexts. High RCVs may pose challenges for AD BBMs with low fold changes and consequently, short-term variability is important to take into consideration when, e.g., estimating intervention effect and longitudinal changes of AD BBM levels., Trial Registration: Clinicaltrials.gov (NCT05175664), date of registration 2021-12-01., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Danish Research Ethics Committee (H-21044863) and followed the tenets of the 1975 Helsinki Declaration. The study was registered at clinicaltrials.gov (NCT05175664). Written informed consent was obtained from each participant prior to enrolment. Consent for publication: Not applicable. Competing interests: KB has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KF serves on a scientific advisory board for Novo Nordisk and Eisai, has given lectures in symposia for Novo Nordisk, and has served or serves as principal investigator in trials for Roche, Biogen, AbbVie, Novo Nordisk and Roche Diagnostics for which fees is paid to the institution and no personal remuneration is received. KF also serves as Editor-in-Chief for Alzheimer´s Research and Therapy (Springer) for which personal remuneration is paid. The other authors have no conflict of interest to report., (© 2025. The Author(s).)

The advancement of disease-modifying treatments (DMTs) for Alzheimer's disease (AD), along with the approval of three amyloid-targeting therapies in the US and several other countries, represents a significant development in the treatment landscape, offering new hope for addressing this once untreatable chronic progressive disease. However, significant challenges persist that could impede the successful integration of this class of drugs into clinical practice. These challenges include determining patient eligibility, appropriate use of diagnostic tools and genetic testing in patient care pathways, effective detection and monitoring of side effects, and improving the healthcare system's readiness by engaging both primary care and dementia specialists. Additionally, there are logistical concerns related to infrastructure, as well as cost-effectiveness and reimbursement issues. This article brings together insights from a diverse group of international researchers and dementia experts and outlines the potential challenges and opportunities, urging all stakeholders to prepare for the introduction of DMTs. We emphasize the need to develop appropriate use criteria, including patient characteristics, specifically for the European healthcare system, to ensure that treatments are administered to the most suitable patients. It is crucial to improve the skills and knowledge of physicians to accurately interpret biomarker results, share decision-making with patients, recognize treatment-related side effects, and monitor long-term treatment. We advocate for investment in patient registries and unbiased follow-up studies to better understand treatment effectiveness, evaluate treatment-related side effects, and optimize long-term treatment. Utilizing amyloid-targeting therapies as a starting point for combination therapies should also be a priority., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bengt Winblad reports financial support was provided by Old Servants Foundation (Gamla Tjänarinnors stiftelse). Christoph Hock reports a relationship with Neurimmune AG that includes: employment. Lars Lannfelt reports a relationship with BioArctic AB that includes: employment. John R Sims reports a relationship with Eli Lilly and Company that includes: employment. Jose Luis Molinuevo reports a relationship with H Lundbeck AB that includes: employment. Philip Scheltens reports a relationship with EQT group that includes: employment. Norbert Zilka reports a relationship with Axon Neuroscience SE that includes: employment. Martin Tolar reports a relationship with Alzheon Inc that includes: employment. Peter Johannsen reports a relationship with Novo Nordisk that includes: employment. Kaj Blennow has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Roche Diagnostics, Sanofi and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. Bengt Winblad is member of the SAB for Axon Neuroscience, AlzeCure, Alzinova, Artery Therapeutics, CoVitality. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions., Methods: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken., Results: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD., Conclusions: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objectives: Distinguishing dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) dementia, particularly in patients with DLB and concomitant AD pathology (DLB/AD+), can be challenging and there is no specific MRI signature for DLB. The aim of this study is to examine the additional value of MRI-based brain volumetry in separating patients with DLB (AD+/-) from patients with AD and controls., Methods: We included 1518 participants from four cohorts (ADC, ADNI, PDBP and PredictND); 147 were patients with DLB (n = 76, DLB/AD+; n = 71, DLB/AD-), 668 patients with AD dementia, and 703 controls. We used an automatic segmentation tool to compute volumes of 70 brain regions, for which age, sex, and head size-dependent z-scores were calculated. We compared individual regions between the diagnostic groups and evaluated whether combining multiple regions improves differentiation. To assess the diagnostic performance, we used the area under the receiver operating characteristic curve (AUC) and sensitivity., Results: The classifier using the combination of 70 volumetric brain regions correctly classified 60% of patients with DLB and 70% of patients with AD dementia. For DLB vs. AD, the classifier produced an AUC of 0.80 (0.77-0.83), which outperformed the best individual region, hippocampus (AUC: 0.73 [0.69-0.76], p < 0.01). For the comparison of DLB/AD+ vs. AD, the classifier increased the AUC to 0.74 (0.68-0.80), which was 0.70 (0.64-0.76) for the hippocampus, p = 0.25., Conclusion: Using a combination of volumetric brain regions improved the classification accuracy, and thus the discrimination, of patients with DLB with and without concomitant AD pathology and AD., Key Points: Question No specific MRI signature for dementia with Lewy bodies (DLB) exists, making the differential diagnosis challenging, especially with dementia due to Alzheimer's disease (AD). Findings Volumes of individual brain regions defined by automatic MRI segmentation differed between DLB and AD patients and controls. Clinical relevance Automatic MRI segmentation can contribute to improving the discrimination of patients with DLB and AD, especially in non-specialized memory clinics., Competing Interests: Compliance with ethical standards. Guarantor: The scientific guarantor of this publication is A.W. Lemstra. Conflict of interest: H.R.M. performs contract research for Combinostics; all funding is paid to her institution. Research programs of W.F. have been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences&Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, Combinostics. W.F. has performed contract research for Biogen MA Inc., and Boehringer Ingelheim. W.F. has been an invited speaker at Boehringer Ingelheim, BiogenMAInc, Danone, Eisai, WebMD Neurology (Medscape), Springer Healthcare. W.F. is consultant to Oxford Health Policy Forum CIC, Roche, and BiogenMAInc. W.F. participated in advisory boards of Biogen MA Inc and Roche. All funding is paid to her institution. W.F. was associate editor of Alzheimer, Research & Therapy in 2020/2021 and is associate editor at Brain. A.G. received a travel grant from Alzheimer Nederland for a research visit to Combinostics. J.L. reports that Combinostics owns the following IPR related to the article: 1. J. Koikkalainen and J. Lötjönen. A method for inferring the state of a system, US 7,840,510 B2. 2. J. Lötjönen, J. Koikkalainen, and J. Mattila. State Inference in a heterogeneous system, US 10,372,786 B2. J.L. is shareholder at Combinostics. F.B. is steering committee or Data Safety Monitoring Board member for Biogen, Merck, Eisai and Prothena. F.B. is advisory board member for Combinostics, Scottish Brain Sciences. Consultant for Roche, Celltrion, Rewind Therapeutics, Merck, Bracco. F.B. has research agreements with ADDI, Merck, Biogen, GE Healthcare, Roche. F.B. is co-founder and shareholder of Queen Square Analytics LTD. The other authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. Statistics and biometry: One of the authors (A.J.T.) has significant statistical expertise. Informed consent: Written informed consent was obtained from all subjects (patients) in this study. Ethical approval: Institutional Review Board approval was obtained. Study subjects or cohorts overlap: Some study subjects or cohorts have been previously reported in studies using the ADC, ADNI and/or PDPB cohorts. Methodology: Retrospective Diagnostic study Multicenter study, (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Several major challenges, including an ageing population and declining workforce and the implementation of recent breakthrough therapies for Alzheimer disease, are prompting a necessary rethink of how people with neurodegenerative dementias are diagnosed and medically managed. Digital health technologies could play a pivotal part in this transformation, with new advances enabling the collection of millions of data points from a single individual. Possible applications include unobtrusive monitoring that aids early detection of disease and artificial intelligence-based health advice. To translate these advances to meaningful benefits for people living with a disease, technologies must be implemented within a system that retains the physician expert as a central figure in decision-making. This Perspective presents a new framework, termed the Digitized Memory Clinic, for the diagnostic pathway of neurodegenerative dementias that incorporates digital health technologies with currently available assessment tools, such as fluid and imaging biomarkers, in an interplay with the physician. The Digitized Memory Clinic will manage people across the entire disease spectrum, from the detection of risk factors for cognitive decline and the earliest symptoms to dementia, and will replace the present paradigm of a pure 'brick-and-mortar' memory clinic. Important ethical, legal and societal barriers associated with the implementation of digital health technologies in memory clinics need to be addressed. The envisioned Digitized Memory Clinic aims to improve diagnostics and enable precise disease-tracking prognostication for individuals with memory disorders and to open new possibilities, such as precision medicine for prevention and treatment., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. Springer Nature Limited.)

