Publications by authors named "Kaj Blennow"

1,316 Publications

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Cerebrospinal fluid markers for synaptic function and Alzheimer type changes in late life depression.

Sci Rep 2021 Oct 13;11(1):20375. Epub 2021 Oct 13.

Department of Neurology, Akershus University Hospital, Lørenskog, Norway.

To explore markers for synaptic function and Alzheimer disease (AD) pathology in late life depression (LLD), predementia AD and normal controls (NC). A cross-sectional study to compare cerebrospinal fluid (CSF) levels of neurogranin (Ng), Beta-site amyloid-precursor-protein cleaving enzyme1 (BACE1), Ng/BACE1 ratio and Amyloid-β 42/40 ratio, phosphorylated-tau and total-tau in LLD with (LLD AD) or without (LLD NoAD) AD pathology, predementia AD and normal controls (NC). We included 145 participants (NC = 41; predementia AD = 66 and LLD = 38). LLD comprised LLD AD (n = 16), LLD NoAD (n = 19), LLD with non-AD typical changes (n = 3, excluded). LLD AD (p < 0.05) and predementia AD (p < 0.0001) showed significantly higher Ng than NC. BACE1 and Ng/BACE1 ratio were altered similarly. Compared to LLD NoAD, LLD AD showed significantly higher Ng (p < 0.001), BACE1 (p < 0.05) and Ng/BACE1 ratio (p < 0.01). All groups had significantly lower Aβ 42/40 ratio than NC (predementia AD and LLD AD, p < 0.0001; LLD NoAD, p < 0.05). Both LLD groups performed similarly on tests of memory and executive function, but significantly poorer than NC. Synaptic function in LLD depended on AD pathology. LLD showed an association to Amyloid dysmetabolism. The LLD groups performed poorer cognitively than NC. LLD AD may be conceptualized as "predementia AD with depression".
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http://dx.doi.org/10.1038/s41598-021-99794-9DOI Listing
October 2021

Modifiable risk factors for dementia and dementia risk profiling. A user manual for Brain Health Services-part 2 of 6.

Alzheimers Res Ther 2021 Oct 11;13(1):169. Epub 2021 Oct 11.

College of Medicine and Health, University of Exeter, Exeter, UK.

We envisage the development of new Brain Health Services to achieve primary and secondary dementia prevention. These services will complement existing memory clinics by targeting cognitively unimpaired individuals, where the focus is on risk profiling and personalized risk reduction interventions rather than diagnosing and treating late-stage disease. In this article, we review key potentially modifiable risk factors and genetic risk factors and discuss assessment of risk factors as well as additional fluid and imaging biomarkers that may enhance risk profiling. We then outline multidomain measures and risk profiling and provide practical guidelines for Brain Health Services, with consideration of outstanding uncertainties and challenges. Users of Brain Health Services should undergo risk profiling tailored to their age, level of risk, and availability of local resources. Initial risk assessment should incorporate a multidomain risk profiling measure. For users aged 39-64, we recommend the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) Dementia Risk Score, whereas for users aged 65 and older, we recommend the Brief Dementia Screening Indicator (BDSI) and the Australian National University Alzheimer's Disease Risk Index (ANU-ADRI). The initial assessment should also include potentially modifiable risk factors including sociodemographic, lifestyle, and health factors. If resources allow, apolipoprotein E ɛ4 status testing and structural magnetic resonance imaging should be conducted. If this initial assessment indicates a low dementia risk, then low intensity interventions can be implemented. If the user has a high dementia risk, additional investigations should be considered if local resources allow. Common variant polygenic risk of late-onset AD can be tested in middle-aged or older adults. Rare variants should only be investigated in users with a family history of early-onset dementia in a first degree relative. Advanced imaging with 18-fluorodeoxyglucose positron emission tomography (FDG-PET) or amyloid PET may be informative in high risk users to clarify the nature and burden of their underlying pathologies. Cerebrospinal fluid biomarkers are not recommended for this setting, and blood-based biomarkers need further validation before clinical use. As new technologies become available, advances in artificial intelligence are likely to improve our ability to combine diverse data to further enhance risk profiling. Ultimately, Brain Health Services have the potential to reduce the future burden of dementia through risk profiling, risk communication, personalized risk reduction, and cognitive enhancement interventions.
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http://dx.doi.org/10.1186/s13195-021-00895-4DOI Listing
October 2021

Changes in Blood Biomarkers of Brain Injury and Degeneration Following Long-Duration Spaceflight.

JAMA Neurol 2021 Oct 11. Epub 2021 Oct 11.

Department of Anesthesiology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

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http://dx.doi.org/10.1001/jamaneurol.2021.3589DOI Listing
October 2021

Interactions between dietary patterns and genetic factors in relation to incident dementia among 70-year-olds.

Eur J Nutr 2021 Oct 10. Epub 2021 Oct 10.

Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Wallinsgatan 6, 431 41, Mölndal, Sweden.

Purpose: To investigate potential interactions between dietary patterns and genetic factors modulating risk for Alzheimer's disease (AD) in relation to incident dementia.

Methods: Data were derived from the population-based Gothenburg H70 Birth Cohort Studies in Sweden, including 602 dementia-free 70-year-olds (examined 1992-93, or 2000-02; 64% women) followed for incident dementia until 2016. Two factors from a reduced rank regression analysis were translated into dietary patterns, one healthy (e.g., vegetables, fruit, and fish) and one western (e.g., red meat, refined cereals, and full-fat dairy products). Genetic risk was determined by APOE ε4 status and non-APOE AD-polygenic risk scores (AD-PRSs). Gene-diet interactions in relation to incident dementia were analysed with Cox regression models. The interaction p value threshold was < 0.1.

Results: There were interactions between the dietary patterns and APOE ε4 status in relation to incident dementia (interaction p value threshold of < 0.1), while no evidence of interactions were found between the dietary patterns and the AD-PRSs. Those with higher adherence to a healthy dietary pattern had a reduced risk of dementia among ε4 non-carriers (HR: 0.77; 95% CI: 0.61; 0.98), but not among ε4 carriers (HR: 0.86; CI: 0.63; 1.18). Those with a higher adherence to the western dietary pattern had an increased risk of dementia among ε4 carriers (HR: 1.37; 95% CI: 1.05; 1.78), while no association was observed among ε4 non-carriers (HR: 0.99; CI: 0.81; 1.21).

