Search

BackgroundThe key Alzheimer’s disease (AD) biomarkers are traditionally measured with techniques/exams that are either expensive (amyloid-positron emission tomography (PET) and tau-PET), invasive (cerebrospinal fluid Aβ42and p-tau181), or poorly specific (atrophy on MRI and hypometabolism on fluorodeoxyglucose-PET). Recently developed plasma biomarkers could significantly enhance the efficiency of the diagnostic pathway in memory clinics and improve patient care. This study aimed to: (1) confirm the correlations between plasma and traditional AD biomarkers, (2) assess the diagnostic accuracy of plasma biomarkers as compared with traditional biomarkers, and (3) estimate the proportion of traditional exams potentially saved thanks to the use of plasma biomarkers.MethodsParticipants were 200 patients with plasma biomarkers and at least one traditional biomarker collected within 12 months.ResultsOverall, plasma biomarkers significantly correlated with biomarkers assessed through traditional techniques: up tor=0.50 (pr=0.43 (p=0.002) among tau, andr=−0.23 (p=0.001) among neurodegeneration biomarkers. Moreover, plasma biomarkers showed high accuracy in discriminating the biomarker status (normal or abnormal) determined by using traditional biomarkers: up to area under the curve (AUC)=0.87 for amyloid, AUC=0.82 for tau, and AUC=0.63 for neurodegeneration status. The use of plasma as a gateway to traditional biomarkers using cohort-specific thresholds (with 95% sensitivity and 95% specificity) could save up to 49% of amyloid, 38% of tau, and 16% of neurodegeneration biomarkers.ConclusionThe implementation of plasma biomarkers could save a remarkable proportion of more expensive traditional exams, making the diagnostic workup more cost-effective and improving patient care.

The vascular endothelial growth factor (VEGF) family of genes has been implicated in the clinical development of Alzheimer’s Disease (AD). A previous study identified associations between gene expression of VEGF family members in the prefrontal cortex and cognitive performance and AD pathology. This study explored if those associations were also observed in the blood. Consistent with previous observations in brain tissue, higher blood gene expression of placental growth factor (PGF) was associated with a faster rate of memory decline (p=0.04). Higher protein abundance of FMS-related receptor tyrosine kinase 4 (FLT4) in blood was associated with biomarker levels indicative of lower amyloid and tau pathology, opposite the direction observed in brain. Also, higher gene expression of VEGFB in blood was associated with better baseline memory (p=0.008). Notably, we observed that higher gene expression of VEGFB in blood was associated with lower expression of VEGFB in the brain (r=−0.19, p=0.02). Together, these results suggest that the VEGFB, FLT4, and PGF alterations in the AD brain may be detectable in the blood compartment.

Background and purposeCurrently there is an unmet need for a highly standardized blood biomarker test to monitor treatment response in Lyme neuroborreliosis (LNB). Differentiating between active or past infection is challenged by the relatively high frequency of persistent symptoms after the end of antibiotic treatment (estimated 15%–20%), the variable clinical course and the long-lasting Borrelia burgdorferi antibodies. The aim was therefore to evaluate plasma neurofilament light chain (pNfL) as a marker for disease activity in LNB.MethodsThis was a prospective cohort of definite LNB (N = 36) with blood samples and clinical evaluation including Glasgow Outcome Score at treatment initiation and 3 and 6 months’ follow-up. Consecutive plasma was retrospectively analysed for the content of neurofilament light chain by Quanterix® kits (Simoa® NF-light Kit).ResultsPlasma neurofilament light chain significantly decreased between treatment initiation and the 3-month follow-up (median 83 pg/ml vs. median 14 pg/ml (25 pairs), p ConclusionPlasma neurofilament light chain decreases following antibiotic treatment in LNB and is not associated with reporting persistent symptoms. It was therefore speculated that it may prove useful as a treatment response biomarker in LNB. Background and purpose: Currently there is an unmet need for a highly standardized blood biomarker test to monitor treatment response in Lyme neuroborreliosis (LNB). Differentiating between active or past infection is challenged by the relatively high frequency of persistent symptoms after the end of antibiotic treatment (estimated 15%–20%), the variable clinical course and the long-lasting Borrelia burgdorferi antibodies. The aim was therefore to evaluate plasma neurofilament light chain (pNfL) as a marker for disease activity in LNB. Methods: This was a prospective cohort of definite LNB (N = 36) with blood samples and clinical evaluation including Glasgow Outcome Score at treatment initiation and 3 and 6 months’ follow-up. Consecutive plasma was retrospectively analysed for the content of neurofilament light chain by Quanterix® kits (Simoa® NF-light Kit). Results: Plasma neurofilament light chain significantly decreased between treatment initiation and the 3-month follow-up (median 83 pg/ml vs. median 14 pg/ml (25 pairs), p < 0.0001). No significant change was observed between 3 and 6 months’ follow-up (median 14 pg/ml vs. median 12 pg/ml (21 pairs), p = 0.33). At treatment initiation 90% had pNfL above the age-defined reference compared to only 23% and 7% respectively at 3 and 6 months’ follow-up. Decreases in pNfL were mirrored by increasing Glasgow Outcome Score. Reporting persistent symptoms at the 6-month follow-up was not associated with pNfL (relative change from reference or actual values) at baseline or at 6 months’ follow-up. Conclusion: Plasma neurofilament light chain decreases following antibiotic treatment in LNB and is not associated with reporting persistent symptoms. It was therefore speculated that it may prove useful as a treatment response biomarker in LNB.

The blood–brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer’s disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer’s disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT03739905) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer’s disease pathology (P-tau181, amyloid-β42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.

Emerging plasma biomarkers of Alzheimer's disease might be non-invasive tools to trace early Alzheimer's disease-related abnormalities such as the accumulation of amyloid-beta peptides, neurofibrillary tau tangles, glial activation and neurodegeneration. It is, however, unclear which pathological processes in the CNS can be adequately detected by peripheral measurements and whether plasma biomarkers are equally applicable in both clinical and preclinical phases. Here we aimed to explore the timing and performance of plasma biomarkers in mutation carriers compared to non-carriers in autosomal dominant Alzheimer's disease.Samples (n = 164) from mutation carriers (n = 33) and non-carriers (n = 42) in a Swedish cohort of autosomal dominant Alzheimer's disease (APP p.KM670/671NL, APP p.E693G and PSEN1 p.H163Y) were included in explorative longitudinal analyses. Plasma phosphorylated tau (P-tau181), total tau (T-tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) concentrations were measured with a single-molecule array method as previously described. Plasma biomarkers were additionally correlated to Alzheimer's disease core biomarkers in the CSF.Results from the longitudinal analyses confirmed that plasma P-tau181, NfL and GFAP concentrations were higher in mutation carriers compared to non-carriers. This change was observed in the presymptomatic phase and detectable first as an increase in GFAP approximately 10 years before estimated symptom onset, followed by increased levels of P-tau181 and NfL closer to expected onset. Plasma P-tau181 levels were correlated to levels of P-tau181 and T-tau in the CSF.Altogether, plasma P-tau181, GFAP and NfL seem to be feasible biomarkers to detect different Alzheimer's disease-related pathologies already in presymptomatic individuals. Interestingly, changes in plasma GFAP concentrations were detected prior to P-tau181 and NfL. Our results suggest that plasma GFAP might reflect Alzheimer's disease pathology upstream to accumulation of tangles and neurodegeneration. The implications of these findings need additional validation, in particular because of the limited sample size.