Importance: Since 2018, a movement has emerged to define Alzheimer disease (AD) as a purely biological entity based on biomarker findings. The recent revision of the Alzheimer's Association (AA) criteria for AD furthers this direction. However, concerns about a purely biological definition of AD being applied clinically, the understanding of AD by society at large, and the translation of blood-based biomarkers into clinical practice prompt these International Working Group (IWG) updated recommendations., Objective: To consider the revised AA criteria and to offer an alternative definitional view of AD as a clinical-biological construct for clinical use. The recommendations of the 2021 IWG diagnostic criteria are updated for further elaborating at-risk and presymptomatic states., Evidence Review: PubMed was searched for articles published between July 1, 2020, and March 1, 2024, using the terms "biomarker" OR "amyloid" OR "tau" OR "neurodegeneration" OR "preclinical" OR "CSF" OR "PET" OR "plasma" AND "Alzheimer's disease." The references of relevant articles were also searched., Findings: In the new AA diagnostic criteria, AD can be defined clinically as encompassing cognitively normal people having a core 1 AD biomarker. However, recent literature shows that the majority of biomarker-positive cognitively normal individuals will not become symptomatic along a proximate timeline. In the clinical setting, disclosing a diagnosis of AD to cognitively normal people with only core 1 AD biomarkers represents the most problematic implication of a purely biological definition of the disease., Conclusions and Relevance: The ultimate aim of the field was to foster effective AD treatments, including preventing symptoms and dementia. The approach of diagnosing AD without a clinical and biological construct would be unwarranted and potentially concerning without a clear knowledge of when or whether symptoms will ever develop. It is recommended that those who are amyloid-positive only and, more generally, most biomarker-positive cognitively normal individuals, should not be labeled as having AD. Rather, they should be considered as being at risk for AD. The expansion of presymptomatic AD is viewed as a better diagnostic construct for those with a specific pattern of biomarkers, indicating that they are proximate to the expression of symptoms in the near future.

Easily applied diagnostic tools such as digital biomarkers for Alzheimer's disease (AD) are urgently needed due to the recent approval of disease-modifying therapies. We aimed to determine the diagnostic performance of hand-held, quantitative light reflex pupillometry (qLRP) in patients with AD in a proof-of-concept, cross-sectional study. Participants underwent qLRP at a university memory clinic from August 2022 to October 2023. We fitted multivariable logistic regression models with qLRP, sex, and age as predictors evaluated with area under the receiver operating characteristics curve (AUROC). In total, 107 patients with AD, 44 patients with mixed AD and vascular cognitive dysfunction (VCD), 53 patients with dementia with Lewy bodies (DLB), and 50 healthy controls (HCs) were included. Our diagnostic models showed similar discriminatory ability (AUROC range 0.74-0.81) when distinguishing patients with AD from HCs and other dementias. The qLRP seems promising as a bedside digital biomarker to aid in diagnosing AD., Highlights: We demonstrated the diagnostic performance of qLRP in Alzheimer's disease.The diagnostic models were robust in sensitivity analyses.qLRP may assist in the bedside diagnostic evaluation of Alzheimer's disease., Competing Interests: S.G.H. has taught courses for Novo Nordisk with honoraria paid directly to the Danish Dementia Research Center. The remaining authors have no conflicts of interest. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Cued recall taps amnesia of "the hippocampal type" as typically found in Alzheimer's disease (AD). Studies investigating the validity of cued recall measures in AD have typically been conducted in research settings. The Category Cued Memory Test (CCMT-48) measures learning/memory using the same categories during encoding and acquisition. The aim of this study was to investigate how frequently impairments were found on the CCMT-48 mild AD patients from a memory clinic ( N  = 77). We used a case-oriented approach where individually observed scores were compared to expected scores derived from regressions-based normative data. We also investigated if CCMT-48 performances differed in patients with mild AD and Dementia with Lewy Bodies (DLB) ( N  = 90). The results showed a significantly higher frequency of impairment in the AD group as compared to the DLB group for scores below 10th percentile-estimate (impaired: AD 88%; DLB 69%) and 5th percentile-estimate (impaired: AD 82%; DLB 53%). In conclusion, a very high frequency of impairment of a picture-based cued recall test in AD patients (very high sensitivity) in a memory clinic setting. However, specificity is not optimal since impairments also frequently occurred in DLB where memory problems could be assumed to be part of attentional deficits and poor retrieval strategies.

Introduction: Visual rating of the cingulate island sign (CIS) on [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) positron emission tomography (PET) has a high specificity for dementia with Lewy bodies (DLB) in selected cohorts such as DLB versus Alzheimer's disease (AD). In a mixed memory clinical population this study aimed to uncover the prevalence of CIS, the diagnostic accuracy for DLB, and the relationship between CIS and disease severity., Methods: CIS on [ 18 F]FDG-PET was retrospectively assessed with the visual CIS rating scale (CISRs) in 1000 patients with a syndrome diagnosis of mild cognitive impairment (MCI) or dementia with no restrictions in etiological diagnosis., Results: In this cohort 24.3 % had a CISRs score ≥1 and 3.5 % had a CISRs score = 4. The prevalence of a CISRs score ≥1 was highest in DLB (74.0 %, n = 57). A CISRs score ≥1 was present in at least 9 % in other diagnostic groups. The prevalence of CIS across disease severities showed no statistically significant difference (p = 0.23). To differentiate DLB from non-DLB the optimal cut-off was a CISRs score ≥1 (balanced accuracy = 77.1 %) in MCI/mild dementia and a CISRs score ≥2 (balanced accuracy = 80.6 %) in moderate/severe dementia. The positive predictive value of a CISRs score = 4 for DLB was 57.7 % in MCI/mild dementia and 33.3 % in moderate/severe dementia., Conclusion: The CISRs is useful in differentiating DLB from other etiologies in a mixed memory clinical population. Balanced accuracy and positive predictive value may vary across disease severities in the population studied., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In epilepsy, the ictal phase leads to cerebral hyperperfusion while hypoperfusion is present in the interictal phases. Patients with Alzheimer's disease (AD) have an increased prevalence of epileptiform discharges and a study using intracranial electrodes have shown that these are very frequent in the hippocampus. However, it is not known whether there is an association between hippocampal hyperexcitability and regional cerebral blood flow (rCBF). The objective of the study was to investigate the association between rCBF in hippocampus and epileptiform discharges as measured with ear-EEG in patients with Alzheimer's disease. Our hypothesis was that increased spike frequency may be associated with increased rCBF in hippocampus., Methods: A total of 24 patients with AD, and 15 HC were included in the analysis. Using linear regression, we investigated the association between rCBF as measured with arterial spin-labelling MRI (ASL-MRI) in the hippocampus and the number of spikes/sharp waves per 24 h as assessed by ear-EEG., Results: No significant difference in hippocampal rCBF was found between AD and HC (p-value = 0.367). A significant linear association between spike frequency and normalized rCBF in the hippocampus was found for patients with AD (estimate: 0.109, t-value = 4.03, p-value < 0.001). Changes in areas that typically show group differences (temporal-parietal cortex) were found in patients with AD, compared to HC., Conclusions: Increased spike frequency was accompanied by a hemodynamic response of increased blood flow in the hippocampus in patients with AD. This phenomenon has also been shown in patients with epilepsy and supports the hypothesis of hyperexcitability in patients with AD. The lack of a significant difference in hippocampal rCBF may be due to an increased frequency of epileptiform discharges in patients with AD., Trial Registration: The study is registered at clinicaltrials.gov (NCT04436341)., (© 2024. The Author(s).)