Conclusions: The results of this study suggest that there is an interplay between dietary patterns and APOE ε4 status in relation to incident dementia.
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http://dx.doi.org/10.1007/s00394-021-02688-9DOI Listing
October 2021

Apolipoprotein B is a novel marker for early tau pathology in Alzheimer's disease.

Alzheimers Dement 2021 Sep 29. Epub 2021 Sep 29.

Douglas Mental Health University Institute, Montréal, Québec, Canada.

Introduction: We examine the role of brain apolipoprotein B (apoB) as a putative marker of early tau pathology and cognitive decline.

Methods: Cerebrospinal fluid (CSF) samples from cognitively normal and Alzheimer's disease (AD) participants were collected to measure protein levels of apoB and AD biomarkers amyloid beta (Aβ), t-tau and p-tau, as well as synaptic markers GAP43, SYNAPTOTAGMIN-1, synaptosome associated protein 25 (SNAP-25), and NEUROGRANIN. CSF apoB levels were contrasted with positron emission tomography (PET) scan measures of Aβ (18F-NAV4694) and Tau (flortaucipir) along with cognitive assessment alterations over 6 to 8 years.

Results: CSF apoB levels were elevated in AD participants and correlated with t-tau, p-tau, and the four synaptic markers in pre-symptomatic individuals. In the latter, CSF apoB levels correlated with PET flortaucipir-binding in entorhinal, parahippocampal, and fusiform regions. Baseline CSF apoB levels were associated with longitudinal visuospatial cognitive decline.

Discussion: CSF apoB markedly associates with early tau dysregulation in asymptomatic subjects and identifies at-risk individuals predisposed to develop visuospatial cognitive decline over time.
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http://dx.doi.org/10.1002/alz.12442DOI Listing
September 2021

Neurotoxicity with high dose disulfiram and vorinostat used for HIV latency reversal.

AIDS 2021 Sep 29. Epub 2021 Sep 29.

Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia University of California San Francisco, San Francisco, California, United States The Westmead Institute for Medical Research, University of Sydney, Westmead, Australia Johns Hopkins University, Baltimore, Maryland, United States Department of Pharmacy, Radboud University Medical Center, the Netherlands Department of Infectious Disease & Vaccine Research, Merck & Co., Inc., Kenilworth, NJ, USA Department of Infectious Diseases at Institute of Biomedicine, University of Gothenburg, Sweden Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mo[Combining Diaeresis]lndal, Sweden Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK UK Dementia Research Institute at UCL, London, UK Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity Region Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Diseases, Gothenburg, Sweden.

Objective: To examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is safe and can enhance HIV latency reversal.

Design: Vorinostat and disulfiram, can increase HIV transcription in people with HIV (PWH) on antiretroviral therapy (ART). Together these agents may lead to significant HIV latency reversal.

Methods: Virologically suppressed PWH on ART received disulfiram 2000 mg daily for 28 days and vorinostat 400 mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline using a single copy assay. Assessments included cell-associated (CA) unspliced (US) RNA as a marker of latency reversal, HIV DNA in CD4+ T-cells, plasma HIV RNA and plasma concentrations of ART, vorinostat and disulfiram.

Results: The first two participants (P1 and P2) experienced grade 3 neurotoxicity leading to trial suspension. After 24 days, P1 presented with confusion, lethargy, and ataxia having stopped disulfiram and ART. Symptoms resolved by day 29. After 11 days, P2 presented with paranoia, emotional lability, lethargy, ataxia and study drugs were ceased. Symptoms resolved by day 23. CA-US RNA increased by 1.4- and 1.3-fold for P1 and P2 respectively. Plasma HIV RNA was detectable from day 8-37 (peak 81 copies/mL) for P2 but was not increased in P1 Antiretroviral levels were therapeutic and neuronal injury markers were elevated in P1.

Conclusions: The combination of prolonged high dose disulfiram and vorinostat was not safe in PWH on ART and should not be pursued despite evidence of latency reversal.
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http://dx.doi.org/10.1097/QAD.0000000000003091DOI Listing
September 2021

Association of deranged cerebrovascular reactivity with brain injury following cardiac arrest: a post-hoc analysis of the COMACARE trial.

Crit Care 2021 Sep 28;25(1):350. Epub 2021 Sep 28.

Department of Emergency Care and Services, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Background: Impaired cerebrovascular reactivity (CVR) is one feature of post cardiac arrest encephalopathy. We studied the incidence and features of CVR by near infrared spectroscopy (NIRS) and associations with outcome and biomarkers of brain injury.

Methods: A post-hoc analysis of 120 comatose OHCA patients continuously monitored with NIRS and randomised to low- or high-normal oxygen, carbon dioxide and mean arterial blood pressure (MAP) targets for 48 h. The tissue oximetry index (TO) generated by the moving correlation coefficient between cerebral tissue oxygenation measured by NIRS and MAP was used as a dynamic index of CVR with TO > 0 indicating impaired reactivity and TO > 0.3 used to delineate the lower and upper MAP bounds for disrupted CVR. TO was analysed in the 0-12, 12-24, 24-48 h time-periods and integrated over 0-48 h. The primary outcome was the association between TO and six-month functional outcome dichotomised by the cerebral performance category (CPC1-2 good vs. 3-5 poor). Secondary outcomes included associations with MAP bounds for CVR and biomarkers of brain injury.

Results: In 108 patients with sufficient data to calculate TO, 76 patients (70%) had impaired CVR and among these, chronic hypertension was more common (58% vs. 31%, p = 0.002). Integrated TO for 0-48 h was higher in patients with poor outcome than in patients with good outcome (0.89 95% CI [- 1.17 to 2.94] vs. - 2.71 95% CI [- 4.16 to - 1.26], p = 0.05). Patients with poor outcomes had a decreased upper MAP bound of CVR over time (p = 0.001), including the high-normal oxygen (p = 0.002), carbon dioxide (p = 0.012) and MAP (p = 0.001) groups. The MAP range of maintained CVR was narrower in all time intervals and intervention groups (p < 0.05). NfL concentrations were higher in patients with impaired CVR compared to those with intact CVR (43 IQR [15-650] vs 20 IQR [13-199] pg/ml, p = 0.042).

