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Background: Disease-modifying therapies (DMTs) for Alzheimer's disease (AD) have early evidence of efficacy. Widespread delivery of DMTs will require major service reconfiguration. Treatment pathways will need to include triaging for eligibility, regular infusions and baseline and follow-up MRI scanning. A critical step in planning is provision of real-world estimates of patients likely to be eligible for triaging, but these are challenging to obtain., Methods: We performed a retrospective service evaluation of patients attending five memory services across North and East London and a national specialist cognitive disorders service. We examined the likely proportion of patients who would (1) be referred for triaging for DMTs and (2) potentially be suitable for treatments., Results: Data from a total of 1017 patients were included, 517 of whom were seen in community memory services and 500 in a specialist clinic. In the memory services, 367/517 (71%) were diagnosed with possible AD. After exclusions of those in whom cognitive and frailty scores, MRI contraindications or anticoagulant use indicated they would be unlikely to be suitable, an estimated 32% would be eligible for triaging. In the specialist cognitive clinic, where additional investigations are available, 14% of those seen (70/500) would be potentially eligible for treatment., Conclusions: While a sizeable proportion of patients attending memory clinics may be referred for triaging for DMTs for AD, only a minority are likely to be suitable for these, as demonstrated in patients seen in specialist cognitive services. This will need to be considered when designing pathways for DMT delivery., Competing Interests: Competing interests: RD has received honoraria for speaking and/or travelling from Biogen, Merck, Teva, Janssen and Sanofi. She served on the advisory board of Roche, Biogen, Janssen and Merck. She has received grant support from Biogen, Merck, Celgene, Barts Charity, the UK MS Society, NMSS, MRC and the Home Family Charitable Trust. RSW has received honoraria from GE Healthcare, Bial and Britannia and consultancy fees from Therakind. CJM has undertaken advisory board/ consultancy for Biogen, Roche, WAVE, IONIS, Prevail, Lilly, grant income from Biogen and speaker honoraria for Biogen, Roche, EISAI, IONIS, Lilly., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Recent growth in the functionality and use of technology has prompted an increased interest in the potential for remote or decentralized clinical trials in dementia. There are many potential benefits associated with decentralized medication trials, but we currently lack specific recommendations for their delivery in the dementia field., Methods: A modified Delphi method engaged an expert panel to develop recommendations for the conduct of decentralized medication trials in dementia prevention. A working group of researchers and clinicians with expertise in dementia trials further refined the recommendations., Results: Overall, the recommendations support the delivery of decentralized trials in dementia prevention provided adequate safety checks and balances are included. A total of 40 recommendations are presented, spanning aspects of decentralized clinical trials, including safety, dispensing, outcome assessment, and data collection., Discussion: These recommendations provide an accessible, pragmatic guide for the design and conduct of remote medication trials for dementia prevention., Highlights: Clinical trials of medication have begun adopting decentralized approaches. Researchers in the field lack guidance on what would be appropriate circumstances and frameworks for what would be appropriate circumstances and frameworks for the use of decentralized trial methods in dementia prevention. The present report provides consensus-based expert recommendations for decentralized clinical trials for dementia prevention., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), currently marketed for type 2 diabetes and obesity, may offer novel mechanisms to delay or prevent neurotoxicity associated with Alzheimer's disease (AD). The impact of semaglutide in amyloid positivity (ISAP) trial is investigating whether the GLP-1 RA semaglutide reduces accumulation in the brain of cortical tau protein and neuroinflammation in individuals with preclinical/prodromal AD., Methods and Analysis: ISAP is an investigator-led, randomised, double-blind, superiority trial of oral semaglutide compared with placebo. Up to 88 individuals aged ≥55 years with brain amyloid positivity as assessed by positron emission tomography (PET) or cerebrospinal fluid, and no or mild cognitive impairment, will be randomised. People with the low-affinity binding variant of the rs6971 allele of the Translocator Protein 18 kDa (TSPO) gene, which can interfere with interpreting TSPO PET scans (a measure of neuroinflammation), will be excluded.At baseline, participants undergo tau, TSPO PET and MRI scanning, and provide data on physical activity and cognition. Eligible individuals are randomised in a 1:1 ratio to once-daily oral semaglutide or placebo, starting at 3 mg and up-titrating to 14 mg over 8 weeks. They will attend safety visits and provide blood samples to measure AD biomarkers at weeks 4, 8, 26 and 39. All cognitive assessments are repeated at week 26. The last study visit will be at week 52, when all baseline measurements will be repeated. The primary end point is the 1-year change in tau PET signal., Ethics and Dissemination: The study was approved by the West Midlands-Edgbaston Research Ethics Committee (22/WM/0013). The results of the study will be disseminated through scientific presentations and peer-reviewed publications., Trial Registration Number: ISRCTN71283871., Competing Interests: Competing interests: IK has received speaker fees and grant funding (ISAP trial) from Novo Nordisk and is a remunerated medical advisor to digital healthcare companies (Five Lives SAS, Cognetivity, Mantrah) in the dementia field. RRH reports personal fees from Anji Pharmaceuticals, AstraZeneca, Novartis and Novo Nordisk. AIA has received grant funding (ISAP trial) from Novo Nordisk. HZ has served at scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, Wave, has given lectures with honoraria in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Programme (outside submitted work). PE was a consultant to Pfizer, Novo Nordisk, Roche, AstraZeneca, Piramal Life Science, GE Healthcare. He has received speaker fees from Novo Nordisk, Pfizer, Nordea, Piramal Life Science. He has received educational and research grants from GE Healthcare, Novo Nordisk, Piramal Life Science/Life Molecular Imaging, Avid Radiopharmaceuticals and Eli Lilly. He was a member of the Scientific Advisory Board for Novo Nordisk and Cytodyn. CM consults for Biogen, Roche, Eli Lilly, Eisai, IONIS, Alnylam, Prevail, WAVE. She has been awarded an investigator grant from Biogen for ultrafast MRI programme., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Importance: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD)., Objective: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment., Design, Setting, and Participants: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed., Interventions: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks., Main Outcomes and Measures: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL., Results: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo., Conclusions and Relevance: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification., Trial Registration: ClinicalTrials.gov Identifier: NCT04623242.

Background: The authors sought to examine the impact of the K-variant of butyrylcholinesterase (BCHE-K) carrier status on age-at-diagnosis of Alzheimer disease (AD) in APOE4 carriers., Methods: Patients aged 50-74 years with cerebrospinal fluid (CSF) biomarker-confirmed AD, were recruited to clinical trial (NCT03186989 since June 14, 2017). Baseline demographics, disease characteristics, and biomarkers were evaluated in 45 patients according to BCHE-K and APOE4 allelic status in this post-hoc study., Results: In APOE4 carriers (N = 33), the mean age-at-diagnosis of AD in BCHE-K carriers (n = 11) was 6.4 years earlier than in BCHE-K noncarriers (n = 22, P < .001, ANOVA). In APOE4 noncarriers (N = 12) there was no observed influence of BCHE-K. APOE4 carriers with BCHE-K also exhibited slightly higher amyloid and tau accumulations compared to BCHE-K noncarriers. A predominantly amyloid, limited tau, and limbic-amnestic phenotype was exemplified by APOE4 homozygotes with BCHE-K. In the overall population, multiple regression analyses demonstrated an association of amyloid accumulation with APOE4 carrier status (P < .029), larger total brain ventricle volume (P < .021), less synaptic injury (Ng, P < .001), and less tau pathophysiology (p-tau 181 , P < .005). In contrast, tau pathophysiology was associated with more neuroaxonal damage (NfL, P = .002), more synaptic injury (Ng, P < .001), and higher levels of glial activation (YKL-40, P = .01)., Conclusion: These findings have implications for the genetic architecture of prognosis in early AD, not the genetics of susceptibility to AD. In patients with early AD aged less than 75 years, the mean age-at-diagnosis of AD in APOE4 carriers was reduced by over 6 years in BCHE-K carriers versus noncarriers. The functional status of glia may explain many of the effects of APOE4 and BCHE-K on the early AD phenotype., Trial Registration: NCT03186989 since June 14, 2017., (© 2024. The Author(s).)

