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Introduction We developed and validated a clinically applicable decision tree for the use of cerebrospinal fluid biomarkers in the diagnosis of Alzheimer's disease (AD). Methods Subjects with probable AD (n = 1004) and controls (n = 442) were included. A decision tree was modeled using Classification And Regression Tree analysis in a training cohort (AD n = 221; controls n = 221) and validated in an independent cohort (AD n = 783; controls n = 221). Diagnostic performance was compared to previously defined cutoffs (amyloid β 1-42 375 pg/ml). Results Two cerebrospinal fluid AD biomarker profiles were revealed: the “classical” AD biomarker profile (amyloid β 1-42: 647-803 pg/ml; tau >374 pg/ml) and an “atypical” AD biomarker profile with strongly decreased amyloid β 1-42 (, Highlights • Classification And Regression Tree analysis revealed two Alzheimer's disease (AD) biomarker profiles based on cerebrospinal fluid amyloid beta 1-42 and tau. • A “classical AD-like” profile and an atypical AD profile were identified. • Combining both AD biomarker profiles led to a higher diagnostic accuracy. • Both biomarker profiles are incorporated in a readily applicable decision tree.

Background We studied to what degree and at whose initiative 25 informational topics, formerly identified as important, are discussed in diagnostic consultations. Methods Audio recordings of clinician-patient consultations of 71 patients and 32 clinicians, collected in eight Dutch memory clinics, were independently content-coded by two coders. The coding scheme encompassed 25 informational topics. Results Approximately half (Mdn = 12) of the 25 topics were discussed per patient during the diagnostic process, with a higher frequency among individuals receiving a dementia diagnosis (Mdn = 14) compared to others (Mdn = 11). Individual topics ranged from being discussed with 2/71 (3%) to 70/71 (99%) of patients. Patients and/or care partners rarely initiated topic discussion (10%). When they did, they often enquired about one of the least frequently addressed topics. Conclusion Most patients received information on approximately half of the important informational topics. Providing the topic list to patients and care partners beforehand could allow consultation preparation and stimulate participation.

Background: We studied to what degree and at whose initiative 25 informational topics, formerly identified as important, are discussed in diagnostic consultations. Methods: Audio recordings of clinician-patient consultations of 71 patients and 32 clinicians, collected in eight Dutch memory clinics, were independently content-coded by two coders. The coding scheme encompassed 25 informational topics. Results: Approximately half (Mdn = 12) of the 25 topics were discussed per patient during the diagnostic process, with a higher frequency among individuals receiving a dementia diagnosis (Mdn = 14) compared to others (Mdn = 11). Individual topics ranged from being discussed with 2/71 (3%) to 70/71 (99%) of patients. Patients and/or care partners rarely initiated topic discussion (10%). When they did, they often enquired about one of the least frequently addressed topics. Conclusion: Most patients received information on approximately half of the important informational topics. Providing the topic list to patients and care partners beforehand could allow consultation preparation and stimulate participation. Keywords: diagnostic process; information provision; informational needs; informative topics; memory clinics.

Introduction This study explores clinicians’ views on and experiences with when, how, and by whom decisions about diagnostic testing for Alzheimer's disease are made and how test results are discussed with patients. Methods Following a preparatory focus group with 13 neurologists and geriatricians, we disseminated an online questionnaire among 200 memory clinic clinicians. Results Respondents were 95 neurologists and geriatricians (response rate 47.5%). Clinicians (74%) indicated that decisions about testing are made before the first encounter, yet they favored a shared decision-making approach. Patient involvement seems limited to receiving information. Clinicians with less tolerance for uncertainty preferred a bigger say in decisions (P < .05). Clinicians indicated to always communicate the diagnosis (94%), results of different tests (88%–96%), and risk of developing dementia (66%). Discussion Clinicians favor patient involvement in deciding about diagnostic testing, but conversations about decisions and test results can be improved and supported.