Conclusion: Impaired CVR over 48 h was more common in patients with chronic hypertension and associated with poor outcome. Decreased upper MAP bound and a narrower MAP range for maintained CVR were associated with poor outcome and more severe brain injury assessed with NfL. Trial registration ClinicalTrials.gov, NCT02698917 .
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http://dx.doi.org/10.1186/s13054-021-03764-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477475PMC
September 2021

Enhancing the Sensitivity of Memory Tests: Reference Data for the Free and Cued Selective Reminding Test and the Logical Memory Task from Cognitively Healthy Subjects with Normal Alzheimer's Disease Cerebrospinal Fluid Biomarker Levels.

J Alzheimers Dis 2021 Sep 18. Epub 2021 Sep 18.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Background: Cognitive performance of a given individual should be interpreted in the context of reference standards obtained in cognitively healthy populations. Recent evidence has shown that removing asymptomatic individuals with biomarker evidence of Alzheimer's disease (AD) pathology from normative samples increases the sensitivity of norms to detect memory impairments. These kind of norms may be useful for defining subtle cognitive decline, the transitional cognitive decline between normal cognition and mild cognitive impairment.

Objective: The present study aims to provide norms for the Free and Cued Selective Reminding Test (FCSRT) and the Logical Memory subtest of the Wechsler Memory Scale-IV in a sample of individuals aged 50-70 years with normal levels of amyloid (A) and tau (T) cerebrospinal fluid (CSF) biomarkers.

Methods: The sample was composed of 248 individuals from the ALFA+ study with negative amyloid-β and tau CSF biomarker levels. Regression-based norms were developed, including adjustments for age, education, and sex when applicable.

Results: We found that education was associated with the performance in all the variables of both tests while age had a marginal effect only in the delayed free recall of the FCSRT. Sex was also related to the performance in the FCSRT, with women outperforming men. Equations to calculate z-scores and normative percentile tables were created. As compared with previously published norms the reference data presented were more sensitive but less specific, as expected.

Conclusion: The use of the norms provided in this work, in combination with the already published conventional norms, may contribute to detecting subtle memory impairment.
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http://dx.doi.org/10.3233/JAD-210640DOI Listing
September 2021

The circadian rest-activity pattern predicts cognitive decline among mild-moderate Alzheimer's disease patients.

Alzheimers Res Ther 2021 09 25;13(1):161. Epub 2021 Sep 25.

Unitat Trastorns Cognitius, Clinical Neuroscience Research, Hospital Universitari Santa Maria, IRBLleida, Lleida, Spain.

Background: Alterations in circadian rhythms are present in the presymptomatic stage of Alzheimer's disease (AD), possibly contributing to its pathogenesis. However, it is unknown whether such alterations are associated with worse outcomes once individuals are diagnosed with symptomatic disease. We aimed to evaluate the association between the circadian rest-activity pattern and AD-related features in patients with mild-moderate AD.

Methods: We assessed the circadian rest-activity pattern of consecutive patients with mild-moderate AD through actigraphy for 14 days. Cerebrospinal fluid was obtained to determine the levels of important pathological markers including amyloid-beta protein (Aβ42), phosphorylated tau (P-tau), total tau (T-tau), and neurofilament light (NF-L). Neuropsychological evaluation was conducted at the beginning of the study and after 12 months of follow-up. Linear regression models were performed considering the global population and Aβ42+ patients only.

Results: The cohort included 100 patients with mild-moderate AD. The median age [p;p] was 76.0 [73.0;80.0] years and 63.0% were female. Older age (effect size [SE] of 0.324 [0.096]; p = 0.001) and male sex (0.780 [0.193]; p = 0.001) were associated with increased fragmentation and decreased synchronization of the rhythm, respectively. After adjusting for age, sex, and season of the year, increased levels of T-tau (effect size [95% CI] of 0.343 [0.139 to 0.547]; p = 0.001) and NF-L (0.444 [0.212 to 0.676]; p = 0.001) were associated with a higher amplitude of the rest-activity rhythm. Increased fragmentation of the rhythm at baseline was associated with greater cognitive decline after one year of follow-up independent of age, sex, T-tau/Aβ42 ratio, educational level, and season of the year (- 0.715 [- 1.272 to - 0.157]; p = 0.013). Similar findings were obtained considering only the Aβ42+ patients.

Conclusions: Our results suggest a potential role of the circadian rest-activity pattern in predicting the cognitive decline of patients with mild-moderate AD. Further studies are warranted to confirm these findings and to elucidate whether there is causality among the observed associations.
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http://dx.doi.org/10.1186/s13195-021-00903-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466995PMC
September 2021

Sulfatide in health and disease. The evaluation of sulfatide in cerebrospinal fluid as a possible biomarker for neurodegeneration.

Mol Cell Neurosci 2021 Oct 23;116:103670. Epub 2021 Sep 23.

Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Sulfatide (3-O-sulfogalactosylceramide, SM4) is a glycosphingolipid, highly multifunctional and particularly enriched in the myelin sheath of neurons. The role of sulfatide has been implicated in various biological fields such as the nervous system, immune system, host-pathogen recognition and infection, beta cell function and haemostasis/thrombosis. Thus, alterations in sulfatide metabolism and production are associated with several human diseases such as neurological and immunological disorders and cancers. The unique lipid-rich composition of myelin reflects the importance of lipids in this specific membrane structure. Sulfatide has been shown to be involved in the regulation of oligodendrocyte differentiation and in the maintenance of the myelin sheath by influencing membrane dynamics involving sorting and lateral assembly of myelin proteins as well as ion channels. Sulfatide is furthermore essential for proper formation of the axo-glial junctions at the paranode together with axonal glycosphingolipids. Alterations in sulfatide metabolism are suggested to contribute to myelin deterioration as well as synaptic dysfunction, neurological decline and inflammation observed in different conditions associated with myelin pathology (mouse models and human disorders). Body fluid biomarkers are of importance for clinical diagnostics as well as for patient stratification in clinical trials and treatment monitoring. Cerebrospinal fluid (CSF) is commonly used as an indirect measure of brain metabolism and analysis of CSF sulfatide might provide information regarding whether the lipid disruption observed in neurodegenerative disorders is reflected in this body fluid. In this review, we evaluate the diagnostic utility of CSF sulfatide as a biomarker for neurodegenerative disorders associated with dysmyelination/demyelination by summarising the current literature on this topic. We can conclude that neither CSF sulfatide levels nor individual sulfatide species consistently reflect the lipid disruption observed in many of the demyelinating disorders. One exception is the lysosomal storage disorder metachromatic leukodystrophy, possibly due to the genetically determined accumulation of non-metabolised sulfatide. We also discuss possible explanations as to why myelin pathology in brain tissue is poorly reflected by the CSF sulfatide concentration. The previous suggestion that CSF sulfatide is a marker of myelin damage has thereby been challenged by more recent studies using more sophisticated laboratory techniques for sulfatide analysis as well as improved sample selection criteria due to increased knowledge on disease pathology.
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http://dx.doi.org/10.1016/j.mcn.2021.103670DOI Listing
October 2021

CSF Synaptic Biomarkers in the Preclinical Stage of Alzheimer Disease and Their Association With MRI and PET: A Cross-sectional Study.