Introduction: Increasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double-blind phase 3 DIAN-TU-001 trial tested clinical and cognitive declines with increasing doses of solanezumab or gantenerumab., Methods: We used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 trial to test amyloid positron emission tomography (PET) reduction as a potential surrogate biomarker., Results: LC analysis categorized participants into three classes: amyloid no change, amyloid reduction, and amyloid growth, based on longitudinal amyloid Pittsburgh compound B PET standardized uptake value ratio data. The amyloid-no-change class was at an earlier disease stage for amyloid amounts and dementia. Despite similar baseline characteristics, the amyloid-reduction class exhibited reductions in the annual decline rates compared to the amyloid-growth class across multiple biomarker, clinical, and cognitive outcomes., Discussion: LC analysis indicates that amyloid reduction is associated with improved clinical outcomes and supports its use as a surrogate biomarker in clinical trials., Highlights: We used latent class (LC) analysis to test amyloid reduction as a surrogate biomarker. Despite similar baseline characteristics, the amyloid-reduction class exhibited remarkably better outcomes compared to the amyloid-growth class across multiple measures. LC analysis proves valuable in testing amyloid reduction as a surrogate biomarker in clinical trials lacking significant treatment effects., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU)., Methods: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials., Results: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome., Conclusion: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden., Competing Interests: EMM receives Grant Funding from NIA; Institutional funding from Eli Lilly, Hoffmann-La Roche, Eisai. He is a DSMB member (paid directly) for Alector; Eli Lilly; a Scientific Advisory Board Member (paid directly to me) for Alzamend, Fondation Alzheimer. He acts as a Consultant/Advisor for Sage Therapeutics, Eli Lilly, Sanofi, AstraZeneca,Hoffmann La-Roche. DBC is Medical Director for DIAN-TU and supported by DIAN-TU grants in this role. He receives research support from National Institute of Mental Health, National Institute of Neurological Diseases and Stroke, National Institute of Aging, National Institute of AIDS and Infectious Disease He has served on DSMB or adjudication committees for Sanofi/Genzyme, Wave Life Sciences, Seagen, Atara Biotherapeutics, Teva, CellEvolve, Excision Biotherapeutics and Arena. He receives support for contributing to Up-To-Date. BJS is the site principal investigator for DIAN-TU at Washington University and receives research support from NIH, Eli Lilly, Biogen, Hoffman LaRoche, Eisai and Janssen. She has served on advisory boards for Eisai and Biogen. CJM has received grants from Biogen; honoraria or advisory board fees from Biogen, Eli Lilly, Roche, IONIS, Eisai, Alector; participated in company sponsored symposia for Biogen and Eisai. RJB is the Director of the DIAN-TU and Principal Investigator of the DIAN-TU-001. He receives research support from the National Institute on Aging of the National Institutes of Health, DIAN-TU Trial Pharmaceutical Partners (Eli Lilly and Company, F. Hoffman-La Roche, Ltd., and Avid Radiopharmaceuticals), Alzheimer’s Association, GHR Foundation, Anonymous Organization, DIAN-TU Pharma Consortium (Active: AbbVie, Biogen, BMS, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann-La Roche, Ltd./Genentech,. Previous: Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, United Neuroscience). CHvD receives research support from the National Institute on Aging of the National Institutes of Health, Biogen, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann-La Roche, Ltd./Genentech, UCB, and Cerevel. He serves as a consultant for F. Hoffman La Roche, Ltd., Eisai, Ono, and Cerevel. SG is member of scientific advisory boards of Alzheon, AmyriAD, Eisai, Enigma USA, Lilly, Medesis, NovoNordisk, Okutsa. Editorial board member JPAD, Neurotorium. DG is paid consultant for Esai and Roche Diagnostics. GYRH discloses that he has received grants or contracts from CIHR, NIA/NIH, has been a clinical trials investigator supported by Anavex, Biogen, Cassava, and Lilly, and has participated in expert advisory committee supported by Biogen, Eisai, Roche, and NovoNordisk. Dr. Hsiung is the current president of C5R (Consortium of Canadian Centres for Clinical Cognitive Research). JP is member of an IDMC for Biogen. EDR serves on a data monitoring committee for Eli Lilly, has received licensing fees from Genentech, and has served as a consultant for AGTC. All other authors have nothing to disclose.

A proportion of patients infected with severe acute respiratory syndrome coronavirus 2 experience a range of neuropsychiatric symptoms months after infection, including cognitive deficits, depression and anxiety. The mechanisms underpinning such symptoms remain elusive. Recent research has demonstrated that nervous system injury can occur during COVID-19. Whether ongoing neural injury in the months after COVID-19 accounts for the ongoing or emergent neuropsychiatric symptoms is unclear. Within a large prospective cohort study of adult survivors who were hospitalized for severe acute respiratory syndrome coronavirus 2 infection, we analysed plasma markers of nervous system injury and astrocytic activation, measured 6 months post-infection: neurofilament light, glial fibrillary acidic protein and total tau protein. We assessed whether these markers were associated with the severity of the acute COVID-19 illness and with post-acute neuropsychiatric symptoms (as measured by the Patient Health Questionnaire for depression, the General Anxiety Disorder assessment for anxiety, the Montreal Cognitive Assessment for objective cognitive deficit and the cognitive items of the Patient Symptom Questionnaire for subjective cognitive deficit) at 6 months and 1 year post-hospital discharge from COVID-19. No robust associations were found between markers of nervous system injury and severity of acute COVID-19 (except for an association of small effect size between duration of admission and neurofilament light) nor with post-acute neuropsychiatric symptoms. These results suggest that ongoing neuropsychiatric symptoms are not due to ongoing neural injury., Competing Interests: H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen 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). I.K. declares grant fundind and speaker fees from Novo Nordisk., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Tau plays a key role in Alzheimer's disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPT Rx ) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPT Rx . Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPT Rx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPT Rx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPT Rx and 12 to placebo. Adverse events were reported in 94% of MAPT Rx -treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPT Rx -treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPT Rx groups. Clinicaltrials.gov registration number: NCT03186989 ., (© 2023. The Author(s).)