Introduction The Alzheimer's biomarkers in daily practice (ABIDE) project is designed to translate knowledge on diagnostic tests (magnetic resonance imaging [MRI], cerebrospinal fluid [CSF], and amyloid positron emission tomography [PET]) to daily clinical practice with a focus on mild cognitive impairment (MCI) Methods ABIDE is a 3-year project with a multifaceted design and is structured into interconnected substudies using both quantitative and qualitative research methods. Results Based on retrospective data, we develop personalized risk estimates for MCI patients. Prospectively, we collect MRI and CSF data from 200 patients from local memory clinics and amyloid PET from 500 patients in a tertiary setting, to optimize application of these tests in daily practice. Furthermore, ABIDE will develop strategies for optimal patient-clinician conversations. Discussion Ultimately, this will result in a set of practical tools for clinicians to support the choice of diagnostic tests and facilitate the interpretation and communication of their results.

Background: As a result of advances in diagnostic testing in the field of Alzheimer disease (AD), patients are diagnosed in earlier stages of the disease, for example, in the stage of mild cognitive impairment (MCI). This poses novel challenges for a clinician during the diagnostic workup with regard to diagnostic testing itself, namely, which tests are to be performed, but also on how to engage patients in this decision and how to communicate test results. As a result, tools to support decision making and improve risk communication could be valuable for clinicians and patients. Objective: The aim of this study was to present the design, development, and testing of a Web-based tool for clinicians in a memory clinic setting and to ascertain whether this tool can (1) facilitate the interpretation of biomarker results in individual patients with MCI regarding their risk of progression to dementia, (2) support clinicians in communicating biomarker test results and risks to MCI patients and their caregivers, and (3) support clinicians in a process of shared decision making regarding the diagnostic workup of AD. Methods: A multiphase mixed-methods approach was used. Phase 1 consisted of a qualitative needs assessment among professionals, patients, and caregivers; phase 2, consisted of an iterative process of development and the design of the tool (ADappt); and phase 3 consisted of a quantitative and qualitative assessment of usability and acceptability of ADappt. Across these phases, co-creation was realized via a user-centered qualitative approach with clinicians, patients, and caregivers. Results: In phase 1, clinicians indicated the need for risk calculation tools and visual aids to communicate test results to patients. Patients and caregivers expressed their needs for more specific information on their risk for developing AD and related consequences. In phase 2, we developed the content and graphical design of ADappt encompassing 3 modules: a risk calculation tool, a risk communication tool including a summary sheet for patients and caregivers, and a conversation starter to support shared decision making regarding the diagnostic workup. In phase 3, ADappt was considered to be clear and user-friendly. Conclusions: Clinicians in a memory clinic setting can use ADappt, a Web-based tool, developed using multiphase design and co-creation, for support that includes an individually tailored interpretation of biomarker test results, communication of test results and risks to patients and their caregivers, and shared decision making on diagnostic testing.

Introduction To improve the detection of changes in Alzheimer's disease (AD), we designed the cognitive-functional composite (CFC). As a first validation step, we investigated its test–retest reliability and feasibility of use. Methods We performed a test–retest study with 2–3 weeks between assessments, including patients with mild cognitive impairment (MCI) or mild AD dementia and cognitively healthy participants. We calculated intraclass correlation coefficients (ICCs) type absolute agreement for all CFC measures and compared baseline and retest scores using paired-samples t-tests. We evaluated feasibility by interviewing participants. Results Forty-three patients (40% female, mean age = 69.9) and 30 controls (50% female, mean age = 65) were included. Subtest intraclass correlation coefficients ranged from .70 to .96. We found negligible improvements after retesting on only two subtests. Overall, patients perceived the administration of the CFC as feasible. Discussion The CFC is a stable and feasible measure in MCI and mild AD dementia, and thereby meets important quality metrics for clinically meaningful outcome measures., Highlights • We investigated stability and feasibility of the cognitive-functional composite (CFC). • We demonstrated good test–retest reliability for all CFC subtests. • We only found negligible practice effects on two CFC subtests. • Overall, patients experienced the administration of the CFC as feasible.