Background and Objectives Increased anxious-depressive symptomatology is observed in the preclinical stage of Alzheimer disease (AD), which may accelerate disease progression. We investigated whether β-amyloid, cortical thickness in medial temporal lobe structures, neuroinflammation, and sociodemographic factors were associated with greater anxious-depressive symptoms during the COVID-19 confinement. Methods This retrospective observational study included cognitively unimpaired older adults from the Alzheimer's and Families cohort, the majority with a family history of sporadic AD. Participants performed the Hospital Anxiety and Depression Scale (HADS) during the COVID-19 confinement. A subset had available retrospective (on average: 2.4 years before) HADS assessment, amyloid [18F] flutemetamol PET and structural MRI scans, and CSF markers of neuroinflammation (interleukin-6 [IL-6], triggering receptor expressed on myeloid cells 2, and glial fibrillary acidic protein levels). We performed multivariable linear regression models to investigate the associations of prepandemic AD-related biomarkers and sociodemographic factors with HADS scores during the confinement. We further performed an analysis of covariance to adjust by participants' prepandemic anxiety-depression levels. Finally, we explored the role of stress and lifestyle changes (sleep patterns, eating, drinking, smoking habits, and medication use) on the tested associations and performed sex-stratified analyses. Results We included 921 (254 with AD biomarkers) participants. β-amyloid positivity (B = 3.73; 95% CI = 1.1 to 6.36; p = 0.006), caregiving (B = 1.37; 95% CI 0.24–2.5; p = 0.018), sex (women: B = 1.95; 95% CI 1.1–2.79; p < 0.001), younger age (B = −0.12; 95% CI −0.18 to −0.052; p < 0.001), and lower education (B = −0.16; 95% CI −0.28 to −0.042; p = 0.008) were associated with greater anxious-depressive symptoms during the confinement. Considering prepandemic anxiety-depression levels, we further observed an association between lower levels of CSF IL-6 (B = −5.11; 95% CI −10.1 to −0.13; p = 0.044) and greater HADS scores. The results were independent of stress-related variables and lifestyle changes. Stratified analysis revealed that the associations were mainly driven by women. Discussion Our results link AD-related pathophysiology and neuroinflammation with greater anxious-depressive symptomatology during the COVID-19-related confinement, notably in women. AD pathophysiology may increase neuropsychiatric symptomatology in response to stressors. This association may imply a worse clinical prognosis in people at risk for AD after the pandemic and thus deserves to be considered by clinicians., This research was supported by Alzheimer's Association research grants (AARG 2019-AARG-644641 and AARG 2019-AARG-644641-RAPID) to E.M. Arenaza-Urquijo. E.M. Arenaza-Urquijo holds a Ramón y Cajal fellowship (RYC2018-026053-I) and a grant of the Ministry of Science and Innovation (PID2019-111514RA-I00). The research leading to these results has received funding from la Caixa Foundation (LCF/PR/GN17/10300004), the Alzheimer's Association, and an international anonymous charity foundation through the TriBEKa Imaging Platform project. Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under grant 2017-SGR-892.

Background and purpose A wide range of neuroradiological findings has been reported in patients with coronavirus disease 2019 (COVID-19), ranging from subcortical white matter changes to infarcts, haemorrhages and focal contrast media enhancement. These have been descriptively but inconsistently reported and correlations with clinical findings and biomarkers have been difficult to extract from the literature. The purpose of this study was to quantify the extents of neuroradiological findings in a cohort of patients with COVID-19 and neurological symptoms, and to investigate correlations with clinical findings, duration of intensive care and biomarkers in blood. Material and methods Patients with positive SARS-CoV-2 and at least one new-onset neurological symptom were included from April until July 2020. Nineteen patients were examined regarding clinical symptoms, biomarkers in blood and MRI of the brain. In order to quantify the MRI findings, a semi-quantitative neuroradiological severity scale was constructed a priori, and applied to the MR images by two specialists in neuroradiology. Results and conclusions The score from the severity scale correlated significantly with blood biomarkers of CNS injury (glial fibrillary acidic protein, total-tau, ubiquitin carboxyl-terminal hydrolase L1) and inflammation (C-reactive protein), Glasgow Coma Scale score, and the number of days spent in intensive care. The underlying radiological assessments had inter-rater agreements of 90.5%/86% (for assessments with 2/3 alternatives). Total intraclass correlation was 0.80. Previously reported neuroradiological findings in COVID-19 have been diverse and heterogenous. In this study, the extent of findings in MRI examination of the brain, quantified using a structured report, shows correlation with relevant biomarkers.

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume. This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Programme, Neurodegenerative Disease Research (JPND). Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Part of the work described in this study was carried out in the context of the Parelsnoer Institute (PSI). PSI was part of and funded by the Dutch Federation of University Medical Centers and has received initial funding from the Dutch Government (from 2007-2011). Since 2020, this work was carried out in the context of Parelsnoer clinical biobanks at Health-RI (https://www.health-ri.nl/initiatives/parelsnoer).Part of the genotyping included in this work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Alfredo Ramirez is also supported by the German Research Foundation (DFG) grants Nr: RA 1971/6-1, RA1971/7-1, and RA 1971/8-1. We would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Grifols SA, Fundacion bancaria 'La Caixa', Fundacio ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'). The position held by I.dR. is funded by grant. FI20/00215. PFIS Contratos Predoctorales de Formacion en Investigacion en Salud. We would like to thank UCL Genomics, London, UK, for performing the genotyping analyses of the samples within the Gothenburg H70 Birth Cohort Studies and Clinical AD Sweden. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444, and P01AG003991. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenom ics.wustl.edu/)and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Research at the Belgian EADB site is funded in part by the Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund. The work of Valdecilla was supported by grants from the Instituto de Salud Carlos III (Fondo de Investigacion Sanitario, PI08/0139, PI12/02288, PI16/01652, and PI20/01011), the JPND (DEMTEST PI11/03028), the CIBERNED, and the Siemens Healthineers. We thank the Valdecilla Biobank (PT17/0015/0019), integrated into the Spanish Biobank Network, for their support and collaboration in sample collection and management. Our heartfelt thanks to the participants of the Valdecilla Cohort for their generosity. The work of ADGEN was supported by EU Joint Programme-Neurodegenerative Disease Research (301220) and the Academy of Finland (338182). The DELCODE study (Study-ID:BN012) was supported and conducted by the German Center for Neurodegenerative Diseases (DZNE). The data samples were provided by the DELCODE study group. Details and participating sites can be found at www.dzne.de/en/research/studies/clinical-studies/delco de. The German Dementia Competence Network (KND) is funded by the German Federal Ministry of Education and Research (BMBF) grants Number: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711. WF, SvdL, HHolstege, CT and PhS are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and HealthHolland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD (www.aboard-project.nl).ABOARD also receives funding from de Hersenstichting, Edwin Bouw Fonds and Gieskes-Strijbisfonds. IEJ was partially supported by NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). AZ was supported by the Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361), and the Dementia Foundation (2020-04-13, 2021-0417). ISk was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALFagreement (ALF 716681), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 20050762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 20132496), Swedish Brain Power, Hjarnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163), the Alzheimer's Association Zenith Award (ZEN-01-3151), the Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159), the Alzheimer's Association (IIRG-03-6168, IIRG-09-131338) and the Bank of Sweden Tercentenary Foundation. SK was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALF GBG-771071), the Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825), and the Swedish Research Council (2019-02075). MW was supported by the Swedish Research Council 2016-01590. DP was supported by BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057. 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 (2018092016862), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB was supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjarnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG06839801), and the Alzheimer's Association 2021 Zenith Award (ZEN-21848495). CC receives support from the National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614), and the Chuck Zuckerberg Initiative (CZI).

