Plasma amyloid-β oligomerization assay as a pre-screening test for amyloid status

Objective We assessed the performance of plasma amyloid oligomerization tendency (OAβ) as a marker for abnormal amyloid status. Additionally, we examined long-term storage effects on plasma OAβ. Methods We included 399 subjects regardless of clinical diagnosis from the Amsterdam Dementia Cohort and European Medical Information Framework for AD project (age, 63.8 ± 6.6; 44% female). Amyloid status was determined by visual read on positron emission tomography (PET; nabnormal = 206). Plasma OAβ was measured using the multimer detection system (MDS). Long-term storage effects on MDS-OAβ were assessed using general linear models. Associations between plasma MDS-OAβ and Aβ-PET status were assessed using logistic regression and receiver operating characteristics analyses. Correlations between plasma MDS-OAβ and CSF biomarker levels were evaluated using Pearson correlation analyses. Results MDS-OAβ was higher in individuals with abnormal amyloid, and it identified abnormal Aβ-PET with an area under the curve (AUC) of 0.74 (95% CI, 0.67–0.81), especially in samples with a storage duration < 4 years. Combining APOEe4 and age with plasma MDS-OAβ revealed an AUC of 81% for abnormal amyloid PET status (95% CI, 74–87%). Plasma MDS-OAβ correlated negatively with MMSE (r = − 0.29, p < .01) and CSF Aβ42 (r = − 0.20, p < 0.05) and positively with CSF Tau (r = 0.20, p = 0.01). Conclusions Plasma MDS-OAβ combined with APOEe4 and age accurately identifies brain amyloidosis in a large Aβ-confirmed population. Using plasma MDS-OAβ as a screener reduced the costs and number of PET scans needed to screen for amyloidosis, which is relevant for clinical trials. Additionally, plasma MDS-OAβ levels appeared affected by long-term storage duration, which could be of interest for others measuring plasma Aβ biomarkers.The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The clinical database structure was developed with funding from Stichting Dioraphte. The VUmc Biobank is supported by VUmc. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372, resources of which are composed of financial contribution from the European Unions Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution

Nature and implications of sex differences in AD pathology

A new study has identified key differences between women and men with regard to the nature and burden of Alzheimer disease (AD) pathology in the brain. In addition to highlighting possible sex differences in AD pathophysiology, the findings could have important implications for the diagnosis and management of this condition

Decision tree supports the interpretation of CSF biomarkers in Alzheimer's disease

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 (<647 pg/ml) and normal tau concentrations (<374 pg/ml). Compared to previous cutoffs, the decision tree performed better on diagnostic accuracy (86% [84-88] vs 80% [78-83]). Discussion: Two cerebrospinal fluid AD biomarker profiles were identified and incorporated in a readily applicable decision tree, which improved diagnostic accuracy

Sex differences in CSF biomarkers vary by Alzheimer disease stage and APOE ε4 genotype

OBJECTIVE: To evaluate sex differences in CSF biomarkers, taking the potential modifying role of clinical disease stage and APOE ε4 genotype into account. METHOD: We included participants (n = 1,801) with probable Alzheimer disease (AD) dementia (n = 937), mild cognitive impairment (MCI; n = 437), and subjective cognitive decline (SCD; n = 427). Main outcomes were CSF β-amyloid1-42 (Aβ42), total tau (t-Tau), and tau phosphorylated at threonine 181 (p-Tau) levels. Age-corrected 3-way interactions between sex, disease stage (i.e., syndrome diagnosis at baseline), and APOE ε4 were tested with linear regression analyses for each outcome measure. In case of significant interactions (p < 0.05), sex differences were further evaluated by stratifying analyses for clinical disease stage and APOE ε4 genotype, including age as a covariate. RESULTS: Three-way interactions were significant for t-Tau (p < 0.001) and p-Tau (p < 0.01) but not Aβ42. In APOE ε4 carriers, women showed higher p-Tau concentrations than men in SCD (Cohen d [95% confidence interval]: t-Tau = 0.52 [0.19-0.84], p < 0.001; p-Tau = 0.44 [0.11-0.77] p = 0.004) and MCI (Cohen d [95% CI]: t-Tau = 0.54 [0.28-0.80], p < 0.001; p-Tau = 0.52 [0.26-0.77], p < 0.001) but not in AD dementia. In APOE ε4 noncarriers, women showed higher p-Tau concentrations in MCI (Cohen d [95% CI]: t-Tau = 0.49 [0.17-0.80], p = 0.002; p-Tau = 0.47 [0.16-0.78], p = 0.003) and AD dementia (Cohen d [95% CI]: t-Tau = 0.42 [0.19-0.65], p < 0.001; p-Tau = 0.38 [0.15-0.61] p = 0.002) but not in SCD. CONCLUSIONS: Within APOE ε4 carriers, sex differences in CSF p-Tau are more evident in early disease stages, whereas for APOE ε4 noncarriers, sex differences are more evident in advanced disease stages. These findings suggest that the effect of APOE ε4 on sex differences in CSF biomarkers depends on disease stage in AD