Objectives: Efficacy and safety results from the EMERGE (NCT02484547) and ENGAGE (NCT02477800) phase 3 studies of aducanumab in early Alzheimer's disease (AD) have been published. In EMERGE, but not in ENGAGE, high-dose aducanumab demonstrated significant treatment effects across primary and secondary endpoints. Low-dose aducanumab results were consistent across studies with non-significant differences versus placebo that were intermediate to the high-dose arm in EMERGE. The present investigation examined data from EMERGE and ENGAGE through post-hoc analyses to determine factors that contributed to discordant results between the high-dose arms of the two studies., Design: EMERGE and ENGAGE were 2 phase 3, randomized, double-blind, placebo-controlled, parallel-group studies., Setting: EMERGE and ENGAGE were 2 global multicenter studies involving 348 sites in 20 countries., Participants: Participants in EMERGE and ENGAGE were aged 50 to 85 years and had mild cognitive impairment or mild AD dementia with confirmed amyloid pathology. The randomized and dosed population (all randomized patients who received at least one dose of study treatment) included 1638 patients in EMERGE and 1647 in ENGAGE., Intervention: In EMERGE and ENGAGE, participants were randomized to receive low- or high-dose aducanumab or placebo (1:1:1) once every 4 weeks., Measurements: In this paper, 4 areas were investigated through post-hoc analyses to understand the discordance in the high-dose arms of the EMERGE and ENGAGE studies: baseline characteristics, amyloid-related imaging abnormalities, non-normality of the data, and dosing/exposure to aducanumab., Results: Post-hoc analyses showed that outcomes in the ENGAGE high-dose group were affected by an imbalance in a small number of patients with extremely rapid progression and by lower exposure to the target dose of 10 mg/kg. These factors were confounded and present in early enrolled patients but were not present in later-enrolled patients who were randomized to the target dosing regimen of 10 mg/kg after titration. Neither baseline characteristics nor amyloid-related imaging abnormalities contributed to the difference in results between the high-dose arms., Conclusions: Results were consistent across studies in later enrolled patients in which the incidence of rapidly progressing patients was balanced across treatment arms., Competing Interests: These studies were funded by Biogen. YT, GD, KH, KKM, IN, SW, YZ, TC, and SBH are employees and shareholders of Biogen. CvH, PB, CM, LN, RR, and AS are former employees of Biogen. CM is a current employee of Cortexyme. PSA was Chair of the Steering Committee; has received research support from Eisai, Eli Lilly, Janssen, the Alzheimer’s Association, NIH, and FNIH; and has consulted for ImmunoBrain Checkpoint, Merck, and Roche. FB was supported by the NIHR Biomedical Research Centre at UCLH. He receives personal fees for consultancy from Bayer, Biogen, Combinostics, IXICO, Novartis, and Roche. SC was an ENGAGE trial site investigator and an Aducanumab Steering Committee member. She is a consultant to Alnylam, Biogen, Cognivue, Cogstate, Eisai, Eli Lilly, INmune Bio, Novo Nordisk, ProMIS Neurosciences, RetiSpec, and Roche and receives research support (paid to institution) from AgeneBio, Alector, Alnylam, Anavex, Biogen, Eisai, Eli Lilly, Genentech, Novo Nordisk, RetiSpec, Roche, UCB, and Vielight. OH has acquired research support (for the institution) from Avid Radiopharmaceuticals, Biogen, Eisai, Eli Lilly, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, ALZPath, Biogen, Cerveau, and Roche. TI is a consultant to Eisai and Roche. CJM was an ENGAGE trial site investigator and an Aducanumab Steering Committee member. She is supported by the NIHR Biomedical Research Centre at UCLH and has acted as a consultant to Biogen, Ionis, and Roche. CvD was an EMERGE trial site investigator. He is a consultant to Eisai and Roche and receives research support from Biogen, Biohaven, Eisai, Eli Lilly, Genentech, Janssen, Merck, Novartis, and Roche. BV was a trial site investigator and an Aducanumab Steering Committee member. He is supported by CHU-T and has acted as a consultant to Biogen, Eli Lilly, Merck, and Roche.

Objective: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD)., Methods: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors., Results: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E., Interpretation: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729-744., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Although cerebrospinal fluid (CSF) biomarker testing is incorporated into some current guidelines for the diagnosis of dementia (such as England's National Institute for Health and Care Excellence (NICE)), it is not widely accessible for most patients for whom biomarkers could potentially change management. Here we share our experience of running a clinical cognitive CSF service and discuss recent developments in laboratory testing including the use of the CSF amyloid-β 42/40 ratio and automated assay platforms. We highlight the importance of collaborative working between clinicians and laboratory staff, of preanalytical sample handling, and discuss the various factors influencing interpretation of the results in appropriate clinical contexts. We advocate for broadening access to CSF biomarkers by sharing clinical expertise, protocols and interpretation with colleagues working in psychiatry and elderly care, especially when access to CSF may be part of a pathway to disease-modifying treatments for Alzheimer's disease and other forms of dementia., Competing Interests: Competing interests: RWP is codirector of the NfL consortium (an industry-funded research consortium) and has given educational lectures sponsored by GE Healthcare. JDR has served on a medical advisory board and had a consultancy agreement with Alector, Arkuda Therapeutics, Wave Life Sciences and Prevail Therapeutics, and had a consultancy agreement also with UCB, AC Immune, Astex Pharmaceuticals, Biogen, Takeda and Eisai. CJM has been an advisor to IONIS, Biogen, Lilly and Roche, is on the international steering committee for aducanumab, and has lectured for Biogen. NCF’s research group has received payment for consultancy or for conducting studies from Biogen, Eli Lilly Research Laboratories, Ionis and Roche. NCF received no personal compensation for the aforementioned activities. NCF also serves on a Data Safety Monitoring Board for Biogen. JMS has received research funding from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly), has consulted for Roche Pharmaceuticals, Biogen, Merck, and Eli Lilly, given educational lectures sponsored by GE Healthcare, Eli Lilly, and Biogen, and serves on a data safety monitoring committee for Axon Neuroscience SE. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; and has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche. HZ is a cofounder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Programme., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Demonstrating a slowing in the rate of cognitive decline is a common outcome measure in clinical trials in Alzheimer's disease (AD). Selection of cognitive endpoints typically includes modeling candidate outcome measures in the many, richly phenotyped observational cohort studies available. An important part of choosing cognitive endpoints is a consideration of improvements in performance due to repeated cognitive testing (termed "practice effects"). As primary and secondary AD prevention trials are comprised predominantly of cognitively unimpaired participants, practice effects may be substantial and may have considerable impact on detecting cognitive change. The extent to which practice effects in AD prevention trials are similar to those from observational studies and how these potential differences impact trials is unknown. In the current study, we analyzed data from the recently completed DIAN-TU-001 clinical trial (TU) and the associated DIAN-Observational (OBS) study. Results indicated that asymptomatic mutation carriers in the TU exhibited persistent practice effects on several key outcomes spanning the entire trial duration. Critically, these practice related improvements were larger on certain tests in the TU relative to matched participants from the OBS study. Our results suggest that the magnitude of practice effects may not be captured by modeling potential endpoints in observational studies where assessments are typically less frequent and drug expectancy effects are absent. Using alternate instrument forms (represented in our study by computerized tasks) may partly mitigate practice effects in clinical trials but incorporating practice effects as outcomes may also be viable. Thus, investigators must carefully consider practice effects (either by minimizing them or modeling them directly) when designing cognitive endpoint AD prevention trials by utilizing trial data with similar assessment frequencies., Competing Interests: EC, KH, and RY are full-time employees and/or stockholders of Eli Lilly. RB has received funding from Avid Radiopharmaceuticals, Jansse, Hoffman La-Roche/Genentech, Eli LIlly & Co., Eisai, Biogen, AbbVie, and Bristol Meyer Squibbs, has royalties/licenses from C2N Diagnostics, consulting fees from Eisai, Amgen, and Hoffman La-Roche, honoraria from the Korean Dementia Association and the American Neurological Association, and is on the data safety monitoring board or advisory board for Roche/Genentech and Biogen. Unrelated to this article, RB serves as the principal investigator of the DIAN-TU, which is supported by the Alzheimer’s Association, GHR Foundation, an anonymous organization, and the DIAN-TU Pharma Consortium (Active: Eli Lilly and Company/Avid Radiopharmaceuticals, F. Hoffman-La Roche/Genentech, Biogen, Eisai, and Janssen. Previous: Abbvie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, and United Neuroscience). In addition, in-kind support has been received from CogState and Signant Health. G-YH has received research support as a clinical trials site investigator from Anavax, Biogen, Eli Lilly, and Roche, has received research grants from the CIHR, Alzheimer Society of Canada, and NIA/NIH, is supported by the Ralph Fisher Professorship in dementia research from the Alzheimer Society of British Columbia, and has participated in expert advisory committees sponsored by Biogen and Roche. GD’s research is supported by NIH (K23AG064029), the Alzheimer’s Association, and Chan Zuckerberg Initiative, and he serves as a consultant for Parabon Nanolabs Inc., as a Topic Editor (Dementia) for DynaMed (EBSCO), and as the Clinical Director of the Anti-NMDA Receptor Encephalitis Foundation (Inc, Canada; uncompensated) and owns stock in ANI pharmaceuticals. DH, former Department Head of Neurology where the research was conducted, is an inventor on patents for one of the treatments (solanezumab), which has been tested in the DIAN-TU clinical trials. If solanezumab is approved as a treatment for Alzheimer’s disease or Dominantly Inherited Alzheimer’s Disease, Washington University, and will receive part of the net sales of solanezumab from Eli Lilly, which has licensed the patents related to solanezumab from Washington University. The remaining 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 © 2022 Aschenbrenner, Hassenstab, Wang, Li, Xiong, McDade, Clifford, Salloway, Farlow, Yaari, Cheng, Holdridge, Mummery, Masters, Hsiung, Surti, Day, Weintraub, Honig, Galvin, Ringman, Brooks, Fox, Snyder, Suzuki, Shimada, Gräber and Bateman.)

Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau-related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Alzheimer's disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta., Objectives: We evaluated the efficacy and safety of aducanumab in early Alzheimer's disease., Design: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer's disease., Setting: These studies involved 348 sites in 20 countries., Participants: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50-85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study., Intervention: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks., Measurements: The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints., Results: EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo [95% CI, -0.69 to -0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, -0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema., Conclusions: Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose- and time-dependent reduction in pathophysiological markers of Alzheimer's disease was observed in both trials., Competing Interests: These studies were funded by Biogen. SBH, YT, KKM, TC, SW, GD, KH, IN, and YZ are employees and shareholders of Biogen. SC (Dr Chalkias), AS, LN, RR, CvH, CM and LS were employees of Biogen at the time of this work. CM is a current employee of Cortexyme. LS and CvH are current employees of Takeda Pharmaceutical Co. SC is a current employee at Moderna. RR is a current employee at Vigil Neuro. PSA was chair of the Steering Committee and has consulted for Biogen, has received research support from Eli Lilly, Janssen, Eisai, the Alzheimer’s Association, the National Institutes of Health, and the Foundation for the National Institutes of Health; he has consulted for Merck, Roche and ImmunoBrain Checkpoint. PSA is co-editor in chief of JPAD with no personal compensation; he did not have a role in the editorial process/review for this manuscript. FB was supported by NIHR Biomedical Research Centre at UCLH. He receives personal fees for consultancy from Bayer, Biogen, Roche, IXICO Ltd, Novartis, and Combinostics. SC (Dr Cohen) was an ENGAGE trial site investigator and an Aducanumab Steering Committee member. She is a consultant (no personal fees received) to Biogen, Cassava Sciences, Cogstate, INmune Bio, ProMIS Neuroscience, and RetiSpec and receives research support (paid to institution) from AgeneBio, Anavex, Biogen, Cassava, Eisai, Genentech, Green Valley, Eli Lilly, Janssen, RetiSpec, Roche, and Vielight. OH received research support (for the institution) from AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, Biogen, Cerveau, and Roche. TI is a consultant to Eisai and Roche. CJM was an ENGAGE trial site investigator and an Aducanumab Steering Committee member. She is supported by NIHR Biomedical Research Centre at UCLH and has acted as a consultant to Biogen, Roche, and IONIS. CvD was an EMERGE trial site investigator. He is a consultant for Roche, Eisai, and Ono and receives research support from Biogen, Eisai, Roche, Genentech, Eli Lilly, Janssen, Merck, Novartis, and Biohaven. BV is an investigator in clinical trials sponsored by Biogen, Lilly, Roche, Eisai Pharmaceuticals, and the Toulouse University Hospital (Inspire Geroscience Program). He has served as SAB member for Biogen, Alzheon, Green Valey, Norvo Nordisk, Longeveron, but received no personal compensation. He has served as consultant and/or SAB member for Roche, Lilly, Eisai, TauX with personal compensation. His family members have equity ownership interest in Serdi. He is member of the Editorial Board of JPAD with no personal compensation. He did not have a role in the editorial or peer review for this manuscript at JPAD.

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and have the following interests to declare: CJM is on the Therapeutics Evaluation Committee for the DIAN-TU trial platform led by Washington University; she is a member of the Biogen steering committee for the aducanumab programme; she has been on advisory committees for Roche, IONIS, and WAVE.

We envisage the development of new Brain Health Services to achieve primary and secondary dementia prevention. These services will complement existing memory clinics by targeting cognitively unimpaired individuals, where the focus is on risk profiling and personalized risk reduction interventions rather than diagnosing and treating late-stage disease. In this article, we review key potentially modifiable risk factors and genetic risk factors and discuss assessment of risk factors as well as additional fluid and imaging biomarkers that may enhance risk profiling. We then outline multidomain measures and risk profiling and provide practical guidelines for Brain Health Services, with consideration of outstanding uncertainties and challenges. Users of Brain Health Services should undergo risk profiling tailored to their age, level of risk, and availability of local resources. Initial risk assessment should incorporate a multidomain risk profiling measure. For users aged 39-64, we recommend the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) Dementia Risk Score, whereas for users aged 65 and older, we recommend the Brief Dementia Screening Indicator (BDSI) and the Australian National University Alzheimer's Disease Risk Index (ANU-ADRI). The initial assessment should also include potentially modifiable risk factors including sociodemographic, lifestyle, and health factors. If resources allow, apolipoprotein E ɛ4 status testing and structural magnetic resonance imaging should be conducted. If this initial assessment indicates a low dementia risk, then low intensity interventions can be implemented. If the user has a high dementia risk, additional investigations should be considered if local resources allow. Common variant polygenic risk of late-onset AD can be tested in middle-aged or older adults. Rare variants should only be investigated in users with a family history of early-onset dementia in a first degree relative. Advanced imaging with 18-fluorodeoxyglucose positron emission tomography (FDG-PET) or amyloid PET may be informative in high risk users to clarify the nature and burden of their underlying pathologies. Cerebrospinal fluid biomarkers are not recommended for this setting, and blood-based biomarkers need further validation before clinical use. As new technologies become available, advances in artificial intelligence are likely to improve our ability to combine diverse data to further enhance risk profiling. Ultimately, Brain Health Services have the potential to reduce the future burden of dementia through risk profiling, risk communication, personalized risk reduction, and cognitive enhancement interventions., (© 2021. The Author(s).)