Background: Anti-IgLON5 disease is a rare but potentially reversible cause of cognitive impairment, sleep disturbances, dysautonomia, and movement disorders. It is an autoimmune encephalitis which, due to its insidious onset, could mimic neurodegenerative disorders, and multiple symptoms overlap with those seen in dementia with Lewy bodies (DLB). We hypothesized that the symptomatology and findings in patients with anti-IgLON5 disease overlapped with that of DLB., Objectives: To assess the commonality of features in anti-IgLON5 disease and DLB and identify potential red flags for anti-IgLON5 disease in patients undergoing diagnostic evaluation for DLB., Methods: We searched in MEDLINE, Web of Science, and Embase from inception on December the 8th, 2022 with the search term "IgLON5". We performed a systematic review of case reports and case series of anti-IgLON5 disease, and two reviewers independently extracted data on symptoms and findings. Frequencies of symptoms were compared with consensus criteria for DLB., Results: We included 57 studies with 127 individual case reports of anti-IgLON5 disease (mean age 63 years at diagnosis, median symptom duration 2 years). Cognitive dysfunction was reported in 45% of cases, REM-sleep behavioral disorder in 15%, and 14% had parkinsonism. Respiratory insufficiency was reported in 37%, and bulbar symptoms in 67%., Conclusions: We found a significant overlap between anti-IgLON5 disease and DLB. We propose that anti-IgLON5 disease should be considered in young patients with DLB with chorea, gaze palsy, early dysphagia, or prominent respiratory symptoms. Our study contributes to the emerging knowledge on symptoms and biomarkers in anti-IgLON5 disease., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Quantitative light reflex pupillometry (qLRP) may be a promising digital biomarker in neurodegenerative diseases such as Alzheimer's disease (AD), as neuropathological changes have been found in the midbrain structures governing the light reflex. Studies investigating test-retest reliability and short-term, intra-subject variability of qLRP in these patient groups are missing. Our objective was therefore to investigate the test-retest reliability and short-term, intra-subject variability of qLRP in a memory clinic setting, where patients with neurodegenerative disease are frequently evaluated., Methods: Test-retest reliability study. We recruited patients from a tertiary memory clinic and qLRP was carried out at a baseline visit and then repeated on day 3-14 and on day 21-35 using a hand-held pupillometer. We evaluated the test-retest reliability of qLRP by calculating intraclass correlation coefficients (ICCs) and intra-subject, short-term variability by fitting linear mixed models. We compared ICCs for subgroups based on age, sex, disease severity (MCI vs. mild dementia), AD diagnosis, and amount of neurodegeneration (cerebrospinal fluid-total tau levels)., Results: In total, 40 patients (mean age 72 years, 15 female, 22 with mild dementia) were included in the study. We found good-excellent reliability (ICC range 0.86-0.93) for most qLRP parameters. qLRP parameters exhibited limited intra-subject variability and we found no large sources of variability when examining subgroups., Conclusion: qLRP was found to have acceptable test-retest reliability and the study results pave the way for research using longitudinal or cross-sectional measurements to assess the construct in identifying and prognosticating neurodegenerative diseases., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to report., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Despite the number of people living with Alzheimer disease (AD), awareness of the early stages of this condition, including mild cognitive impairment due to AD-which poses management challenges-continues to be low. To identify areas for improvement in early AD management, dementia specialists convened in a virtual roundtable meeting., Methodology: A modified version of the nominal group technique was followed to prioritize specific topics and allow experts to provide their opinions. The overarching topics prioritized and discussed were (1) education and support for primary care physicians on cognitive assessment, detection of mild cognitive impairment, and patient monitoring; (2) nonpharmacological interventions; (3) and the introduction of disease-modifying therapies., Conclusions: Consensus was achieved regarding the need for educating primary care physicians on identifying people with cognitive impairment and for better diagnostic tools for its detection and early management. Management of mild cognitive impairment due to AD should encompass an adequate follow-up schedule aiming to maintain function for as long as possible, and primary care physicians and patients should be aware of the benefits of nonpharmacological interventions., Competing Interests: K.S.F. serves on a scientific advisory board for Novo Nordisk, for which no compensation is received. H.Z. has served on scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZpath, Annexon, Apellis, Artery Therapeutics Inc., AZ Therapies Inc., Cognition Therapeutics Inc., Denali Therapeutics, Eisai, NervGen, Novo Nordisk, OptoCeutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed (now, Biosplice Therapeutics), Siemens Healthineers, Triplet Therapeutics, and Wave Life Sciences. He has given lectures in symposia sponsored by Cellectricon, Fujirebio, AlzeCure, Biogen, and Roche. He is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside this submitted work). S.G. has served on scientific advisory boards for Advantage Therapeutics, Alzheon, AmyriAD, Biogen Canada, Eisai Canada, Enigma, Lilly Canada, Lundbeck, Medesis, Roche Canada, Sharon Francis Foundation, and TauRx. Further, he is on the editorial board of the Journal of Prevention of Alzheimer’s Disease . M.B. is an employee of the Ace Alzheimer Center and an advisory board member for Grifols, Roche, Eli Lilly, Araclon Biotech, Merck, Zambon, Biogen, Novo Nordisk, Bioiberica, Eisai, Servier, and Schwabe Pharma. S.M. serves on the board of directors of Senscio Systems, Inc., and on the scientific advisory board of AiCure Technologies, ALZpath, and Boston Millennia Partners. He has received consulting fees from Biogen, C2N Diagnostics, Eisai, Novartis, and Roche/Genentech. X.M. and V.P. are employees of the Ace Alzheimer Center and have no conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Portable digital health technologies (DHTs) could help evaluate non-cognitive symptoms, but evidence to support their use in patients with dementia with Lewy bodies (DLB) is uncertain., Objective: 1) To describe portable or wearable DHTs used to obtain digital biomarkers in patients with DLB, 2) to assess the digital biomarkers' ability to evaluate non-cognitive symptoms, and 3) to assess the feasibility of applying digital biomarkers in patients with DLB., Methods: We systematically searched databases MEDLINE, Embase, and Web of Science from inception through February 28, 2023. Studies assessing digital biomarkers obtained by portable or wearable DHTs and related to non-cognitive symptoms were eligible if including patients with DLB. The quality of studies was assessed using a modified check list based on the NIH Quality assessment tool for Observational Cohort and Cross-sectional Studies. A narrative synthesis of data was carried out., Results: We screened 4,295 records and included 20 studies. Seventeen different DHTs were identified for assessment of most non-cognitive symptoms related to DLB. No thorough validation of digital biomarkers for measurement of non-cognitive symptoms in DLB was reported. Studies did not report on aspects of feasibility in a systematic way., Conclusions: Knowledge about feasibility and validity of individual digital biomarkers remains extremely limited. Study heterogeneity is a barrier for establishing a broad evidence base for application of digital biomarkers in DLB. Researchers should conform to recommended standards for systematic evaluation of digital biomarkers.

