The prediagnostic general practitioner care of sarcoma patients: A real-world data study.

BACKGROUND: Limited understanding exists regarding early sarcoma symptoms presented during general practitioner (GP) consultations. The study explores GP visit patterns and recorded diagnoses in the 12 months preceding sarcoma diagnosis. METHODS: Sarcoma cases diagnosed from 2010 to 2020 were identified through the Netherlands Cancer Registry alongside general practice data. Sarcoma cases were age and gender matched to cancer-free controls (2:1 or 1:1 ratio). RESULTS: A total of 787 individuals with soft-tissue sarcoma (STS) and 188 individuals with bone sarcoma (BS) were identified. There was a significant difference in monthly GP contacts from 4 months to the last month before STS diagnosis, and 2 months before BS diagnosis between cases and controls. Most prevalent diagnoses recorded by the GP for STS cases included musculoskeletal neoplasm (26.6%), uncomplicated hypertension (15.6%), and cystitis/other urinary infections (12.2%). For BS cases, musculoskeletal neoplasm (42.8%), knee symptoms/complaints (9.7%), and shoulder symptoms/complaints (9.7%) were most frequent. CONCLUSIONS AND DISCUSSION: A significant difference in GP contacts between cases and controls preceding sarcoma diagnosis. STS cases were predominantly diagnosed with nonspecific symptoms, whereas BS cases with diagnoses more suggestive of BS. Better understanding of the prediagnostic trajectory could aid GPs in early identification of sarcoma.

Contributions of amyloid beta and cerebral small vessel disease in clinical decline.

INTRODUCTION: We assessed whether co-morbid small vessel disease (SVD) has clinical predictive value in preclinical or prodromal Alzheimer's disease. METHODS: In 1090 non-demented participants (65.4 ± 10.7 years) SVD was assessed with magnetic resonance imaging and amyloid beta (Aß) with lumbar puncture and/or positron emission tomography scan (mean follow-up for cognitive function 3.1 ± 2.4 years). RESULTS: Thirty-nine percent had neither Aß nor SVD (A-V-), 21% had SVD only (A-V+), 23% Aß only (A+V-), and 17% had both (A+V+). Pooled cohort linear mixed model analyses demonstrated that compared to A-V- (reference), A+V- had a faster rate of cognitive decline. Co-morbid SVD (A+V+) did not further increase rate of decline. Cox regression showed that dementia risk was modestly increased in A-V+ (hazard ratio [95% confidence interval: 1.8 [1.0-3.2]) and most strongly in A+ groups. Also, mortality risk was increased in A+ groups. DISCUSSION: In non-demented persons Aß was predictive of cognitive decline, dementia, and mortality. SVD modestly predicts dementia in A-, but did not increase deleterious effects in A+. HIGHLIGHTS: Amyloid beta (Aß; A) was predictive for cognitive decline, dementia, and mortality. Small vessel disease (SVD) had no additional deleterious effects in A+. SVD modestly predicted dementia in A-. Aß should be assessed even when magnetic resonance imaging indicates vascular cognitive impairment.

Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation.

Alzheimer's disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (ß-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with these markers. Genetic and biomarker information was available for 480 participants from two studies: EMIF-AD and ADNI. We applied a principal component (PC) analysis to derive biomarkers combinations, which represent statistically independent biological processes. We then tested whether rare variants in 9576 protein-coding genes associate with these PCs using a Meta-SKAT test. We also tested whether the PCs are intermediary to gene effects on AD symptoms with a SMUT test. One PC loaded on NfL and YKL-40, indicators of neuronal injury and inflammation. Four genes were associated with this PC: IFFO1, DTNB, NLRC3, and SLC22A10. Mediation tests suggest, that these genes also affect dementia symptoms via inflammation/injury. We also observed an association between a PC loading on Neurogranin, a marker for synaptic functioning, with GABBR2 and CASZ1, but no mediation effects. The results suggest that rare variants in IFFO1, DTNB, NLRC3, and SLC22A10 heighten susceptibility to neuronal injury and inflammation, potentially by altering cytoskeleton structure and immune activity disinhibition, resulting in an elevated dementia risk. GABBR2 and CASZ1 were associated with synaptic functioning, but mediation analyses suggest that the effect of these two genes on synaptic functioning is not consequential for AD development.

Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits.

INTRODUCTION: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. METHODS: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808). RESULTS: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively. DISCUSSION: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.

Cerebrospinal fluid proteomic profiling of individuals with mild cognitive impairment and suspected non-Alzheimer's disease pathophysiology.

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 (Aß)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.

Harmonizing neuropsychological assessment for mild neurocognitive disorders in Europe.

INTRODUCTION: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts. METHODS: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives. RESULTS: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes. DISCUSSION: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.

Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics.