Synaptic degeneration is a key part of the pathophysiology of neurodegenerative diseases, and biomarkers reflecting the pathological alterations are greatly needed.Seventeen synaptic proteins were quantified in a pathology-confirmed cerebrospinal fluid cohort of patients with Alzheimer's disease (AD; n = 63), frontotemporal lobar degeneration (FTLD; n = 53), and Lewy body spectrum of disorders (LBD; n = 21), as well as healthy controls (HC; n = 48).Comparisons revealed four distinct patterns: markers decreased across all neurodegenerative conditions compared to HC (the neuronal pentraxins), markers increased across all neurodegenerative conditions (14-3-3 zeta/delta), markers selectively increased in AD compared to other neurodegenerative conditions (neurogranin and beta-synuclein), and markers selectively decreased in LBD and FTLD compared to HC and AD (AP2B1 and syntaxin-1B).Several of the synaptic proteins may serve as biomarkers for synaptic dysfunction in AD, LBD, and FTLD. Additionally, differential patterns of synaptic protein alterations seem to be present across neurodegenerative diseases.A panel of synaptic proteins were quantified in the cerebrospinal fluid using mass spectrometry. We compared Alzheimer's disease, frontotemporal degeneration, and Lewy body spectrum of disorders. Pathology was confirmed by autopsy or familial mutations. We discovered synaptic biomarkers for synaptic degeneration and cognitive decline. We found differential patterns of synaptic proteins across neurodegenerative diseases.

What is this summary about? This is a plain language summary of an article published in Alzheimer’s & Dementia. It looks at a type of test called a lumbar puncture (also known as spinal tap) used in people suspected of having Alzheimer’s disease or some other form of dementia. This summary focuses on how to do a lumbar puncture safely. Why is this important? Alzheimer’s disease is a progressive condition, which means it gets worse over time. This leads to difficulties with thinking and memory. People with Alzheimer’s disease show a build up of proteins called amyloid-β and tau in the brain. This is followed by a gradual loss of brain cells and brain function. The changes in the brain are thought to occur years before symptoms appear. Lumbar puncture is a medical procedure during which samples of cerebrospinal fluid are collected. In Alzheimer’s disease, it is used to examine cerebrospinal fluid biomarkers that can help diagnose disease. Lumbar puncture is traditionally considered as a painful and invasive procedure with frequent side effects. However, multiple studies indicate that a lumbar puncture can be performed safely. Side effects are typically mild and do not require specialist intervention. What are the key takeaways? Despite the low risk of serious complications associated with a lumbar puncture, physicians and their patients may be reluctant to recommend or undergo this procedure. Patient education, specialist training, as well as new methods concerning patient safety are important factors to support the widespread use of lumbar puncture in Alzheimer’s disease.

What is this summary about? This is a plain language summary of an article published in Nature Reviews Neurology. It explains how Alzheimer's disease is diagnosed. It also looks at whether a newer way to assess people with Alzheimer's disease could help improve how the condition is diagnosed, monitored, and treated. Why is this important? Alzheimer's disease is a long-term progressive brain disease that leads to difficulties with thinking and memory. It is a progressive condition, which means it gets worse over time. Biological changes occur in the brain of people with Alzheimer's disease. This includes a build-up of toxic protein clusters called amyloid plaques and tau tangles, gradual damage to the brain cells (neurodegeneration), and brain shrinkage due to loss of neurons. It is often due to multiple factors and doctors usually diagnose Alzheimer's disease by looking at a person's symptoms and ruling out other causes of dementia. However, research shows that people diagnosed in this way do not always have the biological changes in the brain that are related to Alzheimer's disease. This means that some people may be misdiagnosed. Additionally, there may be a delay in the appearance of Alzheimer's symptoms, by which point changes in the brain may be severe. For example, people with Alzheimer's disease show biological changes in the brain, years before symptoms appear. What are the key takeaways? An assessment of biological changes in the brain, by measuring substances that indicate disease progress (biomarkers), may offer a fuller picture of a person's Alzheimer's disease, how advanced it is, and which treatments are likely to work best. A recently developed classification scheme known as the AT(N) system provides a way to assess and describe the biological changes in amyloid (A), tau (T), and neurodegeneration (N) that occur in people with Alzheimer's disease. The goal is to include biomarker testing in clinical practice to help physicians and practitioners diagnose, monitor, and treat people with Alzheimer's disease more effectively. The AT(N) system is being used for various purposes in clinical studies, and has the potential to assist physicians and practitioners in early detection, accurate diagnosis, staging, and treatment selection for people with Alzheimer's disease.

This increasing body of literature indicates that menopause hormonal replacement therapy (MHT) may substantially mitigate the risk of developing late-life cognitive decline due to progressive Alzheimer's disease (AD) pathophysiology. For the first time, we investigated the question whether MHT impacts AD biomarker-informed pathophysiological dynamics in de-novo diagnosed menopausal women.We analyzed baseline and longitudinal differences between MHT-taking and -not women in terms of concentrations of core pathophysiological AD plasma biomarkers, validated in symptomatic and cognitively healthy individuals, including biomarkers of (1) the amyloid-β (Aβ) pathway, (2) tau pathophysiology, (3) neuronal loss, and (4) axonal damage and neurodegeneration.We report a prominent and significant treatment response at the Aβ pathway biomarker level. Women at genetic risk for AD (APOE e4 allele carriers) have particularly shown favorable results from treatment.To our knowledge, we present first prospective clinical evidence on effects of MHT on AD pathophysiology during menopause.

Recent evidence has shown that the marker of reactive astrogliosis, glial fibrillary acidic protein (GFAP), has a stronger relationship with cerebral amyloid beta (Aβ) pathology in blood than in cerebrospinal fluid (CSF). This study investigates if pre-analytical treatment of blood and CSF contribute to these unexpected findings.Paired CSF and serum samples from 49 individuals (Aβ-negative = 28; Aβ-positive = 21) underwent a series of seven freeze-thaw cycles (FTCs). All samples were analyzed for GFAP and neurofilament light (NfL) using single molecule array technology including a fresh unfrozen sample from each patient.FTC significantly affected CSF GFAP concentration (-188.12 pg/ml per FTC) but not serum GFAP. In the same samples, NfL remained stable. Serum GFAP had a higher discrimination of Aβ burden than CSF GFAP, irrespective of FTC, which also included unfrozen samples.This study demonstrates large stability differences of GFAP in CSF and serum. However, this disparity does not seem to fully explain the stronger association of serum GFAP with Aβ pathology. Further work should investigate mechanisms of GFAP release into the bloodstream under pathological conditions.

Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison of p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-β (Aβ) status and predict future progression to Alzheimer's dementia. The study included 135 patients with baseline diagnosis of mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average of 4.9 years. Seventy-one participants had abnormal Aβ-status (i.e. abnormal CSF Aβ42/40) at baseline; and 45 of these Aβ-positive participants progressed to Alzheimer's dementia during follow-up. P-tau concentrations were determined in baseline plasma and CSF. P-tau217 and p-tau181 were both measured using immunoassays developed by Lilly Research Laboratories (Lilly) and mass spectrometry assays developed at Washington University (WashU). P-tau217 was also analysed using Simoa immunoassay developed by Janssen Research and Development (Janss). P-tau181 was measured using Simoa immunoassay from ADxNeurosciences (ADx), Lumipulse immunoassay from Fujirebio (Fuji) and Splex immunoassay from Mesoscale Discovery (Splex). Both p-tau181 and p-tau231 were quantified using Simoa immunoassay developed at the University of Gothenburg (UGOT). We found that the mass spectrometry-based p-tau217 (p-tau217WashU) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aβ status [area under curve (AUC) = 0.947; Pdiff < 0.015] or progression to Alzheimer's dementia (AUC = 0.932; Pdiff < 0.027). Among immunoassays, p-tau217Lilly had the highest AUCs (0.886–0.889), which was not significantly different from the AUCs of p-tau217Janss, p-tau181ADx and p-tau181WashU (AUCrange 0.835–0.872; Pdiff > 0.09), but higher compared with AUC of p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji and p-tau181Splex (AUCrange 0.642–0.813; Pdiff ≤ 0.029). Correlations between plasma and CSF values were strongest for p-tau217WashU (R = 0.891) followed by p-tau217Lilly (R = 0.755; Pdiff = 0.003 versus p-tau217WashU) and weak to moderate for the rest of the p-tau biomarkers (Rrange 0.320–0.669). In conclusion, our findings suggest that among all tested plasma p-tau assays, mass spectrometry-based measures of p-tau217 perform best when identifying mild cognitive impairment patients with abnormal brain Aβ or those who will subsequently progress to Alzheimer's dementia. Several other assays (p-tau217Lilly, p-tau217Janss, p-tau181ADx and p-tau181WashU) showed relatively high and consistent accuracy across both outcomes. The results further indicate that the highest performing assays have performance metrics that rival the gold standards of Aβ-PET and CSF. If further validated, our findings will have significant impacts in diagnosis, screening and treatment for Alzheimer's dementia in the future.

Background and aimsTo investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19).MethodsWe conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU)admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL.ResultsWe identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2 ± 15.0years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13-3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with ahigher likelihood of ICU admission, need ofMV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need ofMV and ICU admission, respectively.ConclusionsBlood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19.

It is unclear whether cerebrospinal fluid (CSF) biomarkers of neurodegeneration predict brain atrophy in cognitively healthy older adults, whether these associations can be explained by phosphorylated tau181 (p-tau) and the 42 amino acid form of amyloid-β (Aβ42) biomarkers, and which neural substrates may drive these associations. We addressed these questions in 2 samples of cognitively healthy older adults who underwent longitudinal structural MRI up to 7 years and had baseline CSF levels of heart-type fatty-acid binding protein (FABP3)=, total-tau, neurogranin, and neurofilament light (NFL) (n = 189, scans = 721). The results showed that NFL, total-tau, and FABP3 predicted entorhinal thinning and hippocampal atrophy. Brain atrophy was not moderated by Aβ42 and the associations between NFL and FABP3 with brain atrophy were independent of p-tau. The spatial pattern of cortical atrophy associated with the biomarkers overlapped with neurogenetic profiles associated with expression in the axonal (total-tau, NFL) and dendritic (neurogranin) components. CSF biomarkers of neurodegeneration are useful for predicting specific features of brain atrophy in older adults, independently of amyloid and tau pathology biomarkers.

Considering the wide range of outcomes following sport-related concussions, biomarkers are needed to detect underlying pathological changes. The objective was to analyze the use of plasma phosphorylated tau 181 (pTau181) as a non-invasive measure of underlying brain changes in a cohort of retired contact sports athletes at risk of neurodegeneration.Fifty-four retired contact sport athletes and 27 healthy controls whose blood plasma was analyzed for pTau181 were included. A portion (N = 21) of retired athletes had a 2-years follow-up visit. All participants had completed a neuropsychological battery and MRI imaging.Plasma pTau181 was significantly higher in retired athletes compared to healthy controls (8.94 ± 5.08 pg/mL vs. 6.00 ± 2.53 pg/mL, respectively; 95% BCa CI 1.38-4.62; p = 0.02); and was significantly associated with fornix fractional anisotropy values only in the athletes group (β = - 0.002; 95% BCa CI - 0.003 to - 0.001; p = 0.002). When the retired athletes cohort was divided into high vs. normal pTau181 groups, the corpus callosum (CC) volume and white-matter integrity was significantly lower in high pTau181 compared to older healthy controls (CC volume: 1.57 ± 0.19 vs. 2.02 ± 0.32, p = 0.002; CC medial diffusivity: 0.96 ± 0.04 × 10Although high plasma pTau181 levels were associated with abnormalities in CC and fornix, baseline pTau181 did not predict longitudinal changes in regional brain volumes or white-matter integrity in the athletes. pTau181 may be useful for identifying those with brain abnormalities related to repeated concussion but not for predicting progression.

To investigate the diagnostic and prognostic value of axonal injury biomarkers in patients with inflammatory polyneuropathies.Neurofilament light chain (NfL) and total tau (T-tau) were measured in the cerebrospinal fluid (CSF) and plasma in 41 patients with Guillain-Barré syndrome (GBS), 32 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 10 with paraproteinemia-related demyelinating polyneuropathy (PDN), and 8 with multifocal motor neuropathy (MMN), in comparison with 39 disease-free controls and 59 other controls. Outcome was measured with the GBS-disability score (GBS-ds) or Inflammatory Neuropathy Cause and Treatment (INCAT) disability score.Neurofilament light chain levels in CSF and plasma were higher in GBS, CIDP, and PDN vs. disease-free controls. Patients with MMN had higher NfL levels in plasma vs. disease-free controls, but lower levels in CSF and plasma vs. patients with amyotrophic lateral sclerosis (ALS). T-tau levels in plasma were higher in GBS, CIDP, PDN, and MMN vs. all control groups. Neurofilament light chain levels in CSF and plasma in patients with GBS correlated with GBS-ds, as higher levels were associated with inability to run after 6 and 12 months. NfL levels in CSF and plasma in CIDP did not correlate significantly with outcome.Acute and chronic inflammatory neuropathies are associated with an increase in levels of NfL in CSF and plasma, but NfL is validated as a prognostic biomarker only in GBS. NfL could be used in differentiating patients with MMN from ALS. T-tau in plasma is a novel biomarker that could be used in a diagnostic assessment of patients with acute and chronic inflammatory polyneuropathies.

BACKGROUND: Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics. METHODS: Individuals were classified based on CSF amyloid beta (Aβ)1-42 (A) and phosphorylated tau (T), as cognitively normal A-T- (CN), MCI A-T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed. RESULTS: A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus. CONCLUSION: The pathophysiology of MCI-SNAP (A-T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD. ispartof: ALZHEIMERS & DEMENTIA vol:19 issue:3 pages:807-820 ispartof: location:United States status: published

The effect of random error on the performance of blood-based biomarkers for Alzheimer's disease (AD) must be determined before clinical implementation.We measured test-retest variability of plasma amyloid beta (Aβ)42/Aβ40, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau (p-tau)217 and simulated effects of this variability on biomarker performance when predicting either cerebrospinal fluid (CSF) Aβ status or conversion to AD dementia in 399 non-demented participants with cognitive symptoms.Clinical performance was highest when combining all biomarkers. Among single-biomarkers, p-tau217 performed best. Test-retest variability ranged from 4.1% (Aβ42/Aβ40) to 25% (GFAP). This variability reduced the performance of the biomarkers (≈ΔAUC [area under the curve] -1% to -4%) with the least effects on models with p-tau217. The percent of individuals with unstable predicted outcomes was lowest for the multi-biomarker combination (14%).Clinical prediction models combining plasma biomarkers-particularly p-tau217-exhibit high performance and are less effected by random error. Individuals with unstable predicted outcomes ("gray zone") should be recommended for further tests.