Background: This study prospectively examined the association between adverse experiences (physical abuse, sexual abuse and parental substance use problems [SUPs]), not being employed, in education or training (NEET) and being in need of acute psychiatric help among patients receiving treatment for substance use disorders. Methods: A total of 580 adolescents and early adults aged 15-25 years enrolled in treatment for drug use disorders were included in the analyses. Treatment data were linked to participants' register data on employment, education and acute contact to psychiatric services for the following two years. Multivariable logistic regression models were used to examine associations between the three adverse experiences, NEET and need of acute psychiatric help, adjusting for confounders such as age, gender, ethnicity, treatment response and treatment condition. Results: More than half of the participants were NEET two years after treatment enrolment. After controlling for demographics and treatment conditions, NEET was predicted by parental substance use problems (odds ratio [OR] = 1.89, 95% confidence interval [CI] 1.31- 2.70), exposure to physical abuse (OR = 1.48, 95% CI 1.03-2.13) and non-abstinence (abstinence was negatively associated with NEET, OR = 0.53, 95% CI 0.37-0.76). Being exposed to two (OR = 3.17, 95% CI 1.93-5.21) and three types of adverse experiences (OR = 3.14, 95% CI = 1.47-6.70) predicted NEET more strongly than exposure to one type. One out of 10 participants sought acute care from psychiatric services at least once within two years after treatment. Only sex and ethnic minority status were associated with contacting psychiatric services acutely. Conclusion: The present study suggests that adverse experiences, such as being exposed to parental problematic substance use and physical abuse, may be important predictors for NEET after treatment for SUDs., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Patients with dementia with Lewy bodies (DLB) have a higher probability of seizures than in normal aging and in other types of neurodegenerative disorders. Depositions of α-synuclein, a pathological hallmark of DLB, can induce network excitability, which can escalate into seizure activity. Indicator of seizures are epileptiform discharges as observed using electroencephalography (EEG). However, no studies have so far investigated the occurrence of interictal epileptiform discharges (IED) in patients with DLB., Objectives: To investigate if IED as measured with ear-EEG occurs with a higher frequency in patients with DLB compared to healthy controls (HC)., Methods: In this longitudinal observational exploratory study, 10 patients with DLB and 15 HC were included in the analysis. Patients with DLB underwent up to three ear-EEG recordings, each lasting up to 2 days, over a period of 6 months., Results: At baseline, IED were detected in 80% of patients with DLB and in 46.7% of HC. The spike frequency (spikes or sharp waves/24 hours) was significantly higher in patients with DLB as compared to HC with a risk ratio of 2.52 (CI, 1.42-4.61; P-value = 0.001). Most IED occurred at night., Conclusions: Long-term outpatient ear-EEG monitoring detects IED in most patients with DLB with an increased spike frequency compared to HC. This study extends the spectrum of neurodegenerative disorders in which epileptiform discharges occurs at an elevated frequency. It is possible that epileptiform discharges are, therefore, a consequence of neurodegeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Physical activity and exercise have been suggested as effective interventions for the prevention and management of mild cognitive impairment (MCI) and dementia, but there are no international guidelines., Objectives: To create a set of evidence- and expert consensus-based prevention and management recommendations regarding physical activity (any bodily movement produced by skeletal muscles that results in energy expenditure) and exercise (a subset of physical activity that is planned, structured, repetitive), applicable to a range of individuals from healthy older adults to those with MCI/dementia., Methods: Guideline content was developed with input from several scientific and lay representatives' societies. A systematic search across multidisciplinary databases was carried out until October 2021. Recommendations for prevention and management were developed according to the GRADE and complemented by consensus statements from the expert panels., Recommendations: Physical activity may be considered for the primary prevention of dementia. In people with MCI there is continued uncertainty about the role of physical activity in slowing the conversion to dementia. Mind-body interventions have the greatest supporting evidence. In people with moderate dementia, exercise may be used for maintaining disability and cognition. All these recommendations were based on a very low/low certainty of evidence., Conclusions: Although the scientific evidence on the beneficial role of physical activity and exercise in preserving cognitive functions in subjects with normal cognition, MCI or dementia is inconclusive, this panel, composed of scientific societies and other stakeholders, recommends their implementation based on their beneficial effects on almost all facets of health., (© 2023. The Author(s).)

Aim: The aim of the present study was to investigate the association between childhood family structures, including the presence or absence of problematic parental substance use (PPSU), and adverse outcomes during adolescence/young adulthood. Methods: The study population included 9,770 young people (aged 15-25 years) from samples drawn for two national surveys in Denmark during 2014-2015. By combining surveys with national register data, five types of childhood family structures were constructed based on whether the child experienced PPSU and/or family separation and the number of years the child lived with a parent with substance use problems. Using binary logistic regression models, the relationships between family structure and adverse outcomes in young adulthood (i.e., hospital admissions, mental disorders and criminality) were investigated. Results: Young people who experienced PPSU and did not live with both parents had higher odds of the different long-term adverse outcomes compared with young people who did not experience PPSU, and similar odds of the outcomes compared to youth who had not experienced PPSU and did not live with both parents. The highest odds of adverse outcomes were found among young people who experienced PPSU and lived with the parent with substance use problems for less than five years. Conclusions: Living with both parents protected against adverse outcomes in young adulthood, and if PPSU was present, the odds of adverse outcomes increased. The hypothesis that there would be a positive association between years living with a parent with substance use problems and adverse outcomes in young adulthood was not supported. Awareness should be raised in health service, educational and legal institutions about the risk for young people from families with PPSU who do not live with both parents., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Cancer is a significant threat to public health and a leading cause of morbidity across the globe. Of all cancers, brain cancer can be particularly catastrophic as treatment often fails to achieve the desired degree of effectiveness and diagnosis remains associated with a high mortality rate. Africa, as a continent with resource-limited countries, needs to allocate the necessary proper healthcare infrastructure to significantly reduce cancer rates and improve patient survival. In addition, the relative paucity of data within this field in Africa makes effective management a challenge., Objective: This review is aimed at elucidating the currently available evidence base with regard to the epidemiology and etiology of brain cancer within resource-limited African countries. This review hopes to bring to the attention of the wider clinical community the growing burden of brain cancer within Africa and to encourage future research into this field of research., Methods: The available literature for this Systematic Review was searched on two bibliographic databases, PubMed and Scopus, using an individually verified, prespecified approach. In addition, the Global Cancer Observatory and Global Burden of Disease databases were also utilized. Studies reporting on the epidemiology, etiology, and impact of brain cancer in Africa were suitable for inclusion. The level of evidence of the included studies was considered as per the Centre for Evidence-Based Medicine recommendations., Results: Out of the four databases searched, 3848 articles were initially screened rigorously, filtered into 54 articles, and finally assessed qualitatively and quantitatively. We have demonstrated a poor survival rate and lack of proper funds/resources necessary to report, identify, and treat cases, as well as the dearth of comprehensive research on the subject of brain cancer that has become a challenging healthcare concern in many African developing nations. Also, because of the gradual improvement in healthcare facilities and the increasing population within many countries in Africa, the number of patients with central nervous system and intracranial tumors is rising specifically in the elder population. In addition, the population in West Africa is at a higher risk of HIV-related malignancies due to the high prevalence of HIV in West Africa. The burden of brain cancer in Africa is increasing in comparison with the developed parts of the world in which it is decreasing. Moreover, the mismanagement of cancers in Africa leads to higher morbidity and mortality and decreased quality of life., Conclusion: This study addresses the burden of brain cancer as a major public health crisis in Africa. Improved treatment modalities and access to screening are required to better address the burden of this disease. Therefore, there is a clear need for more substantial and comprehensive research on etiology, epidemiology, and treatment of brain cancer within Africa to understand its epidemiological distribution and provide a means for managing and reducing the associated morbidity and mortality., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) may lead to different cognitive profiles. The performance on single language tests have been investigated in these patient-groups, but few studies have compared DLB and AD patients' language performances on different types of tests. The aim was to compare performances for patients with DLB, AD and healthy controls on different aspects of language function. Boston Naming Test, Naming of famous faces and verbal fluency (both semantic and lexical) were investigated in 90 DLB patients, 77 matched AD patients (MMSE score ≥ 21), and in a control group ( N  = 61). The patients had significantly lower scores on all tests compared to controls. The AD patients scored significantly lower than DLB patients on naming measures whereas the lexical fluency score was significantly lower in DLB. No significant differences were found for the semantic fluency. The frequency of impairment on the Boston Naming Test was higher in AD as compared to DLB, whereas the frequency of impairment on the lexical fluency test was significantly higher in DLB. In conclusion, DLB may lead to a different language profile than AD, and performance on language-based tests may help to differentiate patients with AD and DLB.