Importance: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations., Objective: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency., Design, Setting, and Participants: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021., Interventions: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days., Main Outcomes and Measures: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau])., Results: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03)., Conclusions and Relevance: In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible., Trial Registration: ClinicalTrials.gov Identifier: NCT02149160.

Background: A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies in COVID-19 neurology remains unclear., Methods: This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies [aCL] IgA, IgM, IgG; anti-beta-2 glycoprotein-1 [aβ 2 GPI] IgA, IgM, IgG; anti-phosphatidylserine/prothrombin [aPS/PT] IgM, IgG; and anti-domain I β 2 GPI (aD1β2GPI) IgG., Findings: There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups ( p  < 0.001). Moderate-high titre of aPS/PT IgG was found in 2 out of 3 (67%) patients with acute disseminated encephalomyelitis [ADEM]. aPS/PT IgG titres negatively correlated with oxygen requirement (FiO 2 R =-0.15 p  = 0.040) and was associated with venous thromboembolism ( p  = 0.043). In contrast, aCL IgA ( p  < 0.001) and IgG ( p  < 0.001) was associated with non-neurological COVID-hospitalised controls compared to the other groups and correlated positively with d-dimer and creatinine but negatively with FiO 2 ., Interpretation: Our findings show that aPS/PT IgG is associated with COVID-19-associated ADEM. In contrast, aCL IgA and IgG are seen much more frequently in non-neurological hospitalised patients with COVID-19. Characterisation of antiphospholipid antibody persistence and potential longitudinal clinical impact are required to guide appropriate management., Funding: This work is supported by UCL Queen Square Biomedical Research Centre (BRC) and Moorfields BRC grants (#560441 and #557595). LB is supported by a Wellcome Trust Fellowship (222102/Z/20/Z). RWP is supported by an Alzheimer's Association Clinician Scientist Fellowship (AACSF-20-685780) and the UK Dementia Research Institute. KB is supported by the Swedish Research Council (#2017-00915) and the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and theUK Dementia Research Institute at UCL. BDM is supported by grants from the MRC/UKRI (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). MSZ, MH and RS are supported by the UCL/UCLH NIHR Biomedical Research Centre and MSZ is supported by Queen Square National Brain Appeal., Competing Interests: LAB reports grants from GlaxoSmithKline, grants from Wellcome Trust, outside the submitted work.; RWP reports grants from Neurofilament light consortium, personal fees from GE healthcare educational talk, outside the submitted work.; CP is co-inventor for a patented Domain I-based potential therapeutic for APS.; KB reports personal fees from Abcam (advisory board / consultant), personal fees from Axon (advisory board / consultant), personal fees from Biogen (advisory board / consultant), personal fees from Julius Clinical (data monitoring committee), personal fees from Lilly (advisory board / consultant), personal fees from MagQu (advisory board / consultant), personal fees from Novartis (data monitoring committee), personal fees from Roche Diagnostic (advisory board / consultant), personal fees from Siemens Healthineers (advisory board / consultant), outside the submitted work; and is co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program.; CM reports personal fees from Biogen (sit on steering committee for aducanumab fees for time spent), personal fees from Roche (advisory board member fees for time spent), personal fees from Washington University (sit on therapeutic evalutation committee fees for time spent), outside the submitted work.; BS reports grants from UKRI/DHSC Global Effort on COVID-19 Research (Medical Research Council), non-financial support from UK National Institute for Health Research Global Health Research Group on Brain Infections, outside the submitted work.; MSZ reports receiving personal fees from UCB, for lecturing, outside the submitted work.; DJW reports personal fees from Bayer, personal fees from Alnylam, personal fees from Portola, outside the submitted work.; TS is on the Data Safety Monitoring Committee of Study to Evaluate the Safety and Immunogenicity of a Candidate Ebola Vaccine in Children GSK3390107A (ChAd3 EBO-Z) vaccine from GSK, is a panel member of Covid-19 Vaccine Benefit Risk Expert Working Group, which assesses the benefits and risks of Covid-19 vaccines at the Medicines and Healthcare Regulatory Agency (UK), is a member of COVID-19 Therapeutics Advisory Panel at the United Kingdom Department of Health & Social Care, and is Chair/Co-Chair of theCOVID-19 Rapid Response and Rolling Funding Initiatives, which supported development of the Oxford-Astra Zeneca Covid-19 vaccine, at the National Institute for Health Research, outside the submitted work. In addition, TS has a patent Test for bacterial meningitis based on a blood test, filed for patent pending.; HZ reports personal fees from Wave (Advisory board / consultant), personal fees from Roche Diagnostics (Advisory board / consultant), personal fees from Biogen (Sponsored lecture), personal fees (Advisory board / consultant) from Samumed, Eisai, Denali, Nervgen, Roche Diagnostics, Siemens Healthineers, Pinteon Therapeutics, AZTherapies, CogRx, personal fees (Sponsored lecture) from Alzecure, Cellectricon, and Fujirebio, outside the submitted work; and is Co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program.; JMS reports work support from National Institute for Health Research University College London Hospitals Biomedical Research Centre, during the conduct of the study; personal fees from Roche Pharmaceuticals (consulting), personal fees from Eli Lilly (consulting, lecturing), Drug Safety Monitoring Board at Axon Neuroscience, non-financial support from AVID Radiopharmaceuticals (PET tracer provision), consulting on educational activities from Biogen, personal fees from Merck (consulting), royalties from Oxford University Press, royalties from Henry Stewart Talks, grants from Wolfson Foundation, grants from Engineering and Physical Sciences Research Council (EP/J020990/1), grants from Medical Research Council Dementias Platform UK (MR/L023784/1), grants from Alzheimer's Research UK (ARUK-Network 2012-6-ICE; ARUK-PG2017-1946; ARUK-PG2017-1946), grants from Brain Research UK (UCC14191), grants from Weston Brain Institute (UB170045), grants from European Union's Horizon 2020 research and innovation programme (Grant 666,992), grants from British Heart Foundation (PG/17/90/33,415), personal fees from Alzheimer's Research UK (Chief Medical Officer), personal fees from UK Dementia Research Institute (Medical Advisor), outside the submitted work.; HC reports institutional research support and support to attend scientific meetings, and honoraria for lectures paid to UCLH charities from Bayer Healthcare, and consultancy fees paid to University College London Hospitals Charity from UCB Biopharma, outside the submitted work.; All other authors have nothing to disclose., (© 2021 The Author(s).)