Lumbar puncture patient video increases knowledge and reduces uncertainty: An RCT

Background: Patients often perceive a lumbar puncture (LP) as an invasive procedure. We aimed to evaluate the impact of a 3-minute educational animation-video explaining the LP procedure, on patients’ knowledge, uncertainty, anxiety, and post-LP complications. Methods: We included 203 newly referred memory clinic patients, who were randomly assigned to one of three conditions: (1) home viewing of the video, (2) clinic viewing of the video, or (3) control condition (care as usual). Participants completed questionnaires measuring knowledge as information recall, uncertainty, anxiety, and post-LP complications, the latter when patients underwent an LP procedure (n = 145). Results: Viewing the video increased information recall for both home (P <.001), and clinic viewers (P <.001) compared to controls. Levels of uncertainty decreased after viewing (Pfor interaction=.044), particularly for clinic viewers. Viewing the video or not did not affect anxiety and post-LP complications. Discussion: Preparing individuals for an LP by means of an educational video can help to increase knowledge about the procedure and reduce feelings of uncertainty

Sex differences in memory clinic patients with possible vascular cognitive impairment

Introduction: We aimed to establish sex differences in vascular brain damage of memory clinic patients with possible vascular cognitive impairment (VCI). Methods: A total of 860 memory clinic patients (aged 67.7 ± 8.5; 46% female) with cognitive complaints and vascular brain damage (ie, possible VCI) from the prospective TRACE-VCI (Utrecht-Amsterdam Clinical Features and Prognosis in Vascular Cognitive Impairment) cohort study with 2-year follow-up were included. Age-adjusted female-to-male differences were calculated with general linear models, for demographic variables, vascular risk factors, clinical diagnosis, cognitive performance, and brain magnetic resonance imaging markers. Results: We found no difference in age nor distribution of clinical diagnoses between females and males. Females performed worse on the MMSE (Mini-Mental State Examination) and CAMCOG (Cognitive and Self-Contained Part of the Cambridge Examination for Mental Disorders of the Elderly). Females had a larger white matter hyperintensity volume, while males more often showed (lacunar) infarcts. There was no difference in microbleed prevalence. Males had smaller normalized total brain and gray matter volumes. During follow-up, occurrence of cognitive decline and institutionalization was comparable, but mortality was higher in males. Discussion: Our results suggest that susceptibility and underlying etiology of VCI might differ by sex. Males seem to have more large vessel brain damage compared to females that have more small vessel brain damage

Lumbar puncture patient video increases knowledge and reduces uncertainty: An RCT

Background: Patients often perceive a lumbar puncture (LP) as an invasive procedure. We aimed to evaluate the impact of a 3-minute educational animation-video explaining the LP procedure, on patients’ knowledge, uncertainty, anxiety, and post-LP complications. Methods: We included 203 newly referred memory clinic patients, who were randomly assigned to one of three conditions: (1) home viewing of the video, (2) clinic viewing of the video, or (3) control condition (care as usual). Participants completed questionnaires measuring knowledge as information recall, uncertainty, anxiety, and post-LP complications, the latter when patients underwent an LP procedure (n = 145). Results: Viewing the video increased information recall for both home (P <.001), and clinic viewers (P <.001) compared to controls. Levels of uncertainty decreased after viewing (Pfor interaction=.044), particularly for clinic viewers. Viewing the video or not did not affect anxiety and post-LP complications. Discussion: Preparing individuals for an LP by means of an educational video can help to increase knowledge about the procedure and reduce feelings of uncertainty