Alzheimer's disease is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. CSF contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether Alzheimer's disease biological subtypes can be detected in CSF proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 911 tested) proteins differed between Alzheimer's disease (defined as having abnormal amyloid, n = 425) and controls (defined as having normal CSF amyloid and tau and normal cognition, n = 127). Using these proteins for data-driven clustering, we identified three robust pathophysiological Alzheimer's disease subtypes within each cohort showing (i) hyperplasticity and increased BACE1 levels; (ii) innate immune activation; and (iii) blood-brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals were labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, and 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for Alzheimer's disease (all P > 0.01). Additional pathological comparisons that were available for a subset in ADNI suggested that subtypes showed similar severity of Alzheimer's disease pathology, and did not differ in the frequencies of co-pathologies, providing further support that found subtypes truly reflect Alzheimer's disease heterogeneity. Compared to controls, all non-demented Alzheimer's disease individuals had increased risk of showing clinical progression (all P < 0.01). Compared to subtype 1, subtype 2 showed faster clinical progression after correcting for age, sex, level of education and tau levels (hazard ratio = 2.5; 95% confidence interval = 1.2, 5.1; P = 0.01), and subtype 3 at trend level (hazard ratio = 2.1; 95% confidence interval = 1.0, 4.4; P = 0.06). Together, these results demonstrate the value of CSF proteomics in studying the biological heterogeneity in Alzheimer's disease patients, and suggest that subtypes may require tailored therapy.

Replication study of plasma proteins relating to Alzheimer's pathology.

INTRODUCTION: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. METHODS: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. RESULTS: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. DISCUSSION: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels.

INTRODUCTION: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. METHODS: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. RESULTS: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. DISCUSSION: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.

Vascular risk factors are associated with longitudinal changes in cerebrospinal fluid tau markers and cognition in preclinical Alzheimer's disease.

INTRODUCTION: Vascular factors increase the risk of Alzheimer's disease (AD). We investigated the associations between such factors, longitudinal AD cerebrospinal fluid biomarkers, and cognition. METHODS: 433 cognitively normal participants were classified into four biomarker groups using their baseline amyloid (A+/-) and tau status (T+/-). 184 participants had undergone serial cerebrospinal fluid collection. Frequencies of risk factors and the Framingham Risk Score (FRS) were compared, and we tested the influence of risk factors on change in biomarker concentrations and cognition. RESULTS: The absence of obesity, presence of hypertension, and a high FRS were associated with an increase in tau levels, particularly in A+T+ individuals. Risk factors were not associated with amyloid. Depression was associated with higher cognitive scores, whereas high FRS was associated with lower scores and a faster decline. DISCUSSION: Our results demonstrate that vascular risk factors may enhance neurodegeneration but not amyloid accumulation in preclinical AD.

Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype.

INTRODUCTION: We estimated the age-specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration. METHODS: We performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration. RESULTS: The overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE ε4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage. DISCUSSION: Estimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design.

Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum.

INTRODUCTION: We investigated relations between amyloid-ß (Aß) status, apolipoprotein E (APOE) ε4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau). METHODS: We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with Aß status (Aß- vs. Aß+), clinical diagnosis APOE ε4 carriership, baseline cognition, and change in cognition. RESULTS: Ng and T-tau distinguished between Aß+ from Aß- individuals in each clinical group, whereas NFL and YKL-40 were associated with Aß+ in nondemented individuals only. APOE ε4 carriership did not influence NFL, Ng, and YKL-40 in Aß+ individuals. NFL was the best predictor of cognitive decline in Aß+ individuals across the cognitive spectrum. DISCUSSION: Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker.

Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay.

INTRODUCTION: Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. METHODS: 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. RESULTS: A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. DISCUSSION: The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.

Inflammatory biomarkers in Alzheimer's disease plasma.

INTRODUCTION: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a "Holy Grail" of AD research and intensively sought; however, there are no well-established plasma markers. METHODS: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. RESULTS: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOε4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). DISCUSSION: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation.

Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort.

INTRODUCTION: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers. METHODS: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis. RESULTS: Eight metabolites were associated with amyloid ß and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory. DISCUSSION: PFAMs have been found increased and associated with amyloid ß burden in CSF and clinical measures.

Healthcare utilization patterns of individuals with depression after national policy to increase the mental health workforce in primary care: a data linkage study.

BACKGROUND: The deployment of the mental health nurse, an additional healthcare provider for individuals in need of mental healthcare in Dutch general practices, was expected to substitute treatments from general practitioners and providers in basic and specialized mental healthcare (psychologists, psychotherapists, psychiatrists, etc.). The goal of this study was to investigate the extent to which the degree of mental health nurse deployment in general practices is associated with healthcare utilization patterns of individuals with depression. METHODS: We combined national health insurers' claims data with electronic health records from general practices. Healthcare utilization patterns of individuals with depression between 2014 and 2019 (N = 31,873) were analysed. The changes in the proportion of individuals treated after depression onset were assessed in association with the degree of mental health nurse deployment in general practices. RESULTS: The proportion of individuals with depression treated by the GP, in basic and specialized mental healthcare was lower in individuals in practices with high mental health nurse deployment. While the association between mental health nurse deployment and consultation in basic mental healthcare was smaller for individuals who depleted their deductibles, the association was still significant. Treatment volume of general practitioners was also lower in practices with higher levels of mental health nurse deployment. CONCLUSION: Individuals receiving care at a general practice with a higher degree of mental health nurse deployment have lower odds of being treated by mental healthcare providers in other healthcare settings. More research is needed to evaluate to what extent substitution of care from specialized mental healthcare towards general practices might be associated with waiting times for specialized mental healthcare.