Background: Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, nearly all adults with Down syndrome develop Alzheimer's disease pathology by the age of 40 years and are at high risk for dementia given their increased life expectancy compared with adults with Down syndrome in the past. We aimed to compare CSF biomarker patterns in Down syndrome with those of carriers of autosomal dominant Alzheimer's disease mutations to enhance our understanding of disease mechanisms in these two genetic groups at high risk for Alzheimer's disease., Methods: We did a cross-sectional study using data from adults enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study, a multisite longitudinal study of Alzheimer's disease in Down syndrome, as well as a cohort of carriers of autosomal dominant Alzheimer's disease mutations and non-carrier sibling controls enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. For ABC-DS, participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of Jan 31, 2019, were included in the analysis. DIAN participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of June 30, 2018, were evaluated as comparator groups. CSF samples obtained from adults with Down syndrome, similarly aged carriers of autosomal dominant Alzheimer's disease mutations, and non-carrier siblings (aged 30-61 years) were analysed for markers of amyloid β (Aβ 1-40 , Aβ 1-42 ); tau phosphorylated at threonine 181-related processes; neuronal, axonal, or synaptic injury (total tau, visinin-like protein 1, neurofilament light chain [NfL], synaptosomal-associated protein 25); and astrogliosis and neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic or symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker concentrations and age among groups., Findings: We assessed CSF samples from 341 individuals (178 [52%] women, 163 [48%] men, aged 30-61 years). Participants were adults with Down syndrome (n=41), similarly aged carriers of autosomal dominant Alzheimer's disease mutations (n=192), and non-carrier siblings (n=108). Individuals with Down syndrome had patterns of Alzheimer's disease-related CSF biomarkers remarkably similar to carriers of autosomal dominant Alzheimer's disease mutations, including reductions (all p<0·0080) in Aβ 1-42 to Aβ 1-40 ratio and increases in markers of phosphorylated tau-related processes; neuronal, axonal, and synaptic injury (p<0·080); and astrogliosis and neuroinflammation, with greater degrees of abnormality in individuals with dementia. Differences included overall higher concentrations of Aβ and YKL-40 (both p<0·0008) in Down syndrome and potential elevations in CSF tau (p<0·010) and NfL (p<0·0001) in the asymptomatic stage (ie, no dementia symptoms)., Funding: National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Japan Agency for Medical Research and Development., Competing Interests: Declaration of interests AMF has received research funding from the National Institutes of Health/National Institute on Aging, Biogen, Centene, Fujirebio, and Roche Diagnostics. She is a member of the scientific advisory boards for Roche Diagnostics, Genentech, and AbbVie and also consults for Araclon/Grifols, DiademRes, DiamiR, and Otsuka Pharmaceuticals, outside the submitted work. RJB has equity ownership interest in C2N Diagnostics and receives royalty income based on technology (stable isotope labelling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. He receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co-inventor, has submitted the US non-provisional patent application “Cerebrospinal fluid (CSF) tau rate of phosphorylation measurement to define stages of Alzheimer's disease and monitor brain kinases/phosphatases activity.” He has received honoraria from Janssen and Pfizer as a speaker, and from Merck and Pfizer as an advisory board member. He has been an invited speaker, advisory board member, and consultant for F Hoffman La Roche, an invited speaker and consultant for AC Immune and Janssen, and a consultant for Amgen and Eisai, outside the submitted work. AMG has consulted for Eisai, Biogen, Pfizer, AbbVie, Cognition Therapeutics, and GSK. She also served on the Scientific Advisory Board of Denali Therapeutics (2015–2018), outside the submitted work. BJH has received research funding from Roche Pharmaceuticals and Autism Speaks, outside the submitted work. JPC has served on a medical advisory board for Otsuka Pharmaceuticals, outside the submitted work. GSD is supported by National Institutes of Health/National Institute on Aging (K23AG064029). He serves as a topic editor on dementia for DynaMed Plus (EBSCO Industries), a consultant for Parabon NanoLabs, is the clinical director for the Anti-NMDA Receptor Encephalitis Foundation (uncompensated), has provided record review and expert medical testimony on legal cases pertaining to management of Wernicke encephalopathy, and holds stocks (>$10 000) in ANI Pharmaceuticals (a generic pharmaceutical company), outside the submitted work. NRGR takes part in multicentre trials supported by AbbVie, Eli Lilly, and Biogen, outside the submitted work. JL reports speaker fees from Bayer Vital and Roche, consulting fees from Axon Neuroscience and Ionis Pharmaceuticals, author fees from Thieme medical publishers and W Kohlhammer GmbH medical publishers, non-financial support from Abbvie, and compensation for duty as part-time CMO from MODAG, outside the submitted work. CJM has been a member of advisory scientific board for Biogen, IONIS, Wave, and Roche and consulted for Eisai, outside the submitted work. RNM has received funding from the US Alzheimer's Foundation to undertake an intervention trial for the prevention of Alzheimer's disease. He is a member of the scientific advisory board for Eisai, outside the submitted work. SS reports consulting to Eisai, Novartis, Genentech, F Hoffmann-La Roche, Gemvax, Avid Radiopharmaceuticals, and Eli Lilly and Company, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The early and accurate diagnosis of dementia is more important than ever before but remains challenging. Dementia is increasingly the business of neurologists and, with ageing populations worldwide, will become even more so in future. Here we outline a practical, symptom-led, bedside approach to suspecting dementia and its likely diagnosis, inspired by clinical experience and based on recognition of characteristic syndromic patterns. We show how clinical intuition reflects underlying signature profiles of brain involvement by the diseases that cause dementia and suggest next steps that can be taken to define the diagnosis. We propose 'canaries' that provide an early warning signal of emerging dementia and highlight the 'chameleons' that disguise or mimic this, as well as the 'zebras' that herald a rare (and sometimes curable) diagnostic opportunity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Mutations in the Presenilin 1 (PSEN1) gene are the most common cause of autosomal dominant familial Alzheimer's disease. We report the clinical, imaging and postmortem findings of kindred carrying a novel duplication mutation (Ile168dup) in the PSEN1 gene. We interpret the pathogenicity of this novel variant and discuss the additional neurological features (pyramidal dysfunction, myoclonus and seizures) that accompanied cognitive decline. This report broadens the clinical phenotype of PSEN1 insertion mutations while also highlighting the importance of considering duplication, insertion and deletion mutations in cases of young onset dementia., (Copyright © 2021 Elsevier Inc. All rights reserved.)

There are significant health inequalities between Deaf and hearing people, including barriers to accessing care and communication difficulties in consultations. Such problems have particularly affected Deaf people with acquired cognitive deficits, leading to late and missed diagnoses. We therefore established a specialist cognitive clinic for the Deaf community in 2011 at the National Hospital for Neurology and Neurosurgery, which to our knowledge is the first of its kind in the world. In this study, we retrospectively analysed electronic patient records to evaluate the service and its impact since inception. We found that Deaf patients who use British sign language had difficulty obtaining an accurate diagnosis before attending our specialist clinic, highlighting the importance of tailored services for Deaf people. Our results show that the clinic improved communication for patients and accessibility to specialist investigations, ensuring diagnostic accuracy and overall reducing health inequality for this population., (© Royal College of Physicians 2021. All rights reserved.)