Introduction We compared the automated Elecsys and manual Innotest immunoassays for cerebrospinal fluid (CSF) Alzheimer's disease biomarkers in a multicenter diagnostic setting. Methods We collected CSF samples from 137 participants in eight local memory clinics. Amyloid β(1–42) (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) were centrally analyzed with Innotest and Elecsys assays. Concordances between methods were assessed. Results Biomarker results strongly correlated between assays with Spearman's ρ 0.94 for Aβ42, 0.98 for t-tau, and 0.98 for p-tau. Using Gaussian mixture modeling, cohort-specific cut-points were estimated at 1092 pg/mL for Aβ42, 235 pg/mL for t-tau, and 24 pg/mL for p-tau. We found an excellent concordance of biomarker abnormality between assays of 97% for Aβ42 and 96% for both t-tau and p-tau. Discussion The high concordances between Elecsys and Innotest in this nonacademic, multicenter cohort support the use of Elecsys for CSF Alzheimer's disease diagnostics and allow conversion of results between methods., Highlights • Method comparison of 137 CSF samples collected in eight nonacademic memory clinics. • Innotest and Elecsys strongly correlated: ρ = 0.94 Aβ42; 0.98 t-tau; 0.98 p-tau. • Concordances of biomarker abnormalities: 97% Aβ42; 96% t-tau and p-tau. • Concordance of NIA-AA–based Alzheimer's disease profile (Aβ42 decreased and p-tau increased): 89%. • Preanalytical protocol deviations did not show effects on biomarker correlations.

Introduction This study aims to assess patients' and caregivers' views on and experiences with (1) decisions about diagnostic testing for Alzheimer's disease (AD) and (2) receiving test results. Methods We conducted separate focus groups with patients from three hospitals who underwent diagnostic testing for AD ( N = 11) and their caregivers ( N = 11). Audio recordings were transcribed verbatim and analyzed using MaxQDA. Results Patients and caregivers preferred and perceived active involvement in decision making, but the decision to initiate diagnostic testing seems to be made before the clinician-patient encounter. Patients and caregivers indicate that decisions are driven by a strong need to explain the patient's symptoms. They missed information on why different diagnostic tests were used, what the results of these tests were, and to what extent these results were (ab)normal. Discussion The decision-making process around diagnostic testing for AD and the information provision before and after diagnostic testing could be improved.

Background: A correct diagnosis of Alzheimer's Disease (AD) is considered important for access to correct treatment, advice, and care. We aim to estimate the diagnostic accuracy of 18F-Flutemetamol PET. Methods: In the Dutch Flutemetamol Study, 211 participants, suspected of dementia, aged ≤ 70, diagnostic confidence

OBJECTIVE Hyperglycemia-associated microvascular disease may underlie changes in cerebral functioning and cognitive performance in patients with type 1 diabetes. Functional connectivity, an indicator of functional interactions and information exchange between brain regions, provides a measure of cerebral functioning. This study addresses functional connectivity and cognition in type 1 diabetic patients with and without proliferative retinopathy, relative to healthy control subjects, using magnetoencephalography. RESEARCH DESIGN AND METHODS Fluctuations in magnetic field at scalp for Δ, θ, lower and upper α, β, and lower and upper γ frequency bands were measured using magnetoencephalography. Synchronization likelihood, a measure of functional connectivity, was computed. Using neuropsychological tests, cognitive functioning was assessed and its associations with functional connectivity were determined. RESULTS Compared with control subjects, type 1 diabetic patients performed poorer on general cognitive ability, information processing speed, and motor speed, irrespective of their microvascular complication status. Functional connectivity, however, was lowest for type 1 diabetic patients with retinopathy, compared with type 1 diabetic patients without microvascular complications and control subjects, whereas type 1 diabetic patients without microvascular complications showed an increase relative to control subjects. Positive associations were found between functional connectivity and executive functioning, memory, information processing speed, motor speed, and attention. CONCLUSIONS Compared with healthy control subjects, functional connectivity and cognition differed in type 1 diabetic patients irrespective of microvascular complication status, indicating that chronic hyperglycemia, among other factors, may negatively affect brain functioning even before microvascular damage becomes manifest. The association found between synchronization likelihood and cognition suggests functional connectivity plays a significant role in cognitive functioning.