Healthcare utilization patterns for knee and hip osteoarthritis before and after changes in national health insurance coverage: a data linkage study from the Netherlands.

INTRODUCTION: Medical guidelines aim to stimulate stepped care for knee and hip osteoarthritis, redirecting treatments from hospitals to primary care. In the Netherlands, this development was supported by changing health insurance coverage for physio/exercise therapy. The aim of this study was to evaluate healthcare utilization patterns before and after health changes in health insurance coverage. METHOD: We analyzed electronic health records and claims data from patients with osteoarthritis in the knee (N = 32,091) and hip (N = 16,313). Changes between 2013 and 2019 in the proportion of patients treated by the general practitioner, physio/exercise therapist or orthopedic surgeon within 6 months after onset were assessed. RESULTS: Joint replacement surgeries decreased for knee (OR 0.47 [0.41-0.54]) and hip (OR 0.81 [0.71-0.93]) osteoarthritis between 2013-2019. The use of physio/exercise therapy increased (knee: OR 1.38 [1.24-1.53], hip: OR 1.26 [1.08-1.47]). However, the proportion treated by a physio/exercise therapist decreased for patients that had not depleted their annual deductibles (knee: OR 0.86 [0.79 - 0.94], hip: OR 0.90 [0.79 - 1.02]). This might be affected by the inclusion of physio/exercise therapy in basic health insurance in 2018. CONCLUSION: We have found a shift from hospitals to primary care in knee and hip osteoarthritis care. However, the use of physio/exercise therapy declined after changes in insurance coverage for patients that had not depleted their deductibles.

Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning.

BACKGROUND: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (ß-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. METHODS: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. RESULTS: Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. CONCLUSIONS: These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

Detection of primary Sjögren's syndrome in primary care: developing a classification model with the use of routine healthcare data and machine learning.

BACKGROUND: Primary Sjögren's Syndrome (pSS) is a rare autoimmune disease that is difficult to diagnose due to a variety of clinical presentations, resulting in misdiagnosis and late referral to specialists. To improve early-stage disease recognition, this study aimed to develop an algorithm to identify possible pSS patients in primary care. We built a machine learning algorithm which was based on combined healthcare data as a first step towards a clinical decision support system. METHOD: Routine healthcare data, consisting of primary care electronic health records (EHRs) data and hospital claims data (HCD), were linked on patient level and consisted of 1411 pSS and 929,179 non-pSS patients. Logistic regression (LR) and random forest (RF) models were used to classify patients using age, gender, diseases and symptoms, prescriptions and GP visits. RESULTS: The LR and RF models had an AUC of 0.82 and 0.84, respectively. Many actual pSS patients were found (sensitivity LR = 72.3%, RF = 70.1%), specificity was 74.0% (LR) and 77.9% (RF) and the negative predictive value was 99.9% for both models. However, most patients classified as pSS patients did not have a diagnosis of pSS in secondary care (positive predictive value LR = 0.4%, RF = 0.5%). CONCLUSION: This is the first study to use machine learning to classify patients with pSS in primary care using GP EHR data. Our algorithm has the potential to support the early recognition of pSS in primary care and should be validated and optimized in clinical practice. To further enhance the algorithm in detecting pSS in primary care, we suggest it is improved by working with experienced clinicians.

Effects of age, amyloid, sex, and APOE ε4 on the CSF proteome in normal cognition.

Introduction: It is important to understand which biological processes change with aging, and how such changes are associated with increased Alzheimer's disease (AD) risk. We studied how cerebrospinal fluid (CSF) proteomics changed with age and tested if associations depended on amyloid status, sex, and apolipoprotein E Ɛ4 genotype. Methods: We included 277 cognitively intact individuals aged 46 to 89 years from Alzheimer's Disease Neuroimaging Initiative, European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery, and Metabolic Syndrome in Men. In total, 1149 proteins were measured with liquid chromatography mass spectrometry with multiple reaction monitoring/Rules-Based Medicine, tandem mass tag mass spectrometry, and SOMAscan. We tested associations between age and protein levels in linear models and tested enrichment for Reactome pathways. Results: Levels of 252 proteins increased with age independently of amyloid status. These proteins were associated with immune and signaling processes. Levels of 21 proteins decreased with older age exclusively in amyloid abnormal participants and these were enriched for extracellular matrix organization. Discussion: We found amyloid-independent and -dependent CSF proteome changes with older age, perhaps representing physiological aging and early AD pathology.