Introduction Frontotemporal dementia (FTD) encompasses a wide spectrum of genetic, clinical, and histological findings. Sex is emerging as a potential biological variable influencing FTD heterogeneity; however, only a few studies explored this issue with nonconclusive results. Objective To estimate the role of sex in a single-center large cohort of FTD patients. Methods Five hundred thirty-one FTD patients were consecutively enrolled. Demographic, clinical, and neuropsychological features, survival rate, and serum neurofilament light (NfL) concentration were determined and compared between sex. Results The behavioral variant of FTD was more common in men, whereas primary progressive aphasia was overrepresented in women (p p = 0.003), semantic fluency (p = 0.03), Short Story Recall Test (p = 0.003), and the copy of Rey Complex Figure (p = 0.005). On the other hand, men exhibited more personality/behavioral symptoms (Frontal Behavior Inventory [FBI] AB, p = 0.003), displaying higher scores in positive FBI subscales (FBI B, p p = 0.02), irritability (p = 0.006), poor judgment (p = 0.033), aggressivity (p = 0.008), and hypersexuality (p = 0.006) were more common in men, after correction for disease severity. NfL concentration and survival were not statistically different between men and women (p = 0.167 and p = 0.645, respectively). Discussion The present study demonstrated that sex is a potential factor in determining FTD phenotype, while it does not influence survival. Although the pathophysiological contribution of sex in neurodegeneration is not well characterized yet, our findings highlight its role as deserving biological variable in FTD.

Blood-based biomarkers such as tau phosphorylated at threonine 181 (phosphorylated-tau181) represent an accessible, cost-effective and scalable approach for the in vivo detection of Alzheimer’s disease pathophysiology. Plasma-pathological correlation studies are needed to validate plasma phosphorylated-tau181 as an accurate and reliable biomarker of Alzheimer’s disease neuropathological changes. This plasma-to-autopsy correlation study included participants from the Boston University Alzheimer’s Disease Research Center who had a plasma sample analysed for phosphorylated-tau181 between 2008 and 2018 and donated their brain for neuropathological examination. Plasma phosphorelated-tau181 was measured with single molecule array technology. Of 103 participants, 62 (60.2%) had autopsy-confirmed Alzheimer’s disease. Average time between blood draw and death was 5.6 years (standard deviation = 3.1 years). Multivariable analyses showed higher plasma phosphorylated-tau181 concentrations were associated with increased odds for having autopsy-confirmed Alzheimer’s disease [AUC = 0.82, OR = 1.07, 95% CI = 1.03–1.11, P < 0.01; phosphorylated-tau standardized (z-transformed): OR = 2.98, 95% CI = 1.50–5.93, P < 0.01]. Higher plasma phosphorylated-tau181 levels were associated with increased odds for having a higher Braak stage (OR = 1.06, 95% CI = 1.02–1.09, P < 0.01) and more severe phosphorylated-tau across six cortical and subcortical brain regions (ORs = 1.03–1.06, P < 0.05). The association between plasma phosphorylated-tau181 and Alzheimer’s disease was strongest in those who were demented at time of blood draw (OR = 1.25, 95%CI = 1.02–1.53), but an effect existed among the non-demented (OR = 1.05, 95% CI = 1.01–1.10). There was higher discrimination accuracy for Alzheimer’s disease when blood draw occurred in years closer to death; however, higher plasma phosphorylated-tau181 levels were associated with Alzheimer’s disease even when blood draw occurred >5 years from death. Ante-mortem plasma phosphorylated-tau181 concentrations were associated with Alzheimer’s disease neuropathology and accurately differentiated brain donors with and without autopsy-confirmed Alzheimer’s disease. These findings support plasma phosphorylated-tau181 as a scalable biomarker for the detection of Alzheimer’s disease.

Background and ObjectivesTo evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau181 and p-tau231), and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups.MethodsIndividuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age,APOEε4 carrier status, and cognitive status. Each participant underwent blood and CSF collection, and amyloid PET was performed in 103 participants (68%). Plasma Aβ42/Aβ40 was measured by a high-performance immunoprecipitation–mass spectrometry assay. Plasma p-tau181, p-tau231, and NfL were measured by Simoa immunoassays. CSF Aβ42/Aβ40 and amyloid PET status were used as primary and secondary reference standards of brain amyloidosis, respectively.ResultsThere were 76 matched pairs of AA and NHW participants (n = 152 total). For both AA and NHW groups, the median age was 68.4 years, 42% wereAPOEε4 carriers, and 91% were cognitively normal. AA were less likely than NHW participants to have brain amyloidosis by CSF Aβ42/Aβ40 (22% vs 43% positive;p= 0.003). The receiver operating characteristic area under the curve of CSF Aβ42/Aβ40 status with the plasma biomarkers was as follows: Aβ42/Aβ40, 0.86 (95% CI 0.79–0.92); p-tau181, 0.76 (0.68–0.84); p-tau231, 0.69 (0.60–0.78); and NfL, 0.64 (0.55–0.73). In models predicting CSF Aβ42/Aβ40 status with plasma Aβ42/Aβ40 that included covariates (age, sex,APOEε4 carrier status, race, and cognitive status), race did not affect the probability of CSF Aβ42/Aβ40 positivity. In similar models based on plasma p-tau181, p-tau231, or NfL, AA participants had a lower probability of CSF Aβ42/Aβ40 positivity (odds ratio 0.31 [95% CI 0.13–0.73], 0.30 [0.13–0.71], and 0.27 [0.12–0.64], respectively). Models of amyloid PET status yielded similar findings.DiscussionModels predicting brain amyloidosis using a high-performance plasma Aβ42/Aβ40 assay may provide an accurate and consistent measure of brain amyloidosis across AA and NHW groups, but models based on plasma p-tau181, p-tau231, and NfL may perform inconsistently and could result in disproportionate misdiagnosis of AA individuals.