Introduction: The cingulate island sign (CIS) is a metabolic pattern on [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) positron emission tomography (PET) associated with dementia with Lewy bodies (DLB). The aim of this study was to validate the visual CIS rating scale (CISRs) for the diagnosis of DLB and to explore the clinical correlates., Methods: This single-center study included 166 DLB patients and 161 patients with Alzheimer's disease (AD). The CIS on [ 18 F]FDG-PET scans was rated using the CISRs independently by three blinded raters., Results: The optimal cut-off to differentiate DLB from AD was a CISRs score ≥ 1 (sensitivity = 66%, specificity = 84%) whereas a CISRs score ≥ 2 (sensitivity = 58%, specificity = 92%) was optimal to differentiate amyloid positive DLB (n = 43 (82.7%)) and AD. To identify DLB with abnormal (n = 53 (72.6%)) versus normal (n = 20 (27.4%)) dopamine transporter imaging, a CISRs cut-off of 4 had a specificity of 95%. DLB with a CISRs score of 4 performed significantly better in tests on free verbal recall and picture based cued recall, but worse on processing speed compared to DLB with a CISRs score of 0., Conclusion: This study confirms the CISRs as a valid marker for the diagnosis of DLB with a high specificity and a lower, but acceptable, sensitivity. Concomitant AD pathology does not influence diagnostic accuracy of the CISRs. In DLB patients, presence of CIS is associated with relative preserved memory function and impaired processing speed., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: It has been shown under experimental conditions that cognitive performance, especially working memory, is impaired in patients with type I and type II diabetes mellitus during hyperglycemic and hypoglycemic conditions, perhaps due to altered cerebral glucose metabolism. It is not known if patients with neurodegenerative diseases, who also exhibit pathological cerebral glucose metabolism, are affected in a similar manner by their plasma glucose levels., Objective: We aimed to test if performance on two cognitive screening tests was associated with plasma glucose levels in a memory clinic cohort., Methods: We included patients from the Copenhagen Memory Clinic Cohort with an available Mini Mental-State Examination (MMSE) test score and a plasma glucose measurement performed in conjunction with cognitive testing. We built linear regression models with MMSE and Addenbrooke's Cognitive Examination (ACE) test scores as the outcome and plasma glucose as the explaining variable and adjusted models for age, sex, and diabetes (plasma glucose measurement >11.1 mmol/L). We explored non-linear relationships by adding quadratic terms and by fitting a cubic spline regression model., Results: In total, 2714 patients had an available MMSE score and a plasma glucose measurement. MMSE and ACE total scores were not associated with plasma glucose in a linear or non-linear fashion when we adjusted for age, sex, and diabetes., Conclusion: Plasma glucose levels, predominantly within normal ranges, were not associated with performance on routinely applied cognitive tests and do not need to be taken into consideration when interpreting test results from memory clinic patients., (© 2023 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Background: In patients with Alzheimer's disease (AD) without clinical seizures, up to half have epileptiform discharges on long-term in-patient electroencephalography (EEG) recordings. Long-term in-patient monitoring is obtrusive, and expensive as compared to outpatient monitoring. No studies have so far investigated if long-term outpatient EEG monitoring is able to identify epileptiform discharges in AD. Our aim is to investigate if epileptiform discharges as measured with ear-EEG are more common in patients with AD compared to healthy elderly controls (HC)., Methods: In this longitudinal observational study, 24 patients with mild to moderate AD and 15 age-matched HC were included in the analysis. Patients with AD underwent up to three ear-EEG recordings, each lasting up to two days, within 6 months., Results: The first recording was defined as the baseline recording. At baseline, epileptiform discharges were detected in 75.0% of patients with AD and in 46.7% of HC (p-value = 0.073). The spike frequency (spikes or sharp waves/24 h) was significantly higher in patients with AD as compared to HC with a risk ratio of 2.90 (CI: 1.77-5.01, p < 0.001). Most patients with AD (91.7%) showed epileptiform discharges when combining all ear-EEG recordings., Conclusions: Long-term ear-EEG monitoring detects epileptiform discharges in most patients with AD with a three-fold increased spike frequency compared to HC, which most likely originates from the temporal lobes. Since most patients showed epileptiform discharges with multiple recordings, elevated spike frequency should be considered a marker of hyperexcitability in AD., Competing Interests: Declaration of Competing Interest Christian Sandøe Musaeus received an unrestricted grant from T&W engineering. Two authors (Mike Lind Rank, and Martin Christian Hemmsen) who are employees of T&W Engineering contributed to the interpretation and writing of the manuscript. Troels Wesenberg Kjær consults for T&W Engineering., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Etiological diagnosis of neurocognitive disorders of middle-old age relies on biomarkers, although evidence for their rational use is incomplete. A European task force is defining a diagnostic workflow where expert experience fills evidence gaps for biomarker validity and prioritization. We report methodology and preliminary results., Methods: Using a Delphi consensus method supported by a systematic literature review, 22 delegates from 11 relevant scientific societies defined workflow assumptions., Results: We extracted diagnostic accuracy figures from literature on the use of biomarkers in the diagnosis of main forms of neurocognitive disorders. Supported by this evidence, panelists defined clinical setting (specialist outpatient service), application stage (MCI-mild dementia), and detailed pre-assessment screening (clinical-neuropsychological evaluations, brain imaging, and blood tests)., Discussion: The Delphi consensus on these assumptions set the stage for the development of the first pan-European workflow for biomarkers' use in the etiological diagnosis of middle-old age neurocognitive disorders at MCI-mild dementia stages., Highlights: Rational use of biomarkers in neurocognitive disorders lacks consensus in Europe. A consensus of experts will define a workflow for the rational use of biomarkers. The diagnostic workflow will be patient-centered and based on clinical presentation. The workflow will be updated as new evidence accrues., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Three presentations of prodromal dementia with Lewy bodies (DLB) have recently been proposed. This study investigates the frequency of symptoms in the prodromal phase of DLB., Method: Patients diagnosed with DLB between the 1 st of February 2017 and 1 st of February 2021 were retrospectively identified and matched to a group of patients diagnosed with Alzheimer's disease (AD). Patient case files were reviewed identifying the first symptoms and symptoms in the prodromal phase (cognitive impairment, psychiatric symptoms, delirium/acute confusional episodes, RBD, motor symptoms indicative of Parkinson's disease, anosmia, and autonomic dysfunction)., Results: A total of 166 DLB patient and 168 AD patients were included. Of the proposed presentations in patients diagnosed with DLB, 30% presented with cognitive impairment at onset in isolation, 6% with psychiatric symptoms, and 2% with delirium/acute confusional episodes. Prodromal DLB was more likely to present with no cognitive symptoms at initial presentation (38% vs 10%) and was more likely to involve other symptoms (69% vs 26%). Of other possible presentations, Rapid eye-movement sleep Behaviour Disorder (RBD) was found at onset in 22% with a mean prodromal length of 8.4 years (all symptoms: mean 4.3 years, SD 5.8)., Conclusion: We found some supportive evidence of the proposed cognitive and psychiatric presentations of prodromal DLB. Our findings build on previous findings that an RBD presentation exist, and further research is needed to characterise this presentation., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: The development of high-quality clinical practice guidelines (CPGs) takes substantial time, effort, and resources. During the past years, the European Academy of Neurology (EAN) guideline production was significantly increased, so the need to develop clear, transparent, and methodologically solid criteria for prioritizing guideline topics became apparent. With this paper, we aim to define a set of criteria to be applied for prioritizing topics for future EAN guidelines, as well as the procedure for their implementation., Methods: After review of the literature, we identified a recent systematic review that reported on the main prioritization criteria used by health organizations. Based on these, we developed a list of 20 preliminary criteria, which were voted on through a Delphi consensus procedure, including 160 stakeholders. Finally, we established a working procedure on how to submit and select new guideline topic proposals within the EAN. This procedure was reviewed by the EAN Scientific Committee and the Board., Results: The first round, 61.3% of the participants voted, and 86% of them participated in the second round. Seven criteria were approved with this procedure. After the selection of the criteria, a prioritization procedure was launched, and the first 30 topics are reported in this paper. This bottom-up process that involved the whole EAN community was followed by a top-down process, using additional criteria for further selection by the EAN board members., Conclusions: We describe the development of prioritization criteria to be applied in the process of topic selection for future EAN CPGs. We will perform regular reviews and adjustments of the process., (© 2022 European Academy of Neurology.)