Preliminary pathological and biomarker data suggest that SARS-CoV-2 infection can damage the nervous system. To understand what, where and how damage occurs, we collected serum and CSF from patients with COVID-19 and characterized neurological syndromes involving the PNS and CNS ( n  = 34). We measured biomarkers of neuronal damage and neuroinflammation, and compared these with non-neurological control groups, which included patients with ( n  = 94) and without ( n  = 24) COVID-19. We detected increased concentrations of neurofilament light, a dynamic biomarker of neuronal damage, in the CSF of those with CNS inflammation (encephalitis and acute disseminated encephalomyelitis) [14 800 pg/ml (400, 32 400)], compared to those with encephalopathy [1410 pg/ml (756, 1446)], peripheral syndromes (Guillain-Barré syndrome) [740 pg/ml (507, 881)] and controls [872 pg/ml (654, 1200)]. Serum neurofilament light levels were elevated across patients hospitalized with COVID-19, irrespective of neurological manifestations. There was not the usual close correlation between CSF and serum neurofilament light, suggesting serum neurofilament light elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness. We did not find significantly elevated levels of serum neurofilament light in community cases of COVID-19 arguing against significant neurological damage. Glial fibrillary acidic protein, a marker of astrocytic activation, was not elevated in the CSF or serum of any group, suggesting astrocytic activation is not a major mediator of neuronal damage in COVID-19., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Cytokine storm can result from cancer immunotherapy or certain infections, including COVID-19. Though short-term immune-related adverse events are routinely described, longer-term immune consequences and sequential immune monitoring are not as well defined. In 2006, six healthy volunteers received TGN1412, a CD28 superagonist antibody, in a first-in-man clinical trial and suffered from cytokine storm. After the initial cytokine release, antibody effect-specific immune monitoring started on Day + 10 and consisted mainly of evaluation of dendritic cell and T-cell subsets and 15 serum cytokines at 21 time-points over 2 years. All patients developed problems with concentration and memory; three patients were diagnosed with mild-to-moderate depression. Mild neutropenia and autoantibody production was observed intermittently. One patient suffered from peripheral dry gangrene, required amputations, and had persistent Raynaud's phenomenon. Gastrointestinal irritability was noted in three patients and coincided with elevated γδT-cells. One had pruritus associated with elevated IgE levels, also found in three other asymptomatic patients. Dendritic cells, initially undetectable, rose to normal within a month. Naïve CD8 + T-cells were maintained at high levels, whereas naïve CD4 + and memory CD4 + and CD8 + T-cells started high but declined over 2 years. T-regulatory cells cycled circannually and were normal in number. Cytokine dysregulation was especially noted in one patient with systemic symptoms. Over a 2-year follow-up, cognitive deficits were observed in all patients following TGN1412 infusion. Some also had signs or symptoms of psychological, mucosal or immune dysregulation. These observations may discern immunopathology, treatment targets, and long-term monitoring strategies for other patients undergoing immunotherapy or with cytokine storm.

Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there are few reports about their use in clinical practice. Which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared with those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalisable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These data should provide a basis for more informed counselling and clinical decision making.

Family carers of people with Lewy body dementia (LBD) have a particularly high burden of care, as LBD has a faster rate of decline, greater physical dependence and additional neuropsychiatric disturbances compared with other dementias. Despite this, there are no evidence-based support services designed specifically for LBD carers. STrAtegies for RelaTives (START) is an eight-session, individually delivered coping therapy that has been shown in a randomised controlled trial to reduce depression and anxiety symptoms and increase quality of life in carers of people with dementia, with effects lasting several years. We adapted START for LBD, and piloted its use both face-to-face and on the phone with 10 carers to test acceptability and indications of similar effects in this group. Our findings suggest that the therapy was acceptable and feasible using either delivery mode, providing much appreciated and needed strategies, education and support for carers of people with LBD. Trials of effectiveness are now needed., (© Royal College of Physicians 2020. All rights reserved.)

COVID-19 has led to seismic changes in neurological practice in a matter of weeks. The Association of British Neurologists has supported neurology specialists and patients during this rapid reorganisation and its attendant challenges. We have written guidance on structured service transformation, considering the need to sustain long term care while responding to acute developments; we have recognised that staff experience differs and that this, as well as individual risk factors should be considered when redeployment occurs. Appreciating that there may be understandable anxiety when facing a working routine outside normal practice, we have signposted ethical and psychological support for individuals. We have also focused on our patients: we have facilitated a national alert system to register all neurological COVID cases, coordinating research efforts on this new disease; finally we have defined how to identify the most vulnerable patients under our care. When this initial wave of the pandemic subsides, we will have planned for return to the new 'norm', ready to embrace innovation where appropriate, aiming to minimise fall-out in our chronic disease population, and potentially having enhanced and modernised our services., (© Royal College of Physicians 2020. All rights reserved.)

There are over 87 000 Deaf people in the UK with British Sign Language (BSL) as their first language.1 Few healthcare professionals receive training in Deaf awareness or in BSL, and missed diagnoses and inadequate treatment of Deaf patients are estimated to cost the National Health Service £30 million per year.2 Neurologists are likely to encounter Deaf BSL users in their practice, but without prior experience may find consultations challenging, especially within the time constraints and pressure of a standard clinic. In this article, we provide guidance on consulting with Deaf people in a neurology clinic, drawing on experience from our cognitive clinic for Deaf BSL users where effective communication is essential., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

MAPT mutations were the first discovered genetic cause of frontotemporal dementia (FTD) in 1998. Since that time, over 60 MAPT mutations have been identified, usually causing behavioral variant FTD and/or parkinsonism clinically. We describe 2 novel MAPT mutations, D252V and G389&#95;I392del, each presenting in a patient with behavioral variant FTD and associated language and cognitive deficits. Neuroimaging revealed asymmetrical left greater than right temporal lobe atrophy in the first case, and bifrontal atrophy in the second case. Disease duration was 8 years and 5 years, respectively. Postmortem examination in both patients revealed a 3-repeat predominant tauopathy, similar in appearance to Pick's disease. These 2 mutations add to the literature on genetic FTD, both presenting with similar clinical and imaging features to previously described cases, and pathologically showing a primary tauopathy similar to a number of other MAPT mutations., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