Neurology 2021 Sep 23. Epub 2021 Sep 23.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Objective: To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer's and associated with Alzheimer's disease (AD) risk factors, primary pathology, and neurodegeneration markers.

Methods: Cross-sectional study in the ALFA+ cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and GAP-43 were measured using immunoassays and SNAP-25 and synaptotagmin-1 using immunoprecipitation mass spectrometry. AD CSF biomarkers Aβ42/40, p-tau and t-tau, and the neurodegeneration biomarker NfL were also measured. Participants underwent structural MRI, and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers.

Results: All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values) and, importantly, the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism, but lower cortical thickness in AD-related brain regions.

Conclusion: CSF synaptic biomarkers increase in early preclinical stages of the Alzheimer's even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, ε4 and markers of neurodegeneration.
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http://dx.doi.org/10.1212/WNL.0000000000012853DOI Listing
September 2021

Head-to-Head Comparison of 8 Plasma Amyloid-β 42/40 Assays in Alzheimer Disease.

JAMA Neurol 2021 Sep 20. Epub 2021 Sep 20.

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.

Importance: Blood-based tests for brain amyloid-β (Aβ) pathology are needed for widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening and monitoring of treatment responses in clinical trials.

Objective: To compare the performance of plasma Aβ42/40 measured using 8 different Aβ assays when detecting abnormal brain Aβ status in patients with early AD.

Design, Setting, And Participants: This study included 182 cognitively unimpaired participants and 104 patients with mild cognitive impairment from the BioFINDER cohort who were enrolled at 3 different hospitals in Sweden and underwent Aβ positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) and plasma collection from 2010 to 2014. Plasma Aβ42/40 was measured using an immunoprecipitation-coupled mass spectrometry developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography MS developed by Araclon (LC-MS-Arc), and immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma Aβ42/40 was also measured using an IP-MS-based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS-based method from the University of Gothenburg (IP-MS-UGOT) and another immunoassay from Quanterix (IA-Quan) among 227 participants. For validation, 122 participants (51 cognitively normal, 51 with mild cognitive impairment, and 20 with AD dementia) were included from the Alzheimer Disease Neuroimaging Initiative who underwent Aβ-PET and plasma Aβ assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays.

Main Outcomes And Measures: Discriminative accuracy of plasma Aβ42/40 quantified using 8 different assays for abnormal CSF Aβ42/40 and Aβ-PET status.

Results: A total of 408 participants were included in this study. In the BioFINDER cohort, the mean (SD) age was 71.6 (5.6) years and 49.3% of the cohort were women. When identifying participants with abnormal CSF Aβ42/40 in the whole cohort, plasma IP-MS-WashU Aβ42/40 showed significantly higher accuracy (area under the receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc Aβ42/40, IA-Elc Aβ42/40, IA-EI Aβ42/40, and IA-N4PE Aβ42/40 (AUC range, 0.69-0.78; P < .05). Plasma IP-MS-WashU Aβ42/40 performed significantly better than IP-MS-UGOT Aβ42/40 and IA-Quan Aβ42/40 (AUC, 0.84 vs 0.68 and 0.64, respectively; P < .001), while there was no difference in the AUCs between IP-MS-WashU Aβ42/40 and IP-MS-Shim Aβ42/40 (0.87 vs 0.83; P = .16) in the 2 subcohorts where these biomarkers were available. The results were similar when using Aβ-PET as outcome. Plasma IPMS-WashU Aβ42/40 and IPMS-Shim Aβ42/40 showed highest coefficients for correlations with CSF Aβ42/40 (r range, 0.56-0.65). The BioFINDER results were replicated in the Alzheimer Disease Neuroimaging Initiative cohort (mean [SD] age, 72.4 [5.4] years; 43.4% women), where the IP-MS-WashU assay performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay.

Conclusions And Relevance: The results from 2 independent cohorts indicate that certain MS-based methods performed better than most of the immunoassays for plasma Aβ42/40 when detecting brain Aβ pathology.
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http://dx.doi.org/10.1001/jamaneurol.2021.3180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453354PMC
September 2021

Associations between air pollution and biomarkers of Alzheimer's disease in cognitively unimpaired individuals.

Environ Int 2021 12 16;157:106864. Epub 2021 Sep 16.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain. Electronic address:

Background: Air quality contributes to incidence of Alzheimer's disease (AD) although the underlying neurobiological mechanisms are unclear. This study was aimed to examine the association between air pollution and concentrations of cerebrospinal fluid (CSF) AD biomarkers and amyloid-β (Aβ) deposition. Participants and methods The sample included 156 cognitively unimpaired adults aged 57 years (61 at biomarkers assessment) with increased risk of AD from the ALFA + Study. We examined CSF levels of Aβ42, Aβ40, p-Tau, t-Tau, neurofilament light (NfL) and cerebral amyloid load (Centiloid). A Land Use Regression model from 2009 was used to estimate residential exposure to air pollutants including nitrogen dioxide (NO,) and particulate matter (PM, PM, PM). This model was considered a surrogate of long-term exposure until time of data collection in 2013-2014. Participants have resided in the same residence for at least the previous 3 years. Multiple linear regression models were used to estimate associations between air pollutants and biomarkers. The effect modification by CSF Aβ status and APOE-ε4 carriership was also assessed.