Introduction: Aerobic exercise has been shown to modify Alzheimer pathology in animal models, and in patients with multiple sclerosis to reduce neurofilament light (NfL), a biomarker of neurodegeneration., Objective: To investigate whether a 16-week aerobic exercise program was able to reduce serum NfL in patients with mild Alzheimer's disease (AD)., Methods: This is a secondary analysis of data from the multi-center Preserving Cognition, Quality of Life, Physical Health, and Functional Ability in Alzheimer's disease: The Effect of Physical Exercise (ADEX) study. Participants were randomized to 16 weeks of moderate intensity aerobic exercise or usual care. Clinical assessment and measurement of serum NfL was done at baseline and after the intervention., Results: A total of 136 participants were included in the analysis. Groups were comparable at baseline except for APOE ε 4 carriership which was higher in the usual care group (75.3 versus 60.2%; p = 0.04). There was no effect of the intervention on serum NfL [intervention: baseline NfL (pg/mL) 25.76, change from baseline 0.87; usual care: baseline 27.09, change from baseline -1.16, p = 0.09]., Conclusion: The findings do not support an effect of the exercise intervention on a single measure of neurodegeneration in AD. Further studies are needed using other types and durations of exercise and other measures of neurodegeneration., Clinical Trial Registration: clinicaltrials.gov, identifier NCT01681602., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Frederiksen, Jensen, Høgh, Gergelyffy, Waldemar, Andersen, Gottrup, Vestergaard, Wermuth, Søndergaard, Sellebjerg, Hasselbalch and Simonsen.)

Background: Many individuals with Alzheimer's disease (AD) are dependent on nonprofessional care partners. Providing informal care can result in emotional, physical, and financial burdens; however, there is a need for a better understanding of the impact of AD on care partners to support the clinical and economic assessment of potential new treatments., Objective: We conducted a literature review to evaluate the burden experienced by care partners of individuals with AD., Methods: Electronic screening and supplementary searches identified studies published from 2011 to 2022 describing the association between AD and the quality of life (QoL) and physical health of care partners, and the economic or financial burden of AD., Results: Following electronic screening, 62, 25, and 39 studies were included on care partner burden, cost, and healthcare resource use in AD, respectively. Supplementary searches identified an additional 32 studies, resulting in 149 unique studies. These studies showed that care partners of individuals with AD report moderate to severe burden. Higher burden and lower QoL were observed in those caring for individuals with more severe AD. Care partners of individuals with AD experience higher burden, lower QoL, and higher levels of stress, depression, and anxiety than those without caring responsibilities. Informal care costs increased with AD severity and accounted for the greatest proportion of overall societal cost., Conclusions: Care partners of individuals with AD experience emotional and economic burden, which increases with AD severity. These impacts should be quantified comprehensively in future studies and captured in economic evaluations of AD interventions.

Introduction: Significant mortality amongst vulnerable populations, such as people living with dementia, might go undetected during pandemic conditions due to refocus of care efforts. There is an urgent need to fully evaluate the pandemic impact on mortality amongst people living with dementia in order to facilitate future healthcare reforms and prevent deaths. The purpose of this study was to determine whether there was any significant difference in mortality amongst people with dementia without COVID-19 during the COVID-19 pandemic compared to previous years., Methods: A literature search was conducted in 5 databases. The relative risk ratio and confidence interval was used to estimate the change in mortality rates amongst people with dementia during the COVID-19 pandemic. The I 2 value was used to assess heterogeneity, publication bias, and sensitivity analyses were performed., Results: Pooled analysis of 11 studies showed that mortality amongst people living with dementia was significantly increased during the COVID-19 pandemic for people with dementia without COVID-19. Mortality risk increased by 25% during the time period studied. Subgroup analysis was not performed due the low number of included studies., Conclusions: The results of this study suggest that people with dementia had a significant increased mortality during the pandemic even if they did not have COVID-19. People with dementia should participate in efforts that reduce general social spread and pandemic impact on healthcare system such as vaccinations, mask mandates, and testing. These results have clinical implications as preventing direct COVID-19 infection is not enough to adequately protect people living with dementia from increased mortality. Measures to limit social spread of infections and help support patients should also be a focus for clinicians. Further research should focus on the identification of mechanisms and other explanations for increased mortality as well as contributing factors such as living in care homes and differences between countries with various pandemic strategies., (© 2022. The Author(s).)

Comorbidities such as epilepsy, pain, vascular risk factors and infections are common in patients with dementia disorders. The relationship between comorbidities and dementia is complex, and diagnosis and management can be met with barriers due to e.g. lack of insight. An individualized approach is necessary, taking the dementia disorder and other relevant circumstances into consideration. Correct and timely management of comorbidities will help to improve quality of life and slow progression of the cognitive decline.