There is no consensus on how to structure and deliver neurology training. The General Medical Council's annual National Training Survey indicates that the quality of UK neurology training is very variable, but does not explain this variation. We used the survey data to identify the four highest and lowest performing sites for neurology training across the UK. We conducted semistructured interviews with groups of local trainees and, separately, local trainers in an exploratory qualitative study, and identified common themes across a range of aspects of neurology training. Here we present our findings, share case studies from top-performing sites and make recommendations on how best to train a neurologist., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Memory for music has attracted much recent interest in Alzheimer's disease but the underlying brain mechanisms have not been defined in patients directly. Here we addressed this issue in an Alzheimer's disease cohort using activation fMRI of two core musical memory systems., Methods: We studied 34 patients with younger onset Alzheimer's disease led either by episodic memory decline (typical Alzheimer's disease) or by visuospatial impairment (posterior cortical atrophy) in relation to 19 age-matched healthy individuals. We designed a novel fMRI paradigm based on passive listening to melodies that were either previously familiar or unfamiliar (musical semantic memory) and either presented singly or repeated (incidental musical episodic memory)., Results: Both syndromic groups showed significant functional neuroanatomical alterations relative to the healthy control group. For musical semantic memory, disease-associated activation group differences were localised to right inferior frontal cortex (reduced activation in the group with memory-led Alzheimer's disease); while for incidental musical episodic memory, disease-associated activation group differences were localised to precuneus and posterior cingulate cortex (abnormally enhanced activation in the syndromic groups). In post-scan behavioural testing, both patient groups had a deficit of musical episodic memory relative to healthy controls whereas musical semantic memory was unimpaired., Conclusions: Our findings define functional neuroanatomical substrates for the differential involvement of musical semantic and incidental episodic memory in major phenotypes of Alzheimer's disease. The complex dynamic profile of brain activation group differences observed suggests that musical memory may be an informative probe of neural network function in Alzheimer's disease. These findings may guide the development of future musical interventions in dementia., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Adult-onset leukodystrophies and genetic leukoencephalopathies comprise a diverse group of neurodegenerative disorders of white matter with a wide age of onset and phenotypic spectrum. Patients with white matter abnormalities detected on MRI often present a diagnostic challenge to both general and specialist neurologists. Patients typically present with a progressive syndrome including various combinations of cognitive impairment, movement disorders, ataxia and upper motor neuron signs. There are a number of important and treatable acquired causes for this imaging and clinical presentation. There are also a very large number of genetic causes which due to their relative rarity and sometimes variable and overlapping presentations can be difficult to diagnose. In this review, we provide a structured approach to the diagnosis of inherited disorders of white matter in adults. We describe clinical and radiological clues to aid diagnosis, and we present an overview of both common and rare genetic white matter disorders. We provide advice on testing for acquired causes, on excluding small vessel disease mimics, and detailed advice on metabolic and genetic testing available to the practising neurologist. Common genetic leukoencephalopathies discussed in detail include CSF1R , AARS2 , cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and mitochondrial and metabolic disorders., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Verbal adynamia (impaired language generation, as during conversation) has not been assessed systematically in parkinsonian disorders. We addressed this in patients with Parkinson's dementia, progressive supranuclear palsy and corticobasal degeneration. All disease groups showed impaired verbal fluency and sentence generation versus healthy age-matched controls, after adjusting for general linguistic and executive factors. Dopaminergic stimulation in the Parkinson's group selectively improved verbal generation versus other cognitive functions. Voxel-based morphometry identified left inferior frontal and posterior superior temporal cortical correlates of verbal generation performance. Verbal adynamia warrants further evaluation as an index of language network dysfunction and dopaminergic state in parkinsonian disorders.

The primary progressive aphasias are a heterogeneous group of focal 'language-led' dementias that pose substantial challenges for diagnosis and management. Here we present a clinical approach to the progressive aphasias, based on our experience of these disorders and directed at non-specialists. We first outline a framework for assessing language, tailored to the common presentations of progressive aphasia. We then consider the defining features of the canonical progressive nonfluent, semantic and logopenic aphasic syndromes, including 'clinical pearls' that we have found diagnostically useful and neuroanatomical and other key associations of each syndrome. We review potential diagnostic pitfalls and problematic presentations not well captured by conventional classifications and propose a diagnostic 'roadmap'. After outlining principles of management, we conclude with a prospect for future progress in these diseases, emphasising generic information processing deficits and novel pathophysiological biomarkers.

Background: Cerebrospinal fluid (CSF) biomarkers are increasingly being used to support a diagnosis of Alzheimer's disease (AD). Their clinical utility for differentiating AD from non-AD neurodegenerative dementias, such as dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD), is less well established. We aimed to determine the diagnostic utility of an extended panel of CSF biomarkers to differentiate AD from a range of other neurodegenerative dementias., Methods: We used immunoassays to measure conventional CSF markers of amyloid and tau pathology (amyloid beta (Aβ)1-42, total tau (T-tau), and phosphorylated tau (P-tau)) as well as amyloid processing (AβX-38, AβX-40, AβX-42, soluble amyloid precursor protein (sAPP)α, and sAPPβ), large fibre axonal degeneration (neurofilament light chain (NFL)), and neuroinflammation (YKL-40) in 245 patients with a variety of dementias and 30 controls. Patients fulfilled consensus criteria for AD (n = 156), DLB (n = 20), behavioural variant frontotemporal dementia (bvFTD; n = 45), progressive non-fluent aphasia (PNFA; n = 17), and semantic dementia (SD; n = 7); approximately 10% were pathology/genetically confirmed (n = 26). Global tests based on generalised least squares regression were used to determine differences between groups. Non-parametric receiver operating characteristic (ROC) curves and area under the curve (AUC) analyses were used to quantify how well each biomarker discriminated AD from each of the other diagnostic groups (or combinations of groups). CSF cut-points for the major biomarkers found to have diagnostic utility were validated using an independent cohort which included causes of AD (n = 104), DLB (n = 5), bvFTD (n = 12), PNFA (n = 3), SD (n = 9), and controls (n = 10)., Results: There were significant global differences in Aβ1-42, T-tau, T-tau/Aβ1-42 ratio, P-tau-181, NFL, AβX-42, AβX-42/X-40 ratio, APPα, and APPβ between groups. At a fixed sensitivity of 85%, AβX-42/X-40 could differentiate AD from controls, bvFTD, and SD with specificities of 93%, 85%, and 100%, respectively; for T-tau/Aβ1-42 these specificities were 83%, 70%, and 86%. AβX-42/X-40 had similar or higher specificity than Aβ1-42. No biomarker or ratio could differentiate AD from DLB or PNFA with specificity > 50%. Similar sensitivities and specificities were found in the independent validation cohort for differentiating AD and other dementias and in a pathology/genetically confirmed sub-cohort., Conclusions: CSF AβX-42/X-40 and T-tau/Aβ1-42 ratios have utility in distinguishing AD from controls, bvFTD, and SD. None of the biomarkers tested had good specificity at distinguishing AD from DLB or PNFA.

Aberrant rule- and reward-based processes underpin abnormalities of socio-emotional behaviour in major dementias. However, these processes remain poorly characterized. Here we used music to probe rule decoding and reward valuation in patients with frontotemporal dementia (FTD) syndromes and Alzheimer's disease (AD) relative to healthy age-matched individuals. We created short melodies that were either harmonically resolved ('finished') or unresolved ('unfinished'); the task was to classify each melody as finished or unfinished (rule processing) and rate its subjective pleasantness (reward valuation). Results were adjusted for elementary pitch and executive processing; neuroanatomical correlates were assessed using voxel-based morphometry. Relative to healthy older controls, patients with behavioural variant FTD showed impairments of both musical rule decoding and reward valuation, while patients with semantic dementia showed impaired reward valuation but intact rule decoding, patients with AD showed impaired rule decoding but intact reward valuation and patients with progressive non-fluent aphasia performed comparably to healthy controls. Grey matter associations with task performance were identified in anterior temporal, medial and lateral orbitofrontal cortices, previously implicated in computing diverse biological and non-biological rules and rewards. The processing of musical rules and reward distils cognitive and neuroanatomical mechanisms relevant to complex socio-emotional dysfunction in major dementias.