Hippocampal subfields exhibit differential vulnerabilities to Alzheimer’s disease-associated pathology including abnormal accumulation of amyloid-β deposition and neurofibrillary tangles. These pathological processes extensively impact on the structural and functional interconnectivities of the subfields and may explain the association between hippocampal dysfunction and cognitive deficits. In this study, we investigated the degree of alterations in the microstructure of hippocampal subfields across the clinical continuum of Alzheimer’s disease. We applied a grey matter-specific multi-compartment diffusion model (Cortical-Neurite orientation dispersion and density imaging) to understand the differential effects of Alzheimer’s disease pathology on the hippocampal subfield microstructure. A total of 119 participants were included in this cross-sectional study. Participants were stratified into three categories, cognitively normal (n = 47), mild cognitive impairment (n = 52), and Alzheimer’s disease (n = 19). Diffusion MRI, plasma biomarkers and neuropsychological test scores were used to determine the association between the microstructural integrity and Alzheimer’s disease-associated molecular indicators and cognition. For Alzheimer’s disease-related plasma biomarkers, we studied amyloid-β, total tau and neurofilament light; for Alzheimer’s disease-related neuropsychological tests, we included the Trail Making Test, Rey Auditory Verbal Learning Test, Digit Span and Montreal Cognitive Assessment. Comparisons between cognitively normal subjects and those with mild cognitive impairment showed significant microstructural alterations in the hippocampal cornu ammonis (CA) 4 and dentate gyrus region, whereas CA 1–3 was the most sensitive region for the later stages in the Alzheimer’s disease clinical continuum. Among imaging metrics for microstructures, the volume fraction of isotropic diffusion for interstitial free water demonstrated the largest effect size in between-group comparisons. Regarding the plasma biomarkers, neurofilament light appeared to be the most sensitive biomarker for associations with microstructural imaging findings in CA4-dentate gyrus. CA 1–3 was the subfield which had stronger correlations between cognitive performance and microstructural metrics. Particularly, poor performance on the Rey Auditory Verbal Learning Test and Montreal Cognitive Assessment was associated with decreased intracellular volume fraction. Overall, our findings support the value of tissue-specific microstructural imaging for providing pathologically relevant information manifesting in the plasma biomarkers and neuropsychological outcomes across various stages of Alzheimer’s disease.

Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease.We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer's disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR>0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models.In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=-4·28 × 10-2 [SE 0·013], p=0·0012), but not high cortical uptake in PiB-PET (β=-5·51 × 10-3 [0·011], p=0·63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by Aβ42 in CSF (r=0·56 [0·22], p=0·011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=-0·67 [0·25], p=0·0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0·45 [0·21], p=0·035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between Aβ42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0·46 [0·22]), p=0·040) and diminished cognitive decline (r=0·67 [0·22], p=0·0020).Our findings in autosomal dominant Alzheimer's disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing.German Research Foundation, US National Institutes of Health.

Background and Purpose: Left ventricular (LV) mass index is a marker of subclinical LV remodeling that relates to white matter damage in aging, but molecular pathways underlying this association are unknown. This study assessed if LV mass index related to cerebrospinal fluid (CSF) biomarkers of microglial activation (sTREM2 [soluble triggering receptor expressed on myeloid cells 2]), axonal injury (NFL [neurofilament light]), neurodegeneration (total-tau), and amyloid-β, and whether these biomarkers partially accounted for associations between increased LV mass index and white matter damage. We hypothesized higher LV mass index would relate to greater CSF biomarker levels, and these pathologies would partially mediate associations with cerebral white matter microstructure. Methods: Vanderbilt Memory and Aging Project participants who underwent cardiac magnetic resonance, lumbar puncture, and diffusion tensor imaging (n=142, 72±6 years, 37% mild cognitive impairment [MCI], 32% APOE -ε4 positive, LV mass index 51.4±8.1 g/m 2 , NFL 1070±588 pg/mL) were included. Linear regressions and voxel-wise analyses related LV mass index to each biomarker and diffusion tensor imaging metrics, respectively. Follow-up models assessed interactions with MCI and APOE -ε 4 . In models where LV mass index significantly related to a biomarker and white matter microstructure, we assessed if the biomarker mediated white matter associations. Results: Among all participants, LV mass index was unrelated to CSF biomarkers ( P >0.33). LV mass index interacted with MCI ( P =0.01), such that higher LV mass index related to increased NFL among MCI participants. Associations were also present among APOE -ε4 carriers ( P =0.02). NFL partially mediated up to 13% of the effect of increased LV mass index on white matter damage. Conclusions: Subclinical cardiovascular remodeling, measured as an increase in LV mass index, is associated with neuroaxonal degeneration among individuals with MCI and APOE -ε4. Neuroaxonal degeneration partially reflects associations between higher LV mass index and white matter damage. Findings highlight neuroaxonal degeneration, rather than amyloidosis or microglia, may be more relevant in pathways between structural cardiovascular remodeling and white matter damage.

Background and objectives:Studies associate chronic kidney disease (CKD) with neurodegeneration. This study investigated the relation between kidney function, blood, cerebrospinal fluid (CSF), and structural brain MRI markers of neurodegeneration, in a sample including individuals with and without CKD.Methods:Participants from the Gothenburg H70 Birth Cohort Study, with data on plasma-neurofilament light (P-NfL), estimated glomerular filtration rate (eGFR) and structural brain MRI were included. Participants were invited to also have CSF collected. The primary endpoint of the present study was to determine any association between CKD and P-NfL. Secondary endpoints included cross-sectional associations between CKD, eGFR and cerebrospinal fluid (CSF)- and MRI-derived markers of neurodegeneration and Alzheimer’s disease (AD) pathology (MRI: cortical thickness, hippocampal volume, lateral ventricle volume, white matter lesion volume; CSF: β-amyloid (Aβ) 42, Aβ42/40, Aβ42/p-tau, t-tau, p-tau, NfL). Participants with P-NfL and eGFR at baseline were re-examined on eGFR, 5.5 (5.3; 6.1) years (median; IQR) after the first visit, and the predictive value of P-NfL levels on incident CKD was estimated longitudinally, using a Cox proportional hazards model.Results:We included 744 participants, 668 without CKD (Age 71 (70; 71) years, 50% males) and 76 with CKD (age 71 (70;71) years, 39% males). Biomarkers from cerebrospinal fluid (CSF) were analysed in 313 participants. 558 individuals returned for a re-examination of eGFR (75% response rate, age 76 (76; 77), 48% males, 76 new cases of CKD). Participants with CKD had higher P-NfL levels than those with normal kidney function (median; 18.8 versus 14.0 pg/mL, pDiscussion:In a community-based cohort of 70-year olds, P-NfL was associated with both prevalent and incident CKD, while CSF and/or imaging measures did not differ by CKD status. Participants with CKD and dementia presented similar levels of P-NfL.

Background Plasma neurofilament light (NfL) is an indicator of neurodegeneration and/or neuroaxonal injury in persons with Alzheimer’s disease (AD) and a wide range of other neurological disorders. Here, we characterized and compared plasma NfL concentrations in cognitively unimpaired (CU) late-middle-aged and older adults with two, one, or no copies of the APOE ε4 allele, the major genetic risk factor for AD. We then assessed plasma NfL associations with brain imaging measurements of AD-related neurodegeneration (hippocampal atrophy and a hypometabolic convergence index [HCI]), brain imaging measurements of amyloid-β plaque burden, tau tangle burden and white matter hyperintensity volume (WMHV), and delayed and total recall memory scores. Methods Plasma NfL concentrations were measured in 543 CU 69 ± 9 year-old participants in the Arizona APOE Cohort Study, including 66 APOE ε4 homozygotes (HM), 165 heterozygotes (HT), and 312 non-carriers (NC). Robust regression models were used to characterize plasma NfL associations with APOE ε4 allelic dose before and after adjustment for age, sex, and education. They were also used to characterize plasma NfL associations with MRI-based hippocampal volume and WMHV measurements, an FDG PET-based HCI, mean cortical PiB PET measurements of amyloid-β plaque burden and meta-region-of-interest (meta-ROI) flortaucipir PET measurements of tau tangle burden, and Auditory Verbal Learning Test (AVLT) Delayed and Total Recall Memory scores. Results After the adjustments noted above, plasma NfL levels were significantly greater in APOE ε4 homozygotes and heterozygotes than non-carriers and significantly associated with smaller hippocampal volumes (r = − 0.43), greater tangle burden in the entorhinal cortex and inferior temporal lobes (r = 0.49, r = 0.52, respectively), and lower delayed (r = − 0.27), and total (r = − 0.27) recall memory scores (p Conclusions Plasma NfL concentrations are associated with the APOE ε4 allele, brain imaging biomarkers of neurodegeneration, and less good recall memory in CU late-middle-aged and older adults, supporting its value as an indicator of neurodegeneration in the preclinical study of AD.