Results: A consistent pattern of results indicated that greater exposure to NO and PM absorbance was associated with higher levels of brain Aβ deposition, while greater exposure to PM and PMwas associated with higher levels of CSF NfL. Most associations were driven by individuals that were Aβ-positive. Although APOE-ε4 status did not significantly modify these associations, the effect of air pollutants exposure on CSF NfL levels was stronger in APOE-ε4 carriers.

Conclusion: In a population of cognitively unimpaired adults with increased risk of AD, long-term exposure to air pollution was associated with higher levels in biomarkers of AD pathology. While further research is granted to elucidate the mechanisms involved in such associations, our results reinforce the role of air pollution as an environmental risk factor for AD.
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http://dx.doi.org/10.1016/j.envint.2021.106864DOI Listing
December 2021

Cerebrospinal fluid neurogranin in Alzheimer's disease studies: are immunoassay results interchangeable?

Clin Chem Lab Med 2021 Sep 15. Epub 2021 Sep 15.

Département de Biochimie, Université de Paris, GHU AP-HP Nord, Hôpital Lariboisière Fernand-Widal,Paris, France.

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http://dx.doi.org/10.1515/cclm-2021-0505DOI Listing
September 2021

Blood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer's disease: a focused review on recent advances.

J Neurol Neurosurg Psychiatry 2021 Nov 11;92(11):1231-1241. Epub 2021 Sep 11.

Memory, Aging and Cognition Centre, National University Health Systems, Singapore

Discovery and development of clinically useful biomarkers for Alzheimer's disease (AD) and related dementias have been the focus of recent research efforts. While cerebrospinal fluid and positron emission tomography or MRI-based neuroimaging markers have made the in vivo detection of AD pathology and its consequences possible, the high cost and invasiveness have limited their widespread use in the clinical setting. On the other hand, advances in potentially more accessible blood-based biomarkers had been impeded by lack of sensitivity in detecting changes in markers of the hallmarks of AD, including amyloid-β (Aβ) peptides and phosphorylated tau (P-tau). More recently, however, emerging technologies with superior sensitivity and specificity for measuring Aβ and P-tau have reported high concordances with AD severity. In this focused review, we describe several emerging technologies, including immunoprecipitation-mass spectrometry (IP-MS), single molecule array and Meso Scale Discovery immunoassay platforms, and appraise the current literature arising from their use to identify plaques, tangles and other AD-associated pathology. While there is potential clinical utility in adopting these technologies, we also highlight the further studies needed to establish Aβ and P-tau as blood-based biomarkers for AD, including validation with existing large sample sets, new independent cohorts from diverse backgrounds as well as population-based longitudinal studies. In conclusion, the availability of sensitive and reliable measurements of Aβ peptides and P-tau species in blood holds promise for the diagnosis, prognosis and outcome assessments in clinical trials for AD.
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http://dx.doi.org/10.1136/jnnp-2021-327370DOI Listing
November 2021

Diagnostic and prognostic plasma biomarkers for preclinical Alzheimer's disease.

Alzheimers Dement 2021 Sep 8. Epub 2021 Sep 8.

Department of Biomedical Sciences, Macquarie University, North Ryde, New South Wales, Australia.

Introduction: This study involved a parallel comparison of the diagnostic and longitudinal monitoring potential of plasma glial fibrillary acidic protein (GFAP), total tau (t-tau), phosphorylated tau (p-tau181 and p-tau231), and neurofilament light (NFL) in preclinical Alzheimer's disease (AD).

Methods: Plasma proteins were measured using Simoa assays in cognitively unimpaired older adults (CU), with either absence (Aβ-) or presence (Aβ+) of brain amyloidosis.

Results: Plasma GFAP, t-tau, p-tau181, and p-tau231 concentrations were higher in Aβ+ CU compared with Aβ- CU cross-sectionally. GFAP had the highest effect size and area under the curve (AUC) in differentiating between Aβ+ and Aβ- CU; however, no statistically significant differences were observed between the AUCs of GFAP, p-tau181, and p-tau231, but all were significantly higher than the AUC of NFL, and the AUC of GFAP was higher than the AUC of t-tau. The combination of a base model (BM), comprising the AD risk factors, age, sex, and apolipoprotein E gene (APOE) ε4 status with GFAP was observed to have a higher AUC (>90%) compared with the combination of BM with any of the other proteins investigated in the current study. Longitudinal analyses showed increased GFAP and p-tau181 in Aβ+ CU and increased NFL in Aβ- CU, over a 12-month duration. GFAP, p-tau181, p-tau231, and NFL showed significant correlations with cognition, whereas no significant correlations were observed with hippocampal volume.

Discussion: These findings highlight the diagnostic and longitudinal monitoring potential of GFAP and p-tau for preclinical AD.
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http://dx.doi.org/10.1002/alz.12447DOI Listing
September 2021

A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease.

Nat Genet 2021 09 7;53(9):1276-1282. Epub 2021 Sep 7.

Division of Genetic Medicine, Department of Medicine Vanderbilt University Medical Center Nashville, Nashville, TN, USA.

Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer's disease to identify further genetic variants that contribute to Alzheimer's pathology.
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http://dx.doi.org/10.1038/s41588-021-00921-zDOI Listing
September 2021

Predicting progression and cognitive decline in amyloid-positive patients with Alzheimer's disease.

Alzheimers Res Ther 2021 09 6;13(1):151. Epub 2021 Sep 6.

Department of Computer Science and Engineering, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden.

Background: In Alzheimer's disease, amyloid- β (A β) peptides aggregate in the lowering CSF amyloid levels - a key pathological hallmark of the disease. However, lowered CSF amyloid levels may also be present in cognitively unimpaired elderly individuals. Therefore, it is of great value to explain the variance in disease progression among patients with A β pathology.

Methods: A cohort of n=2293 participants, of whom n=749 were A β positive, was selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to study heterogeneity in disease progression for individuals with A β pathology. The analysis used baseline clinical variables including demographics, genetic markers, and neuropsychological data to predict how the cognitive ability and AD diagnosis of subjects progressed using statistical models and machine learning. Due to the relatively low prevalence of A β pathology, models fit only to A β-positive subjects were compared to models fit to an extended cohort including subjects without established A β pathology, adjusting for covariate differences between the cohorts.