Objective The aim of this study was to demonstrate the involvement of the inflammatory proteins IL-6, ACT and CRP early in the pathology process of AD in patients with mild cognitive impairment (MCI) and AD. Methods IL-6, ACT, CRP, Aβ42, phospho-tau (p-tau) and total tau concentrations in serum and CSF of 145 patients with probable AD and 67 patients with MCI were measured by sandwich ELISA. MCI patients were characterized as high- respectively low-risk MCI according to their Aβ42/tau risk profile. Results CSF and serum CRP levels were significantly higher in MCI compared to AD patients after adjustment for age, ApoE ɛ4 genotype and cardiovascular diseases (p

Background Decreased amyloid β (1-42) (Aβ42) and increased (phosphorylated) tau in cerebrospinal fluid (CSF) are considered to be a reflection of plaques, tangles, and neuronal degeneration in Alzheimer's disease (AD). Atrophy of the medial temporal lobe (MTA) on magnetic resonance imaging (MRI) reflects neuronal loss in this area. Objective To compare diagnostic accuracy of CSF biomarkers and MTA in AD versus controls. Methods Aβ42, tau and tau phosphorylated at threonine 181 (Ptau-181) were measured in CSF from 61 AD patients and 32 controls by sandwich enzyme-linked immunosorbent assay. A CSF biomarker profile for AD was constructed. MTA was rated visually on MRI. Results When AD patients and controls were evaluated separately, no correlations were present between the CSF markers and MTA score. Both MTA and CSF biomarker profile were independently associated with the diagnosis AD (MTA: OR (95% CI) = 28 (3–239); CSF biomarker profile: OR (95% CI) = 57 (13–262)). Among individuals younger than 65 years old and without MTA 60% suffered AD, and the finding of an abnormal CSF biomarker profile was limited to AD patients only. Conclusions MTA and CSF biomarkers seem to be of incremental value for the diagnosis AD. CSF analysis is most sensitive in the absence of MTA, and especially among early-onset AD patients.

Various C-terminally truncated amyloid beta peptides (Abeta) are linked to Alzheimer's disease (AD) pathogenesis. Cerebrospinal fluid (CSF) concentrations of Abeta38, Abeta40, and Abeta42 were measured by enzyme-linked immunosorbent assay in 30 patients with AD and 26 control subjects. CSF Abeta42 levels was decreased in patients with AD, whereas CSF Abeta38 and Abeta40 levels were similar in patients with AD and control subjects. All three Abeta peptides were interrelated, particularly CSF Abeta38 and Abeta40. Diagnostic accuracy of CSF Abeta42 concentrations was not improved by applying the ratios of CSF Abeta42 to Abeta38 or Abeta40.

Background: Reported concentrations of amyloid β (1–42) (Aβ42) and tau in cerebrospinal fluid (CSF) differ among reports. We investigated the effects of storage temperature, repeated freeze/thaw cycles, and centrifugation on the concentrations of Aβ42 and tau in CSF. Methods: Stability of samples stored at −80 °C was determined by use of an accelerated stability testing protocol according to the Arrhenius equation. Aβ42 and tau concentrations were measured in CSF samples stored at 4, 18, 37, and −80 °C. Relative CSF concentrations (%) of the biomarkers after one freeze/thaw cycle were compared with those after two, three, four, five, and six freeze/thaw cycles. In addition, relative Aβ42 and tau concentrations in samples not centrifuged were compared with samples centrifuged after 1, 4, 48, and 72 h. Results: Aβ42 and tau concentrations were stable in CSF when stored for a long period at −80 °C. CSF Aβ42 decreased by 20% during the first 2 days at 4, 18, and 37 °C compared with −80 °C. CSF tau decreased after storage for 12 days at 37 °C. After three freeze/thaw cycles, CSF Aβ42 decreased 20%. CSF tau was stable during six freeze/thaw cycles. Centrifugation did not influence the biomarker concentrations. Conclusions: Repeated freeze/thaw cycles and storage at 4, 18, and 37 °C influence the quantitative result of the Aβ42 test. Preferably, samples should be stored at −80 °C immediately after collection.

0 d Authors’ response to commentaries Inflammatory markers in AD and MCI patients with different biomarker profiles—interpretation of serum and CSF levels Alie Schuitemaker*, Miranda G. Dik, Robert Veerhuis, Philip Scheltens, Niki S.M. Schoonenboom, C. Erik Hack, Marinus A. Blankenstein, Cees Jonker a Department of Neurology, Alzheimer’s Center, VU University Medical Center, 1007 MB Amsterdam, the Netherlands b EMGO Institute, VU University Medical Center, 1007 MB Amsterdam, the Netherlands c www.elsevier.com/locate/neuaging