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The study of sex differences in Alzheimer's disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer's disease (>90% in the 7th decade). Yet, sex differences in Alzheimer's disease manifestations have not been fully investigated in these individuals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6; 50.7) years], we compared Alzheimer's disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience sample recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-β 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein ɛ4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein ɛ4, female ɛ4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, P = 0.01). This difference was not seen in males (52.2 versus 52.5 years, P = 0.76). Our exploratory analyses considering sex, apolipoprotein ɛ4 and biomarkers showed that female ɛ4 carriers tended to exhibit lower CSF amyloid-β 42/amyloid-β 40 ratios and lower hippocampal volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer's disease in adults with Down syndrome. Consideration of apolipoprotein ɛ4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine., Competing Interests: O.B. reported receiving personal fees from ADx NeuroSciences outside the submitted work. H.Z. declares that he has served on 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, 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, which is a part of the GU Ventures Incubator Program, outside the submitted work. K.B. declares that he has served as a consultant, on advisory boards, or data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Pharmatrophix, Prothena, Roche Diagnostics and Siemens Healthineers and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program, outside the submitted work. D.A. reported receiving personal fees for advisory board services and/or speaker honoraria from Fujirebio-Europe, Roche, Nutricia, Krka Farmacéutica and Esteve, outside the submitted work. A.L. has served as a consultant or on advisory boards for Fujirebio-Europe, Roche, Biogen and Nutricia, outside the submitted work. J.F. reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Novartis, Lundbeck, Roche, Fujirebio and Biogen, outside the submitted work. O.B., D.A., A.L. and J.F. report holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to ADx, EPI8382175.0). No other competing interests were reported. References1HentzenNB, FerrettiMT, SantuccioneA, et alMapping of European activities on the integration of sex and gender factors in neurology and neuroscience. Eur J Neurol. 2022;29(9):2572–2579.2Spires-JonesTL. Let's talk about sex (in translational neuroscience). Brain Commun. 2022;4(2):fcac028.3GauthierS, Rosa-NetoP, MoraisJA, WebsterC. World Alzheimer Report 2021: Journey through the diagnosis of dementia. 2021.4FerrettiMT, IulitaMF, CavedoE, et alSex differences in Alzheimer disease—The gateway to precision medicine. Nat Rev Neurol. 2018;14(8):457–469.299854745NebelRA, AggarwalNT, BarnesLL, et alUnderstanding the impact of sex and gender in Alzheimer's disease: A call to action. Alzheimers Dement. 2018;14(9):1171–1183.299074236McCarreyAC, AnY, Kitner-TrioloMH, FerrucciL, ResnickSM. 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Background: Cerebrospinal fluid (CSF) Aβ1-42 levels and the Aβ1-42/Aβ1-40 ratio are markers of amyloid pathology, but previous studies suggest that their levels might be influenced by additional pathophysiological processes., Aims: To compare Aβ1-42 and the Aβ1-42/Aβ1-40 ratio in CSF in different neurodegenerative disorders and study their association with other biomarkers (tTau, pTau181, and NfL) and with cognitive and functional progression., Methods: We included all participants from the Sant Pau Initiative on Neurodegeneration (SPIN) with CSF Aβ1-42 and Aβ1-42/Aβ1-40. Participants had diagnoses of Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal lobar degeneration-related syndromes, non-neurodegenerative conditions, or were cognitively normal. We classified participants as "positive" or "negative" according to each marker. We compared CSF levels of tTau, pTau181, and NfL between concordant and discordant groups through ANCOVA and assessed differences in cognitive (MMSE, FCSRT) and functional (GDS, CDR-SOB) progression using Cox regression and linear-mixed models., Results: In the 1791 participants, the agreement between Aβ1-42 and Aβ1-42/Aβ1-40 was 78.3%. The Aβ1-42/Aβ1-40 ratio showed a stronger correlation with tTau and pTau181 than Aβ1-42 and an agreement with tTau and pTau181 of 73.1% and 77.1%, respectively. Participants with a low Aβ1-42/Aβ1-40 ratio showed higher tTau and pTau181 and worse cognitive and functional prognosis, regardless of whether they were positive or negative for Aβ1-42. The results were consistent across stages, diagnostic categories, and use of different cutoffs., Conclusion: Although Aβ1-42 and Aβ1-42/Aβ1-40 are considered markers of the same pathophysiological pathway, our findings provide evidence favoring the use of the Aβ1-42/Aβ1-40 ratio in clinical laboratories in the context of AD., (© 2022. The Author(s).)