Importance: Atrial fibrillation (AF) screening trials have failed to demonstrate a significant reduction in stroke risk. The impact on stroke severity and the importance of prior strokes are unknown., Objective: To assess stroke characteristics in patients undergoing implantable loop recorder (ILR) screening for AF vs usual care and assess the importance of prior stroke., Design, Setting, and Participants: This was a post hoc analysis of the Atrial Fibrillation Detected by Continuous Electrocardiogram Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-Risk Individuals (LOOP) randomized clinical trial. Persons 70 years or older without known AF but diagnosed with 1 or more of the following, hypertension, diabetes, heart failure, or prior stroke, were screened for inclusion. Four sites in Denmark recruited participants by letter between January 31, 2014, and May 17, 2016. The median (IQR) follow-up period was 65 (59-70) months. Data were analyzed from April 1 to May 31, 2022., Interventions: ILR screening for AF and anticoagulation initiation if AF duration of 6 minutes or longer was detected (ILR group) vs usual care (control group)., Main Outcomes and Measures: Adjudicated stroke, classified according to the modified Rankin Scale (mRS) using a score of 3 or more as a cutoff for severe (disabling or lethal) stroke, and according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification for ischemic strokes., Results: A total of 6205 individuals were screened for inclusion, and 6004 were randomized and included in the analysis; 4503 participants (75%; mean [SD] age, 74.7 [4.1] years; 2375 male [52.7%]) were assigned to the control group and 1501 participants (25%; mean [SD] age, 74.7 [4.1] years; 792 male [52.8%]) were assigned to the ILR group. A total of 794 of 4503 participants (17.6%) in the control group had a history of prior stroke compared with 262 of 1501 participants (17.5%) in the ILR group. During follow-up, AF was diagnosed in 1027 participants (control group, 550 [12%] vs ILR group, 477 [32%]), and anticoagulation was initiated in 89% of these (910). A total of 315 participants (5.2%) had a stroke (control group, 249 [5.5%] vs ILR group, 66 [4.4%]), and the median (IQR) mRS score was 2 (1-3) with no difference across the groups. A total of 272 participants (4.5%) had ischemic stroke (control group, 217 [4.8%] vs ILR group, 55 [3.7%]), and 123 (2.0%) had severe stroke (control group, 100 [2.2%] vs ILR group, 23 [1.5%]), and the hazard ratios comparing the control and ILR groups were 0.76 (95% CI, 0.57-1.03; P = .07) and 0.69 (95% CI, 0.44-1.09; P = .11), respectively. For participants without prior stroke, the hazard ratios were 0.68 (95% CI, 0.48-0.97; P = .04) and 0.54 (95% CI, 0.30-0.97; P = .04), respectively., Conclusions and Relevance: This post hoc analysis of the LOOP randomized clinical trial found that ILR screening for AF did not result in a significant decrease in ischemic or severe strokes compared with usual care. Exploratory subgroup analyses indicated a possible reduction of these outcomes among participants without prior stroke., Trial Registration: ClinicalTrials.gov Identifier: NCT02036450.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has hampered the progress of neurological healthcare services for patients across Africa. Before the pandemic, access to these services was already limited due to elevated treatment costs among uninsured individuals, shortage of medicines, equipment, and qualified personnel, immense distance between residing areas and neurological facilities, and a limited understanding of neurological diseases and their presentation by both the health workers and the African population., Methodology: The databases PubMed, Google Scholar, Science Direct, and the National Library of Medicine were searched for literature. All articles on neurological disorders in Africa were considered., Aim: This review article explores the challenges of providing the best services for patients suffering from neurological disorders in Africa amid the COVID-19 pandemic and provides evidence-based recommendations., Results: As Africa's governments made more resources available to support patients affected by COVID-19, neurological care received less priority and the capacity and competency to treat patients with neurological disorders thus suffered substantially. Both short-term and long-term strategies are needed to improve the quality of neurological services after the pandemic in the region., Conclusion: To strengthen Africa's neurological services capability during and after the COVID-19 pandemic, African governments must ensure appropriate healthcare resource allocation, perform neurology management training, and increase health security measures in medication supply. Long-term strategies include incorporating responsible finance and resource procurement and advancement of tele-neurology. International collaboration is essential to promote the sustainable improvement of neurological services in Africa., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Introduction: Aerobic exercise interventions may affect different cognitive domains such as attention, working memory, inhibition, etc . However, the neural mechanisms underlying this relationship, remains uncertain., Objective: To perform a systematic review on exercise intervention studies that use event-related potentials (ERPs) as outcome for cognitive performance., Methods: We identified studies through searches in four databases reporting the effects of either an acute bout or chronic exercise on any ERP associated with cognitive performance. Study population included participants >17 years of age with or without a diagnosis., Results: A total of 5,797 records were initially identified through database searching of which 52 were eligible for inclusion. Most studies were of acute aerobic exercise with moderate intensity. Results were heterogenious across studies, but there was a trend that ERP amplitude increased and (to a lesser extent) latencies decreased post-exercise. The P3 ERP was the most often reported ERP., Conclusion: Heterogeneity across studies regarding methodology limited the possibility to draw definitive conclusions but the most consistent findings were that acute aerobic exercise was associated with higher amplitudes, and to a lesser extent shorter latencies, of ERPs., Competing Interests: The authors declare there are no competing interests., (©2022 Gusatovic et al.)

Exocrine glands in the submucosa of the proximal duodenum secrete alkaline fluid containing mucus to protect the intestinal mucosa from acidic stomach contents. These glands, known as Brunner's glands, express high glucagon-like peptide 1 receptor (GLP-1R) levels. Previous studies have suggested that activation of the GLP-1R induces expression of barrier protective genes in Brunner's glands. Still, the lack of a viable in vitro culture of Brunner's glands has hampered additional studies of the functional consequences of GLP-1R activation. In this study, we established a procedure to isolate and culture cells derived from murine Brunner's glands. The isolated glandular cells retained functional GLP-1R expression in culture, making this in vitro system suitable for the study of GLP-1R activation. We found that cells derived from the Brunner's glands of mice pretreated with semaglutide contained significantly more mucus compared with Brunner's glands from vehicle-treated mice. Our data suggest a protective intestinal response upon semaglutide treatment, but further studies are required to leverage the full potential of cultured Brunner's gland cells.

Aims: To identify young people with different levels of family-related problems, including parental substance use disorder (PSUD), and investigate differences in grades at graduation from compulsory school and further enrollment in education., Methods: Participants included 6784 emerging adults (aged 15-25 years) from samples drawn for two national surveys in Denmark 2014-2015. Latent classes were constructed using the following parental variables: PSUD, offspring not living with both parents, and parental criminality, mental disorders, chronic diseases and long-term unemployment. The characteristics were analyzed using an independent one-way ANOVA. Differences in grade point average and further enrollment were analyzed using linear regression and logistic regression, respectively., Results: Four classes of families were identified: 1. "Low adverse childhood experiences (ACE) families", 2. "Families with PSUD", 3. "Families with unemployment" and 4. "High ACE families". There were significant differences in grades, with the highest average among youth from "Low ACE families" (males = 6.83; females = 7.40) and significant lower averages among both males and females from the other types of families, but lowest among young people from "High ACE families" (Males = 5.58; females = 5.79). Youth from "Families with PSUD" (Males: OR = 1.51; 95% CI: 1.01-2.26; females: OR = 2.16; 95% CI: 1.22-3.85) and "High ACE families" (Males: OR = 1.78; 95% CI: 1.11-2.26) were significantly more likely not to be enrolled in further education compared with "Low ACE families"., Conclusions: Young people who experience PSUD, both as the primary family-related problem as well as among multiple family-related problems, are at increased risk for negative school-related outcomes., Competing Interests: None., (© 2022 The Author(s).)

Importance: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design., Objective: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates., Design, Setting, and Participants: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria., Exposures: Alzheimer disease biomarkers detected on PET or in CSF., Main Outcomes and Measures: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations., Results: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18)., Conclusions and Relevance: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

Background: Previous studies have reported that epileptiform activity may be detectible in nearly half of patients with Alzheimer's disease (AD) on long-term electroencephalographic (EEG) recordings. However, such recordings can be uncomfortable, expensive, and difficult. Ear-EEG has shown promising results for long-term EEG monitoring, but it has not been used in patients with AD., Objective: To investigate if ear-EEG is a feasible method for long-term EEG monitoring in patients with AD., Methods: In this longitudinal, single-group feasibility study, ten patients with mild to moderate AD were recruited. A total of three ear-EEG recordings of up to 48 hours three months apart for six months were planned., Results: All patients managed to wear the ear-EEG for at least 24 hours and at least one full night. A total of 19 ear-EEG recordings were performed (self-reported recording, mean: 37.15 hours (SD: 8.96 hours)). After automatic pre-processing, a mean of 27.37 hours (SD: 7.19 hours) of data with acceptable quality in at least one electrode in each ear was found. Seven out of ten participants experienced mild adverse events. Six of the patients did not complete the study with three patients not wanting to wear the ear-EEG anymore due to adverse events., Conclusion: It is feasible and safe to use ear-EEG for long-term EEG monitoring in patients with AD. Minor adjustments to the equipment may improve the comfort for the participants.