Results: A β pathology status was determined based on the A β/A β ratio. The best predictive model of change in cognitive test scores for A β-positive subjects at the 2-year follow-up achieved an R score of 0.388 while the best model predicting adverse changes in diagnosis achieved a weighted F score of 0.791. A β-positive subjects declined faster on average than those without A β pathology, but the specific level of CSF A β was not predictive of progression rate. When predicting cognitive score change 4 years after baseline, the best model achieved an R score of 0.325 and it was found that fitting models to the extended cohort improved performance. Moreover, using all clinical variables outperformed the best model based only on a suite of cognitive test scores which achieved an R score of 0.228.

Conclusion: Our analysis shows that CSF levels of A β are not strong predictors of the rate of cognitive decline in A β-positive subjects when adjusting for other variables. Baseline assessments of cognitive function accounts for the majority of variance explained in the prediction of 2-year decline but is insufficient for achieving optimal results in longer-term predictions. Predicting changes both in cognitive test scores and in diagnosis provides multiple perspectives of the progression of potential AD subjects.
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http://dx.doi.org/10.1186/s13195-021-00886-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422748PMC
September 2021

The relationship between white matter microstructure and self-perceived cognitive decline.

Neuroimage Clin 2021 Aug 28;32:102794. Epub 2021 Aug 28.

Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.

Subjective cognitive decline (SCD) is a perceived cognitive change prior to objective cognitive deficits, and although it is associated with Alzheimer's disease (AD) pathology, it likely results from multiple underlying pathologies. We investigated the association of white matter microstructure to SCD as a sensitive and early marker of cognitive decline and quantified the contribution of white matter microstructure separate from amyloidosis. Vanderbilt Memory & Aging Project participants with diffusion MRI data and a 45-item measure of SCD were included [n = 236, 137 cognitively unimpaired (CU), 99 with mild cognitive impairment (MCI), 73 ± 7 years, 37% female]. A subset of participants (64 CU, 40 MCI) underwent a fasting lumbar puncture for quantification of cerebrospinal fluid (CSF) amyloid-β(CSF Aβ), total tau (CSF t-tau), and phosphorylated tau (CSF p-tau). Diffusion MRI data was post-processed using the free-water (FW) elimination technique, which allowed quantification of extracellular (FW) and intracellular compartment (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) microstructure. Microstructural values were quantified within 11 cognitive-related white matter tracts, including medial temporal lobe, frontal transcallosal, and fronto-parietal tracts using a region of interest approach. General linear modeling related each tract to SCD scores adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile scores, APOE ε4 carrier status, diagnosis, Geriatric Depression Scale scores, hippocampal volume, and total white matter volume. Competitive models were analyzed to determine if white matter microstructural values have a unique role in SCD scores separate from CSF Aβ. FW-corrected radial diffusivity (RD) was related to SCD scores in 8 tracts: cingulum bundle, inferior longitudinal fasciculus, as well as inferior frontal gyrus (IFG) pars opercularis, IFG orbitalis, IFG pars triangularis, tapetum, medial frontal gyrus, and middle frontal gyrus transcallosal tracts. While CSF Aβ was related to SCD scores in our cohort (R = 39.03%; β = -0.231; p = 0.020), competitive models revealed that fornix and IFG pars triangularis transcallosal tract RD contributed unique variance to SCD scores beyond CSF Aβ (R = 44.35% and R = 43.09%, respectively), with several other tract measures demonstrating nominal significance. All tracts which demonstrated nominal significance (in addition to covariates) were input into a backwards stepwise regression analysis. ILF RD, fornix RD, and UF FW were best associated with SCD scores (R = 46.69%; p = 6.37 × 10). Ultimately, we found that medial temporal lobe and frontal transcallosal tract microstructure is an important driver of SCD scores independent of early amyloid deposition. Our results highlight the potential importance of abnormal white matter diffusivity as an early contributor to cognitive decline. These results also highlight the value of incorporating multiple biomarkers to help disentangle the mechanistic heterogeneity of SCD as an early stage of cognitive decline.
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http://dx.doi.org/10.1016/j.nicl.2021.102794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414539PMC
August 2021

Kappa free light chain index as a diagnostic biomarker in multiple sclerosis: A real-world investigation.

J Neurochem 2021 Sep 3. Epub 2021 Sep 3.

Department of Clinical Neuroscience, Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Kappa free light chain (KFLC) index, a measure for intrathecal production of free kappa chains, has been increasingly recognized for its diagnostic potential in multiple sclerosis (MS) as a quantitative alternative to IgG oligoclonal bands (OCBs). Our objective was to investigate the sensitivity, specificity, and overall diagnostic accuracy of KFLC index in MS. KFLC index was prospectively determined as part of the diagnostic workup in patients with suspected MS (n = 327) between May 2013 and February 2020. Patients with clinically isolated syndrome (CIS), radiologically isolated syndrome (RIS), and MS had markedly higher KFLC index (44.6, IQR 16-128) compared with subjects with other neuro-inflammatory disorders (ONID) and symptomatic controls (SC) (2.19, IQR 1.68-2.98, p < 0.001). KFLC index had a sensitivity of 0.93 (95% CI 0.88-0.95) and specificity of 0.87 (95% CI 0.8-0.92) to discriminate CIS/RIS/MS from ONID and SC (AUC 0.94, 95% CI 0.91-0.97, p < 0.001). KFLC index and intrathecal fraction (IF) KFLC had similar accuracies to detect MS. Treatment with disease-modifying therapy (DMT) did not influence the level of KFLC index and it was not affected by demographic factors or associated with degenerative or inflammatory biomarkers in cerebrospinal fluid (CSF). KFLC index in MS diagnostics has methodological advantages compared to OCB and is independent to subjective interpretation. Moreover, it is an attractive diagnostic tool since the diagnostic specificity and sensitivity of KFLC index are similar with that of OCBs and KFLC and better than for IgG index. We show that KFLC index was influenced neither by DMT nor by demographic factors or other inflammatory or degenerative processes in MS as determined by biomarkers in CSF.
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http://dx.doi.org/10.1111/jnc.15500DOI Listing
September 2021

Amyloid pathology and synaptic loss in pathological aging.