Background: Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases. Studies of glial fibrillary acidic protein (GFAP), an astrocytic damage marker, may help advance our understanding of different neurodegenerative diseases. In this study, we investigated the diagnostic performance of plasma GFAP (pGFAP), plasma neurofilament light chain (pNfL) and their combination for frontotemporal dementia (FTD) and Alzheimer's disease (AD) and their clinical utility in predicting disease progression., Methods: pGFAP and pNfL concentrations were measured in 72 FTD, 56 AD and 83 cognitively normal (CN) participants using the Single Molecule Array technology. Of the 211 participants, 199 underwent cerebrospinal (CSF) analysis and 122 had magnetic resonance imaging. We compared cross-sectional biomarker levels between groups, studied their diagnostic performance and assessed correlation between CSF biomarkers, cognitive performance and cortical thickness. The prognostic performance was investigated, analyzing cognitive decline  through group comparisons by tertile., Results: Unlike pNfL, which was increased similarly in both clinical groups, pGFAP was increased in FTD but lower than in AD (all P < 0.01). Combination of both plasma markers improved the diagnostic performance to discriminate FTD from AD (area under the curve [AUC]: combination 0.78; pGFAP 0.7; pNfL 0.61, all P < 0.05). In FTD, pGFAP correlated with cognition, CSF and plasma NfL, and cortical thickness (all P < 0.05). The higher tertile of pGFAP was associated with greater change in MMSE score and poor cognitive outcome during follow-up both in FTD (1.40 points annually, hazard ratio [HR] 3.82, P < 0.005) and in AD (1.20 points annually, HR 2.26, P < 0.005)., Conclusions: pGFAP and pNfL levels differ in FTD and AD, and their combination is useful for distinguishing between the two diseases. pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD., (© 2021. The Author(s).)

Objectives: All categories included in the AT(N) classification can now be measured in plasma. However, their agreement with cerebrospinal fluid (CSF) markers is not fully established. A blood signature to generate the AT(N) classification would facilitate early diagnosis of patients with Alzheimer's disease (AD) through an easy and minimally invasive approach., Methods: We measured Aβ, pTau181 and neurofilament light (NfL) in 150 plasma samples of the Sant Pau Initiative on Neurodegeneration cohort including patients with mild cognitive impairment, AD dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal participants. We classified participants in the AT(N) categories according to CSF biomarkers and studied the diagnostic value of plasma biomarkers within each category individually and in combination., Results: The plasma Aβ composite, pTau181 and NfL yielded areas under the curve (AUC) of 0.75, 0.78 and 0.88 to discriminate positive and negative participants in their respective A, T and N categories. The combination of all three markers did not outperform pTau181 alone (AUC=0.81) to discriminate A+T+ from A-T- participants. There was a moderate correlation between plasma Aβ composite and CSF Aβ1-42/Aβ1-40 (Rho=-0.5, p<0.001) and between plasma pTau181 and CSF pTau181 in the entire cohort (Rho=0.51, p<0.001). NfL levels in plasma showed high correlation with those in CSF (Rho=0.78, p<0.001)., Conclusions: Plasma biomarkers are useful to detect the AT(N) categories, and their use can differentiate patients with pathophysiological evidence of AD. A blood AT(N) signature may facilitate early diagnosis and follow-up of patients with AD through an easy and minimally invasive approach., Competing Interests: Competing interests: DA is employed by Hospital de la Santa Creu i Sant Pau and received research grants from Pla Estratègic de Recerca i Innovació en Salut (PERIS SLT006/17/125), and from Instituto de Salud Carlos III (PI18/00435 and INT19/00016). He participated in advisory boards from Fujirebio-Europe and Roche Diagnostics and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Esteve and from Krka Farmacéutica S.L. CD is employed by Université de Montpellier and CHU de Montpellier. LM is employed by Biomedical Research Institute Sant Pau. ST is employed by Biomedical Research Institute Sant Pau. TE is employed by Biomedical Research Institute Sant Pau. Declarations of interest: Dr Estellés is funded by a 'Río Hortega' research grant from the Institute of Health Carlos III. NZ is employed by Hospital de la Santa Creu i Sant Pau. IB is employed by Hospital de la Santa Creu i Sant Pau. MC-I is employed by Hospital de la Santa Creu i Sant Pau. II-G is supported by the Global Brain Health Institute (Atlantic Fellow for Equity in Brain Health and pilot award for global brain health leaders GBHI ALZ UK-21-720973) and the 'Juan Rodés' grant from the Institute of Health Carlos III (JR20/00018). MAS-S is employed by Hospital de la Santa Creu i Sant Pau. He is funded by a 'Juan Rodés' research grant from the Institute of Health Carlos III. MA is employed by Biomedical Research Institute Sant Pau. Dr Altuna is funded by a 'Río Hortega' research grant