Background Neuroinflammation, characterized by increased reactivity of microglia and astrocytes in the brain, is known to be present at various stages of the Alzheimer’s disease (AD) continuum. However, its presence and relationship with amyloid pathology in cognitively normal at-risk individuals is less clear. Here, we used positron emission tomography (PET) and blood biomarker measurements to examine differences in neuroinflammation and beta-amyloid (Aβ) and their association in cognitively unimpaired homozygotes, heterozygotes, or non-carriers of the APOE ε4 allele, the strongest genetic risk for sporadic AD. Methods Sixty 60–75-year-old APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) were recruited in collaboration with the local Auria biobank. The participants underwent 11C-PK11195 PET (targeting 18-kDa translocator protein, TSPO), 11C-PiB PET (targeting Aβ), brain MRI, and neuropsychological testing including a preclinical cognitive composite (APCC). 11C-PK11195 distribution volume ratios and 11C-PiB standardized uptake value ratios (SUVRs) were calculated for regions typical for early Aβ accumulation in AD. Blood samples were drawn for measuring plasma glial fibrillary acidic protein (GFAP) and plasma Aβ1-42/1.40. Results In our cognitively unimpaired sample, cortical 11C-PiB-binding increased according to APOE ε4 gene dose (median composite SUVR 1.47 (range 1.38–1.66) in non-carriers, 1.55 (1.43–2.02) in heterozygotes, and 2.13 (1.61–2.83) in homozygotes, P = 0.002). In contrast, cortical composite 11C-PK11195-binding did not differ between the APOE ε4 gene doses (P = 0.27) or between Aβ-positive and Aβ-negative individuals (P = 0.81) and associated with higher Aβ burden only in APOE ε4 homozygotes (Rho = 0.47, P = 0.043). Plasma GFAP concentration correlated with cortical 11C-PiB (Rho = 0.35, P = 0.040), but not 11C-PK11195-binding (Rho = 0.13, P = 0.47) in Aβ-positive individuals. In the total cognitively unimpaired population, both higher composite 11C-PK11195-binding and plasma GFAP were associated with lower hippocampal volume, whereas elevated 11C-PiB-binding was associated with lower APCC scores. Conclusions Only Aβ burden measured by PET, but not markers of neuroinflammation, differed among cognitively unimpaired elderly with different APOE ε4 gene dose. However, APOE ε4 gene dose seemed to modulate the association between neuroinflammation and Aβ.

What is this summary about? This plain language summary of an article published in Molecular Psychiatry, reviews the evidence supporting the role of the amyloid-β (Aβ) pathway and its dysregulation in Alzheimer's disease (AD), and highlights the rationale for drugs targeting the Aβ pathway in the early stages of the disease. Why is this important? Aβ is a protein fragment (or peptide) that exists in several forms distinguished by their size, shape/structure, degree of solubility and disease relevance. The accumulation of Aβ plaques is a hallmark of AD. However, smaller, soluble aggregates of Aβ – including Aβ protofibrils – also play a role in the disease. Because Aβ-related disease mechanisms are complex, the diagnosis, treatment and management of AD should be reflective of and guided by up-to-date scientific knowledge and research findings in this area. This article describes the Aβ protein and its role in AD, summarizing the evidence showing that altered Aβ clearance from the brain may lead to the imbalance, toxic buildup and misfolding of the protein – triggering a cascade of cellular, molecular and systematic events that ultimately lead to AD. What are the key takeaways? The physiological balance of brain Aβ levels in the context of AD is complex. Despite many unanswered questions, mounting evidence indicates that Aβ has a central role in driving AD progression. A better understanding of the Aβ pathway biology will help identify the best therapeutic targets for AD and inform treatment approaches.

Background Aβ42/Aβ40 ratios in cerebrospinal fluid (CSF) and blood are reduced in preclinical Alzheimer’s disease (AD), but their temporal and correlative relationship with cerebral Aβ pathology at this early disease stage is not well understood. In the present study, we aim to investigate such relationships using App knock-in mouse models of preclinical AD. Methods CSF, serum, and brain tissue were collected from 3- to 18-month-old AppNL−F/NL−F knock-in mice (n = 48) and 2–18-month-old AppNL/NL knock-in mice (n = 35). The concentrations of Aβ42 and Aβ40 in CSF and serum were measured using Single molecule array (Simoa) immunoassays. Cerebral Aβ plaque burden was assessed in brain tissue sections by immunohistochemistry and thioflavin S staining. Furthermore, the concentrations of Aβ42 in soluble and insoluble fractions prepared from cortical tissue homogenates were measured using an electrochemiluminescence immunoassay. Results In AppNL−F/NL−F knock-in mice, Aβ42/Aβ40 ratios in CSF and serum were significantly reduced from 12 and 16 months of age, respectively. The initial reduction of these biomarkers coincided with cerebral Aβ pathology, in which a more widespread Aβ plaque burden and increased levels of Aβ42 in the brain were observed from approximately 12 months of age. Accordingly, in the whole study population, Aβ42/Aβ40 ratios in CSF and serum showed a negative hyperbolic association with cerebral Aβ plaque burden as well as the levels of both soluble and insoluble Aβ42 in the brain. These associations tended to be stronger for the measures in CSF compared with serum. In contrast, no alterations in the investigated fluid biomarkers or apparent cerebral Aβ plaque pathology were found in AppNL/NL knock-in mice during the observation time. Conclusions Our findings suggest a temporal sequence of events in AppNL−F/NL−F knock-in mice, in which initial deposition of Aβ aggregates in the brain is followed by a decline of the Aβ42/Aβ40 ratio in CSF and serum once the cerebral Aβ pathology becomes significant. Our results also indicate that the investigated biomarkers were somewhat more strongly associated with measures of cerebral Aβ pathology when assessed in CSF compared with serum.

As the leading cause of dementia, Alzheimer's disease (AD) is a major burden on affected individuals, their families and caregivers, and healthcare systems. Although AD can be identified and diagnosed by cerebrospinal fluid or neuroimaging biomarkers that concord with neuropathological evidence and clinical symptoms, challenges regarding practicality and accessibility hinder their widespread availability and implementation. Consequently, many people with suspected cognitive impairment due to AD do not receive a biomarker-supported diagnosis. Blood biomarkers have the capacity to help expand access to AD diagnostics worldwide. One such promising biomarker is plasma phosphorylated tau (p-tau), which has demonstrated specificity to AD versus non-AD neurodegenerative diseases, and will be extremely important to inform on clinical diagnosis and eligibility for therapies that have recently been approved. This review provides an update on the diagnostic and prognostic performances of plasma p-tau181, p-tau217 and p-tau231, and their associations with in vivo and autopsy-verified diagnosis and pathological hallmarks. Additionally, we discuss potential applications and unanswered questions of plasma p-tau for therapeutic trials, given their recent addition to the biomarker toolbox for participant screening, recruitment and during-trial monitoring. Outstanding questions include assay standardization, threshold generation and biomarker verification in diverse cohorts reflective of the wider community attending memory clinics and included in clinical trials.