J Neurochem 2021 Sep 2. Epub 2021 Sep 2.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory dysfunction and cognitive decline. Pathological aging (PA) describes patients who are amyloid-positive but cognitively unimpaired at time of death. Both AD and PA contain amyloid plaques dominated by amyloid β (Aβ) peptides. In this study, we investigated and compared synaptic protein levels, amyloid plaque load, and Aβ peptide patterns between AD and PA. Two cohorts of post-mortem brain tissue were investigated. In the first, consisting of controls, PA, AD, and familial AD (FAD) individuals, synaptic proteins extracted with tris(hydroxymethyl)aminomethane-buffered saline (TBS) were analyzed. In the second, consisting of tissue from AD and PA patients from three different regions (occipital lobe, frontal lobe, and cerebellum), a two-step extraction was performed. Five synaptic proteins were extracted using TBS, and from the remaining portion Aβ peptides were extracted using formic acid. Subsequently, immunoprecipitation with several antibodies targeting different proteins/peptides was performed for both fractions, which were subsequently analyzed by mass spectrometry. The levels of synaptic proteins were lower in AD (and FAD) compared with PA (and controls), confirming synaptic loss in AD patients. The amyloid plaque load was increased in AD compared with PA, and the relative amount of Aβ40 was higher in AD while for Aβ42 it was higher in PA. In AD loss of synaptic function was associated with increased plaque load and increased amounts of Aβ40 compared with PA cases, suggesting that synaptic function is preserved in PA cases even in the presence of Aβ.
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http://dx.doi.org/10.1111/jnc.15487DOI Listing
September 2021

Comparing the effect of xenon and sevoflurane anesthesia on postoperative neural injury biomarkers: a randomized controlled trial.

Med Gas Res 2022 Jan-Mar;12(1):10-17

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

General anesthesia and surgery are associated with an increase in neural injury biomarkers. Elevations of these neural injury biomarkers in the perioperative period are associated with postoperative delirium. Xenon has been shown to be protective against a range of neurological insults in animal models. It remains to be seen if xenon anesthesia is neuroprotective in the perioperative setting in humans. Twenty-four participants scheduled for lithotripsy were randomized to receive either xenon or sevoflurane general anesthesia. There was no statistically significant difference in the concentrations of postoperative neural injury biomarkers between the xenon and sevoflurane group. Following the procedure there was a significant increase in the concentration from baseline of all three biomarkers at 1 hour post-induction with a return to baseline at 5 hours. General anesthesia for lithotripsy was associated with a significant increase at 1 hour post-induction in the neural injury biomarkers total tau, neurofilament light and tau phosphorylated at threonine 181, a marker of tau phosphorylation. The protocol was approved by the St. Vincent's Hospital Melbourne Ethics Committee (approval No. HREC/18/SVHM/221) on July 20, 2018 and was registered with the Australia New Zealand Clinical Trials Registry (registration No. ACTRN12618000916246) on May 31, 2018.
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http://dx.doi.org/10.4103/2045-9912.324591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447955PMC
September 2021

The Amyloid-β Pathway in Alzheimer's Disease.

Mol Psychiatry 2021 Aug 30. Epub 2021 Aug 30.

Eisai Inc., Neurology Business Group, Woodcliff Lake, NJ, USA.

Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer's disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct Aβ species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for Aβ-targeting therapeutic strategies in development for the early treatment of AD.
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http://dx.doi.org/10.1038/s41380-021-01249-0DOI Listing
August 2021

Brain injury markers in new-onset seizures in adults: A pilot study.

Seizure 2021 Aug 22;92:62-67. Epub 2021 Aug 22.

Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden; Wallenberg Center of Molecular and Translational Medicine, Gothenburg University, Gothenburg, Sweden. Electronic address:

Background: Biochemical markers of brain pathology could potentially contribute to diagnosis and prediction in epilepsy. We describe levels of five brain injury markers in adults with new-onset seizures, and assess group differences in patients with a single seizure, epilepsy, and poststroke epilepsy.

Methods: In this prospective observational study, adults with new-onset seizures were recruited at Sahlgrenska University Hospital, Sweden, and concentrations of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), microtubule-associated protein tau (tau), S100 calcium-binding protein (S100B), and neuron-specific enolase (NSE) were measured. Participants were categorized as epilepsy, poststroke epilepsy (PSE), or single seizure (no additional seizures). Patients were followed until a diagnosis of epilepsy or PSE, or for at least two years in single seizure cases.

Results: The cohort included 23 (37%) individuals with a single seizure, 24 (39%) with epilepsy, and 15 (24%) with PSE. The concentrations of S100B were higher in patients with epilepsy and PSE than in single seizures (p = 0.0023 and p = 0.0162, respectively). The concentrations of NfL were higher in patients with PSE than in single seizures (p=0.0027). After age-normalization, levels of S100B were higher in patients with epilepsy and levels of NfL were higher in patients with PSE (p = 0.0021 and p = 0.0180).

Conclusion: Levels of S100B and NfL were higher in patients with epilepsy or PSE than patients with single seizures. Further studies are needed to investigate the biomarker potential of brain injury markers as predictors of epilepsy course or indicators of epileptogenesis.
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http://dx.doi.org/10.1016/j.seizure.2021.08.012DOI Listing
August 2021

CSF Proteomic Alzheimer's Disease-Predictive Subtypes in Cognitively Intact Amyloid Negative Individuals.

Proteomes 2021 Aug 2;9(3). Epub 2021 Aug 2.

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, 1007 MB Amsterdam, The Netherlands.

We recently discovered three distinct pathophysiological subtypes in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics: one with neuronal hyperplasticity, a second with innate immune system activation, and a third subtype with blood-brain barrier dysfunction. It remains unclear whether AD proteomic subtype profiles are a consequence of amyloid aggregation, or might exist upstream from aggregated amyloid. We studied this question in 127 older individuals with intact cognition and normal AD biomarkers in two independent cohorts (EMIF-AD MBD and ADNI). We clustered 705 proteins measured in CSF that were previously related to AD. We identified in these cognitively intact individuals without AD pathology three subtypes: two subtypes were seen in both cohorts (n = 49 with neuronal hyperplasticity and n = 44 with blood-brain barrier dysfunction), and one only in ADNI (n = 12 with innate immune activation). The proteins specific for these subtypes strongly overlapped with AD subtype protein profiles (overlap coefficients 92%-71%). Longitudinal p-tau and amyloid β 1-42 (Aβ42) CSF analysis showed that in the hyperplasticity subtype p-tau increased (β = 2.6 pg/mL per year, = 0.01) and Aβ42 decreased over time (β = -4.4 pg/mL per year, = 0.03), in the innate immune activation subtype p-tau increased (β = 3.1 pg/mL per year, = 0.01) while in the blood-brain barrier dysfunction subtype Aβ42 decreased (β = -3.7 pg/mL per year, = 0.009). These findings suggest that AD proteomic subtypes might already manifest in cognitively normal individuals and may predispose for AD before amyloid has reached abnormal levels.
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http://dx.doi.org/10.3390/proteomes9030036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396164PMC
August 2021

Microglial activation and tau propagate jointly across Braak stages.