from the Institute of Health Carlos III. IS is employed by Hospital de la Santa Creu i Sant Pau. MBS-S is employed by Biomedical Research Institute Sant Pau. LV is employed by Fundació Catalana Síndrome de Down. SV is employed by Biomedical Research Institute Sant Pau. AS is employed by Biomedical Research Institute Sant Pau. JP is employed by Biomedical Research Institute Sant Pau. CH is employed by Université de Montpellier et CHU de Montpellier. JV is employed by CHU de Montpellier. SL is employed by the University and the Hospital of Montpellier. He participated in advisory boards from Fujirebio-Europe and Roche. TKK is employed by the University of Gothenburg. NA is employed by the University of Gothenburg. KB is employed by Gothenburg University and Sahlgrenska University Hospital. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. HZ is employed by the University of Gothenburg, Sahlgrenska University Hospital and University College London. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. OB is employed by Biomedical Research Institute Sant Pau. Dr Belbin is funded by a 'Miguel Servet' research grant from the Institute of Health Carlos III. RB is employed by Hospital de la Santa Creu i Sant Pau and received research grants from Institute of Health Carlos III, Fundació Bancària Obra Social La Caixa and Fundació La Marató de TV3. He participated in advisory boards from Lilly and Nutricia, and he received speaker honoraria and travel funding from Novartis and Nutricia. JC is employed by Biomedical Research Institute Sant Pau and received research grants from Generalitat de Catalunya and from Institute of Health Carlos III. JF is employed by Hospital de la Santa Creu i Sant Pau and received research grants from Institute of Health Carlos III, Fundació La Marató de TV3, and Pla Estratègic de Recerca i Innovació en Salut (PERIS). AL is employed by Hospital de la Santa Creu i Sant Pau and received research grants from CIBERNED, Institute of Health Carlos III and Fundación BBVA. He participated in advisory boards from Fujirebio-Europe, Nutricia, Biogen, and received speaker honoraria from Lilly., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Alzheimer disease (AD) is the leading cause of death in individuals with Down syndrome (DS). Previous studies have suggested that the APOE ɛ4 allele plays a role in the risk and age at onset of dementia in DS; however, data on in vivo biomarkers remain scarce., Objective: To investigate the association of the APOE ɛ4 allele with clinical and multimodal biomarkers of AD in adults with DS., Design, Setting, and Participants: This dual-center cohort study recruited adults with DS in Barcelona, Spain, and in Cambridge, UK, between June 1, 2009, and February 28, 2020. Included individuals had been genotyped for APOE and had at least 1 clinical or AD biomarker measurement; 2 individuals were excluded because of the absence of trisomy 21. Participants were either APOE ɛ4 allele carriers or noncarriers., Main Outcomes and Measures: Participants underwent a neurological and neuropsychological assessment. A subset of participants had biomarker measurements: Aβ1-42, Aβ1-40, phosphorylated tau 181 (pTau181) and neurofilament light chain (NfL) in cerebrospinal fluid (CSF), pTau181, and NfL in plasma; amyloid positron emission tomography (PET); fluorine 18-labeled-fluorodeoxyglucose PET; and/or magnetic resonance imaging. Age at symptom onset was compared between APOE ɛ4 allele carriers and noncarriers, and within-group local regression models were used to compare the association of biomarkers with age. Voxelwise analyses were performed to assess topographical differences in gray matter metabolism and volume., Results: Of the 464 adults with DS included in the study, 97 (20.9%) were APOE ɛ4 allele carriers and 367 (79.1%) were noncarriers. No differences between the 2 groups were found by age (median [interquartile range], 45.9 [36.4-50.2] years vs 43.7 [34.9-50.2] years; P = .56) or sex (51 male carriers [52.6%] vs 199 male noncarriers [54.2%]). APOE ɛ4 allele carriers compared with noncarriers presented with AD symptoms at a younger age (mean [SD] age, 50.7 [4.4] years vs 52.7 [5.8] years; P = .02) and showed earlier cognitive decline. Locally estimated scatterplot smoothing curves further showed between-group differences in biomarker trajectories with age as reflected by nonoverlapping CIs. Specifically, carriers showed lower levels of the CSF Aβ1-42 to Aβ1-40 ratio until age 40 years, earlier increases in amyloid PET and plasma pTau181, and earlier loss of cortical metabolism and hippocampal volume. No differences were found in NfL biomarkers or CSF total tau and pTau181. Voxelwise analyses showed lower metabolism in subcortical and parieto-occipital structures and lower medial temporal volume in APOE ɛ4 allele carriers., Conclusions and Relevance: In this study, the APOE ɛ4 allele was associated with earlier clinical and biomarker changes of AD in DS. These results provide insights into the mechanisms by which APOE increases the risk of AD, emphasizing the importance of APOE genotype for future clinical trials in DS.