Background Cerebrospinal fluid (CSF) p-tau235 is a novel biomarker highly specific of Alzheimer’s disease (AD). However, CSF p-tau235 has only been studied in well-characterized research cohorts, which do not fully reflect the patient landscape found in clinical settings. Therefore, in this multicentre study, we investigated the performance of CSF p-tau235 to detect symptomatic AD in clinical settings and compared it with CSF p-tau181, p-tau217 and p-tau231. Methods CSF p-tau235 was measured using an in-house single molecule array (Simoa) assay in two independent memory clinic cohorts: Paris cohort (Lariboisière Fernand-Widal University Hospital Paris, France; n=212) and BIODEGMAR cohort (Hospital del Mar, Barcelona, Spain; n=175). Patients were classified by the syndromic diagnosis (cognitively unimpaired [CU], mild cognitive impairment [MCI] or dementia) and their biological diagnosis (amyloid-beta [Aβ]+ or Aβ $$-$$ - ). Both cohorts included detailed cognitive assessments and CSF biomarker measurements (clinically validated core AD biomarkers [Lumipulse CSF Aβ1–42/40 ratio, p-tau181 and t-tau] and in-house developed Simoa CSF p-tau181, p-tau217 and p-tau231). Results High CSF p-tau235 levels were strongly associated with CSF amyloidosis regardless of the clinical diagnosis, being significantly increased in MCI Aβ+ and dementia Aβ+ when compared with all other Aβ− groups (Paris cohort: P ˂0.0001 for all; BIODEGMAR cohort: P ˂0.05 for all). CSF p-tau235 was pronouncedly increased in the A+T+ profile group compared with A−T− and A+T− groups (P ˂0.0001 for all). Moreover, CSF p-tau235 demonstrated high diagnostic accuracies identifying CSF amyloidosis in symptomatic cases (AUCs=0.86 to 0.96) and discriminating AT groups (AUCs=0.79 to 0.98). Overall, CSF p-tau235 showed similar performances to CSF p-tau181 and CSF p-tau231 when discriminating CSF amyloidosis in various scenarios, but lower than CSF p-tau217. Finally, CSF p-tau235 associated with global cognition and memory domain in both cohorts. Conclusions CSF p-tau235 was increased with the presence of CSF amyloidosis in two independent memory clinic cohorts. CSF p-tau235 accurately identified AD in both MCI and dementia patients. Overall, the diagnostic performance of CSF p-tau235 was comparable to that of other CSF p-tau measurements, indicating its suitability to support a biomarker-based AD diagnosis in clinical settings.

Background Neurofilament light (NfL) and neurogranin (Ng) are promising candidate AD biomarkers, reflecting axonal and synaptic damage, respectively. Since there is a need to understand the synaptic and axonal damage in preclinical Alzheimer’s disease (AD), we aimed to determine the cerebrospinal fluid (CSF) levels of NfL and Ng in cognitively unimpaired elderly from the Gothenburg H70 Birth Cohort Studies classified according to the amyloid/tau/neurodegeneration (A/T/N) system. Methods The sample consisted of 258 cognitively unimpaired older adults (age 70, 129 women and 129 men) from the Gothenburg Birth Cohort Studies. We compared CSF NfL and Ng concentrations in A/T/N groups using Student’s T-test and ANCOVA. Results CSF NfL concentration was higher in the A−T−N+ group (p=0.001) and the A−T+N+ group (p=0.006) compared with A−T−N−. CSF Ng concentration was higher in the A−T−N+, A−T+N+, A+T−N+, and A+T+N+ groups (pp Conclusions CSF NfL and Ng concentrations are increased in cognitively normal older adults with biomarker evidence of tau pathology and neurodegeneration.

19 Pág. Centro de Investigación en Sanidad Animal (CISA), Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune cell surface receptor that regulates microglial function and is involved in the pathophysiology of several neurodegenerative diseases. Its soluble form (sTREM2) results from shedding of the TREM2 ectodomain. The role of TREM2 in prion diseases, a group of rapidly progressive dementias remains to be elucidated. In the present study, we analysed the expression of TREM2 and its main sheddase ADAM10 in the brain of sporadic Creutzfeldt-Jakob disease (sCJD) patients and evaluated the role of CSF and plasma sTREM2 as a potential diagnostic marker of prion disease. Our data indicate that, compared to controls, TREM2 is increased in sCJD patient brains at the mRNA and protein levels in a regional and subtype dependent fashion, and expressed in a subpopulation of microglia. In contrast, ADAM10 is increased at the protein, but not the mRNA level, with a restricted neuronal expression. Elevated CSF sTREM2 is found in sCJD, genetic CJD with mutations E200K and V210I in the prion protein gene (PRNP), and iatrogenic CJD, as compared to healthy controls (HC) (AUC = 0.78-0.90) and neurological controls (AUC = 0.73-0.85), while CSF sTREM2 is unchanged in fatal familial insomnia. sTREM2 in the CSF of cases with Alzheimer's disease, and multiple sclerosis was not significantly altered in our series. CSF sTREM2 concentrations in sCJD are PRNP codon 129 and subtype-related, correlate with CSF 14-3-3 positivity, total-tau and YKL-40, and increase with disease progression. In plasma, sTREM2 is increased in sCJD compared with HC (AUC = 0.80), displaying positive correlations with plasma total-tau, neurofilament light, and YKL-40. We conclude that comparative study of TREM2 in brain and biological fluids of prion diseases reveals TREM2 to be altered in human prion diseases with a potential value in target engagement, patient stratification, and disease monitoring., We thank the HUB-ICO-IDIBELL-Biobank and the CERCA Programme of the Generalitat de Catalunya for institutional support. This study was funded by the Instituto Carlos III (Grants Number CP16/00041 and PI19/00144) to FL. This project was also funded by la Fundació La Marató de TV3 (Grants No. 201821-30, 201821-31and 201821-32 to FL, JCE and EV, respectively) and by the Fondo Europeo de Desarrollo Regional (FEDER) through the Interreg V-A España-Francia-Andorra (POCTEFA 2014–2020) programme (at 65%) to IF. AVP is supported by the Beatriu de Pinós programme (2018-BP-00129) from the Ministry of Business and nowledge of the Government of Catalonia, and cofunded by the EU Horizon 2020 programme under an MSCA grant agreement (801370). 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 the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017-00915), the Swedish State Support for Clinical Research (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and the European Union Joint Programme for Neurodegenerative Disorders (JPND2019-466-236). AL is supported by the Ministero della Salute, Italy, for the national surveillance of Creutzfeldt-Jakob disease. This research was also supported in part by the Alberta Synergies in Alzheimer’s and Related Disorders (SynAD) programme which is funded by the Alzheimer Society of Alberta and Northwest Territories through their Hope for Tomorrow programme and the University Hospital Foundation. SynAD operates in partnership with the Neuroscience and Mental Health Institute at the University of Alberta. JADR was supported by grants from the Spanish Ministry of Science, Innovation and Universities (MICINN/FEDER) (RTI2018-099773-B-I00), the CERCA Programme, and by the Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generalitat de Catalunya (SGR2017-648) and CIBERNED (CMED2018-2)