Nat Med 2021 09 26;27(9):1592-1599. Epub 2021 Aug 26.

Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, and Departments of Neurology, Neurosurgery, Psychiatry, Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.

Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer's disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([C]PBR28), amyloid-β (Aβ) ([F]AZD4694) and tau ([F]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 (TREM2) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [C]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of Aβ, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between Aβ and activated microglia sets the pace for tau spread across Braak stages.
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http://dx.doi.org/10.1038/s41591-021-01456-wDOI Listing
September 2021

Blood Biomarkers for Alzheimer's Disease in Down Syndrome.

J Clin Med 2021 Aug 17;10(16). Epub 2021 Aug 17.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 41 Mölndal, Sweden.

Epidemiological evidence suggests that by the age of 40 years, all individuals with Down syndrome (DS) have Alzheimer's disease (AD) neuropathology. Clinical diagnosis of dementia by cognitive assessment is complex in these patients due to the pre-existing and varying intellectual disability, which may mask subtle declines in cognitive functioning. Cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers, although accurate, are expensive, invasive, and particularly challenging in such a vulnerable population. The advances in ultra-sensitive detection methods have highlighted blood biomarkers as a valuable and realistic tool for AD diagnosis. Studies with DS patients have proven the potential blood-based biomarkers for sporadic AD (amyloid-β, tau, phosphorylated tau, and neurofilament light chain) to be useful in this population. In addition, biomarkers related to other pathologies that could aggravate dementia progression-such as inflammatory dysregulation, energetic imbalance, or oxidative stress-have been explored. This review serves to provide a brief overview of the main findings from the limited neuroimaging and CSF studies, outline the current state of blood biomarkers to diagnose AD in patients with DS, discuss possible past limitations of the research, and suggest considerations for developing and validating blood-based biomarkers in the future.
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http://dx.doi.org/10.3390/jcm10163639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397053PMC
August 2021

Neuroinflammation and Alzheimer's Disease: A Machine Learning Approach to CSF Proteomics.

Cells 2021 Jul 29;10(8). Epub 2021 Jul 29.

Section of Neurology, Department of Medicine and Surgery, University of Perugia, 06100 Perugia, Italy.

In Alzheimer's disease (AD), the contribution of pathophysiological mechanisms other than amyloidosis and tauopathy is now widely recognized, although not clearly quantifiable by means of fluid biomarkers. We aimed to identify quantifiable protein biomarkers reflecting neuroinflammation in AD using multiplex proximity extension assay (PEA) testing. Cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment due to AD (AD-MCI) and from controls, i.e., patients with other neurological diseases (OND), were analyzed with the Olink Inflammation PEA biomarker panel. A machine-learning approach was then used to identify biomarkers discriminating AD-MCI (: 34) from OND (: 25). On univariate analysis, SIRT2, HGF, MMP-10, and CXCL5 showed high discriminatory performance (AUC 0.809, = 5.2 × 10, AUC 0.802, = 6.4 × 10, AUC 0.793, = 3.2 × 10, AUC 0.761, = 2.3 × 10, respectively), with higher CSF levels in AD-MCI patients as compared to controls. These same proteins were the best contributors to the penalized logistic regression model discriminating AD-MCI from controls (AUC of the model 0.906, = 2.97 × 10). The biological processes regulated by these proteins include astrocyte and microglia activation, amyloid, and tau misfolding modulation, and blood-brain barrier dysfunction. Using a high-throughput multiplex CSF analysis coupled with a machine-learning statistical approach, we identified novel biomarkers reflecting neuroinflammation in AD. Studies confirming these results by means of different assays are needed to validate PEA as a multiplex technique for CSF analysis and biomarker discovery in the field of neurological diseases.
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http://dx.doi.org/10.3390/cells10081930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391540PMC
July 2021

Effects of Peroral Omega-3 Fatty Acid Supplementation on Cerebrospinal Fluid Biomarkers in Patients with Alzheimer's Disease: A Randomized Controlled Trial-The OmegAD Study.

J Alzheimers Dis 2021 ;83(3):1291-1301

School of Medicine, Örebro University, Örebro, Sweden.

Background: Studies have suggested a connection between a decrease in the levels of polyunsaturated fatty acids (PUFAs) and Alzheimer's disease (AD). We aimed to assess the effect of supplementation with omega-3 fatty acids (n-3 FAs) on biomarkers analyzed in the cerebrospinal fluid (CSF) of patients diagnosed with AD.

Objective: To investigate the effects of daily supplementation with 2.3 g of PUFAs in AD patients on the biomarkers in CSF described below. We also explored the possible correlation between these biomarkers and the performance in the cognitive test Mini-Mental State Examination (MMSE).

Methods: Thirty-three patients diagnosed with AD were randomized to either treatment with a daily intake of 2.3 g of n-3 FAs (n  =  18) or placebo (n  =  15). CSF samples were collected at baseline and after six months of treatment, and the following biomarkers were analyzed: Aβ 38, Aβ 40, Aβ 42, t-tau, p-tau, neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), soluble IL-1 receptor type II (sIL-1RII), and IL-6.

Results: There were no significant differences between the groups concerning the level of the different biomarkers in the CSF at baseline. Within the treatment group, there was a small but significant increase in both YKL-40 (p = 0.04) and NfL (p = 0.03), while the other CSF biomarkers remained stable.

Conclusion: Supplementation with n-3 FAs had a statistically significant effect on NfL and YKL-40, resulting in an increase of both biomarkers, indicating a possible increase of inflammatory response and axonal damage. This increase in biomarkers did not correlate with MMSE score.
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http://dx.doi.org/10.3233/JAD-210007DOI Listing
January 2021
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