Background: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome., Methods: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid β peptides 1-42 and 1-40 and their ratio (Aβ 1-42/1-40 ), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18 F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate., Findings: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aβ 1-42/1-40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18 F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90-100% in the seventh decade of life., Interpretation: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments., Funding: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The SPIN (Sant Pau Initiative on Neurodegeneration) cohort is a multimodal biomarker platform designed for neurodegenerative disease research following an integrative approach., Methods: Participants of the SPIN cohort provide informed consent to donate blood and cerebrospinal fluid samples, receive detailed neurological and neuropsychological evaluations, and undergo a structural 3T brain MRI scan. A subset also undergoes other functional or imaging studies (video-polysomnogram, 18 F-fluorodeoxyglucose PET, amyloid PET, Tau PET). Participants are followed annually for a minimum of 4 years, with repeated cerebrospinal fluid collection and imaging studies performed every other year, and brain donation is encouraged., Results: The integration of clinical, neuropsychological, genetic, biochemical, imaging, and neuropathological information and the harmonization of protocols under the same umbrella allows the discovery and validation of key biomarkers across several neurodegenerative diseases., Discussion: We describe our particular 10-year experience and how different research projects were unified under an umbrella biomarker program, which might be of help to other research teams pursuing similar approaches., (© 2019 The Authors.)

We report on a 19-year-old girl with upper extremity deep vein thrombosis after catheter indwelling whose thrombophilic study disclosed the coexistence of factor V Leiden and the prothrombin G20210A mutation. The family study identified five other members who were also heterozygous for both mutations. This is the first case of upper extremity deep vein thrombosis with the co-inheritance of both genetic defects. It provides further evidence that thrombophilic defects mostly require additional triggering factors to induce a thrombotic event and suggests that in young patients with this venous thrombotic location, a thrombophilic search should be performed even when there are other acquired thrombotic risk factors.

Baby walkers are a potential cause of accidents in infants from 6 months to 1 year of age. We conducted a study to determine the patterns of walker use, the different points of view of the parents and the baby walker-related injuries in our health district. For this purpose, between November 1, 1992 and January 31, 1993, a questionnaire was given to 207 parents of infants between the ages of 3 and 24 months in order to evaluate the socioeconomic situation and to determine the patterns of walker use. We found that 42% of the infants between 4.3 and 13.4 months of age had a baby walker and 46.7% of them used it daily. There was a significant inverse relationship between the walker usage and the maternal level of education. Of the infants who used walkers, 24.9% had experienced an accident (falls 76.2%, injuries 14.3% and hospital admission 4.8%). The accidents were significantly more common in boys. The advantages reported by parents (for using walkers) were: 46.3% none, 34.2% comfort, 10.9% infant amusement, 12.9% help to walk earlier. Dangers reported by the parents included: 27.2% none, 33.5% leg deformities, 43% accidents (33.5% injuries and 12% falling down stairs). In conclusion, our results show a slightly lower number of walker users and walker related accidents when compared to other reports. Parents have mistaken notions about the use of baby walkers. Hence, the need for continued health education campaigns related to this subject remain.

Presentation of an uncommon case referring necrosis of an ectopic inguino-femoral testis caused by an incarcerated inguino-scrotal hernia in a 15-days old baby with a permeable peritoneum-vaginal process. In this case, the hernial incarceration episode was responsible for the organ necrosis due to an haemorrhagic infarction. Orchiectomy was performed, and the pathoanatomical diagnosis was testicular haemorrhagic infarction. Review of the pathogenic mechanisms of testicular ectopia, associated anomalies and likely acute complications: torsion, hernial strangulation, traumatism and infections simulating acute abdomen which, in spite of their rarity, may have serious consequences with regard to testicular viability.