Background: Atrial remodeling is associated with future atrial fibrillation (AF) and stroke. AF has been associated with cognitive impairment and cerebral white matter lesions. We wished to investigate the possible direct association between atrial remodeling and cerebrovascular disease in patients with and without AF documented by implantable loop recorder (ILR)., Methods: Cardiac and cerebral magnetic resonance imaging were acquired in a cross-sectional study, including participants ≥70 years of age with stroke risk factors without known AF. Cerebrovascular disease was visually rated using the Fazekas scale and number of lacunar strokes. Left atrial (LA) and ventricular volumes and function were analyzed. Associations between atrial remodeling and cerebrovascular disease were assessed with logistic regression models. The analyses were stratified according to sinus rhythm or any AF during 3 months of continuous ILR monitoring to account for subclinical AF., Results: Of 200 participants investigated, 87% had a Fazekas score ≥1 and 45% had ≥1 lacunar infarct. Within 3 months of ILR monitoring, AF was detected in 28 (14%) participants. For participants with sinus rhythm (n = 172), lower LA passive emptying fraction was associated with Fazekas score after multivariable adjustment (OR [95% CI]: 0.51 [0.27; 0.86] p = 0.02), and increased LA maximum (OR [95% CI]: 1.38 [1.07; 1.82] p = 0.01) and minimum volumes (OR [95% CI]: 1.48 [1.03; 2.17] p = 0.04) were associated with lacunar infarcts. There were no significant associations in patients with AF., Conclusion: In AF-free patients, as documented by ILR monitoring, we found an independent association between LA passive emptying fraction and Fazekas score and between atrial volumes and lacunar infarcts., (© 2021 S. Karger AG, Basel.)

Introduction: In healthy elderly persons and patients with mild cognitive impairment, physical exercise can increase functional brain connectivity in the default mode network (DMN) measured by restingstate functional magnetic resonance imaging (rs-fMRI). However, no studies have so far investigated the effect of physical exercise on functional resting-state connectivity in the DMN in patients with Alzheimer's disease (AD)., Objective: In a single-blinded randomized controlled trial, we assessed the effects of an aerobic exercise intervention of 16 weeks of physical exercise on DMN connectivity using rs-fMRI in patients with AD., Methods: Forty-five patients were randomly assigned to either a control or exercise group. The exercise group performed 60-min of aerobic exercise three times per week for 16 weeks. All the patients underwent whole-brain rs-fMRI at 3 T, at baseline, and after 16 weeks. Since the posterior cingulate cortex (PCC) and adjacent precuneus constitute a central hub of the DMN, this parietal region was defined as region-ofinterest and used as the seed region for functional connectivity analysis of the rs-fMRI data treating age and gender as covariates., Results: Neither seed-based analysis, seeded in the PCC/precuneus region nor ICA-based analyses, focusing on components of the DMN network, showed any exercise-induced changes in functional resting-state connectivity from baseline to follow-up., Conclusion: 16 weeks of aerobic exercise does not modify functional connectivity of the PCC/precuneus region in patients with AD. A longer intervention may be needed to show the effect of exercise on brain connectivity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: To study the relationship between subclinical atrial fibrillation (AF) and changes in cognitive function in a large cohort of individuals with stroke risk factors., Methods: Individuals with no prior AF diagnosis but with risk factors for stroke were recruited to undergo annual cognitive assessment with the Montreal Cognitive Assessment (MoCA) along with implantable loop recorder (ILR) monitoring for AF for 3 years. If AF episodes lasting ≥6 minutes were detected, oral anticoagulation (OAC) treatment was initiated., Results: A total of 1194 participants (55.2 % men, mean age 74.5 (±3.9)) had a combined duration of heart rhythm monitoring of ≈1.3 million days. Among these, 339 participants (28.3%) had adjudicated AF, with a median AF burden of 0.072% (0.02, 0.39), and 324 (96%) initiated OAC. When stratifying the participants into AF burden groups (No AF, AF low (AF burden <0.25%), and AF high, (AF burden >0.25%)), only participants in the AF low group had a decrease in MoCA score over time (P = .03), although this was not significant after adjustment for stroke risk factors. A subgroup analysis of 175 participants (14.6%) with a MoCA <26 at 3 years found no association to AF diagnosis or burden., Conclusions: In a high-risk population, subclinical AF detected by continuous monitoring and subsequently treated with OAC was not associated with a significant change in MoCA score over a 3-year period., (Copyright © 2021. Published by Elsevier Inc.)

Histone lysine methylations have primarily been linked to selective recruitment of reader or effector proteins that subsequently modify chromatin regions and mediate genome functions. Here, we describe a divergent role for histone H4 lysine 20 mono-methylation (H4K20me1) and demonstrate that it directly facilitates chromatin openness and accessibility by disrupting chromatin folding. Thus, accumulation of H4K20me1 demarcates highly accessible chromatin at genes, and this is maintained throughout the cell cycle. In vitro, H4K20me1-containing nucleosomal arrays with nucleosome repeat lengths (NRL) of 187 and 197 are less compact than unmethylated (H4K20me0) or trimethylated (H4K20me3) arrays. Concordantly, and in contrast to trimethylated and unmethylated tails, solid-state NMR data shows that H4K20 mono-methylation changes the H4 conformational state and leads to more dynamic histone H4-tails. Notably, the increased chromatin accessibility mediated by H4K20me1 facilitates gene expression, particularly of housekeeping genes. Altogether, we show how the methylation state of a single histone H4 residue operates as a focal point in chromatin structure control. While H4K20me1 directly promotes chromatin openness at highly transcribed genes, it also serves as a stepping-stone for H4K20me3-dependent chromatin compaction., (© 2021. The Author(s).)

Aims: To estimate the prevalence of parental substance use disorder (PSUD) in the general population based on young adults' reports adjusted for non-participation using register-based indicators of PSUD., Design: A national sample survey study combined with a retrospective register-based study. Setting Denmark. Participants 10,414 young people (aged 15-25 years) invited to two national sample surveys in 2014 and 2015 (5,755 participants and 4,659 non-participants)., Measurements: A crude prevalence of PSUD was calculated based on participants' reports. Parental data from medical, mortality, prescription, and treatment registers (from the young adults' birth until the time of the surveys) were used to estimate a register-based prevalence of PSUD for both participants and non-participants. Differences between participants and non-participants were analysed using bivariate comparisons. Inverse probability weighting was used to adjust for bias due to non-participation. The crude prevalence of PSUD based on survey data was adjusted using the ratio of incidence proportion of the register-based PSUD compared with the survey-based PSUD., Findings: A total of 731 (12.7%) of the 5,755 survey participants reported PSUD. Register-based PSUD was more common among non-participants (856/4,659; 18.4%) compared with participants (738/5,755; 12.8%, OR = 1.53, 95% CI 1.38-1.70). The adjusted estimate of the survey-based PSUD increased by 2.5 percentage points, from 12.7% to 15.2%., Conclusions: In the absence of register data, youth-reported PSUD is likely to underestimate the number of young people experiencing PSUD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: This review maps the research literature on register-based studies of alcohol's harms to family members and identifies areas for future research., Method: Using a scoping review methodology, the PubMed/MEDLINE, EMBASE, and PsycINFO databases were searched in August 2019 with keywords to identify studies that included register-based outcome sources, a family relationship, and an exposure to heavy drinking. In total, 5,961 records were screened, 403 full-text articles were assessed for eligibility, and 91 studies were included in the final review., Results: Register-based research on alcohol's harms to family members has largely drawn on hospital records to identify heavy drinkers and has primarily focused on children of heavy drinkers; 79 of the included studies solely investigated harms to children, whereas 2 focused on partners and 10 on multiple first-degree or unspecified relatives. Register-based studies show that children of heavy drinkers are at a higher risk for mental disorders, disease and injury hospitalizations, infant and child mortality, criminality, poor employment and educational outcomes, abuse/neglect, and placement in residential/foster care, among other negative outcomes., Conclusions: A substantial body of register-based research shows that children of parents with the most severe alcohol problems are at an increased risk for numerous adverse experiences. Register-based studies have investigated diverse, yet precisely defined outcomes, using large samples followed over long periods, and have examined the contribution of genetic, biological, and environmental factors. Our understanding of alcohol's harms to families could be enhanced by further register-based research on other household family members of heavy drinkers.