Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer's disease.

Staging amyloid-beta (Aß) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aß pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aß ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aß-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aß therapies.

Comparative analysis of multimodal biomarkers for amyloid-beta positivity detection in Alzheimer's disease cohorts.

Introduction: Efforts to develop cost-effective approaches for detecting amyloid pathology in Alzheimer's disease (AD) have gained significant momentum with a focus on biomarker classification. Recent research has explored non-invasive and readily accessible biomarkers, including magnetic resonance imaging (MRI) biomarkers and some AD risk factors. Methods: In this comprehensive study, we leveraged a diverse dataset, encompassing participants with varying cognitive statuses from multiple sources, including cohorts from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and our in-house Dementia Disease Initiation (DDI) cohort. As brain amyloid plaques have been proposed as sufficient for AD diagnosis, our primary aim was to assess the effectiveness of multimodal biomarkers in identifying amyloid plaques, using deep machine learning methodologies. Results: Our findings underscore the robustness of the utilized methods in detecting amyloid beta positivity across multiple cohorts. Additionally, we investigated the potential of demographic data to enhance MRI-based amyloid detection. Notably, the inclusion of demographic risk factors significantly improved our models' ability to detect amyloid-beta positivity, particularly in early-stage cases, exemplified by an average area under the ROC curve of 0.836 in the unimpaired DDI cohort. Discussion: These promising, non-invasive, and cost-effective predictors of MRI biomarkers and demographic variables hold the potential for further refinement through considerations like APOE genotype and plasma markers.

Medial Temporal Lobe Atrophy in Predementia Alzheimer's Disease: A Longitudinal Multi-Site Study Comparing Staging and A/T/N in a Clinical Research Cohort.

BACKGROUND: Atrophy of the medial temporal lobe (MTL) is a biological characteristic of Alzheimer's disease (AD) and can be measured by segmentation of magnetic resonance images (MRI). OBJECTIVE: To assess the clinical utility of automated volumetry in a cognitively well-defined and biomarker-classified multi-center longitudinal predementia cohort. METHODS: We used Automatic Segmentation of Hippocampal Subfields (ASHS) to determine MTL morphometry from MRI. We harmonized scanner effects using the recently developed longitudinal ComBat. Subjects were classified according to the A/T/N system, and as normal controls (NC), subjective cognitive decline (SCD), or mild cognitive impairment (MCI). Positive or negative values of A, T, and N were determined by cerebrospinal fluid measurements of the Aß42/40 ratio, phosphorylated and total tau. From 406 included subjects, longitudinal data was available for 206 subjects by stage, and 212 subjects by A/T/N. RESULTS: Compared to A-/T-/N- at baseline, the entorhinal cortex, anterior and posterior hippocampus were smaller in A+/T+orN+. Compared to NC A- at baseline, these subregions were also smaller in MCI A+. Longitudinally, SCD A+ and MCI A+, and A+/T-/N- and A+/T+orN+, had significantly greater atrophy compared to controls in both anterior and posterior hippocampus. In the entorhinal and parahippocampal cortices, longitudinal atrophy was observed only in MCI A+ compared to NC A-, and in A+/T-/N- and A+/T+orN+ compared to A-/T-/N-. CONCLUSION: We found MTL neurodegeneration largely consistent with existing models, suggesting that harmonized MRI volumetry may be used under conditions that are common in clinical multi-center cohorts.

Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns.

White matter hyperintensities (WMHs) are associated with vascular risk and Alzheimer's disease. In this study, we examined relations between WMH load and distribution, amyloid pathology and vascular risk in 339 controls and cases with either subjective (SCD) or mild cognitive impairment (MCI). Regional deep (DWMH) and periventricular (PWMH) WMH loads were determined using an automated algorithm. We stratified on Aß1-42 pathology (Aß+/-) and analyzed group differences, as well as associations with Framingham Risk Score for cardiovascular disease (FRS-CVD) and age. Occipital PWMH (p = 0.001) and occipital DWMH (p = 0.003) loads were increased in SCD-Aß+ compared with Aß- controls. In MCI-Aß+ compared with Aß- controls, there were differences in global WMH (p = 0.003), as well as occipital DWMH (p = 0.001) and temporal DWMH (p = 0.002) loads. FRS-CVD was associated with frontal PWMHs (p = 0.003) and frontal DWMHs (p = 0.005), after adjusting for age. There were associations between global and all regional WMH loads and age. In summary, posterior WMH loads were increased in SCD-Aß+ and MCI-Aß+ cases, whereas frontal WMHs were associated with vascular risk. The differences in WMH topography support the use of regional WMH load as an early-stage marker of etiology.

Detecting At-Risk Alzheimer's Disease Cases.

While APOEɛ4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aß42 (pAß) and APOEɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAß and APOEɛ4 frequency compared to NC. Also, NCFD had higher APOEɛ4 frequencies without increased fraction of pAß compared to NC, and cases recruited from memory clinics had higher fractions of pAß and APOEɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAß enriched, whereas self-referred and NCFD cases more frequently are pAß negative but at risk (APOEɛ4 positive), suitable for primary intervention.

Loss of opposite left ventricular basal and apical rotation predicts acute response to cardiac resynchronization therapy and is associated with long-term reversed remodeling.

BACKGROUND: Normal left ventricular (LV) torsion is caused by opposite basal and apical rotation. Opposite rotation can be lost in heart failure, but might be restored by pacing; therefore, the predictive value of the loss of opposite base-apex rotation in heart failure patients for the response to cardiac resynchronization therapy (CRT) was studied. METHODS AND RESULTS: In 34 CRT candidates and 12 controls, basal and apical LV rotations were calculated using magnetic resonance image tagging. Loss of opposite rotation was quantified by the correlation between both rotation curves: a negative correlation indicates normal, opposite rotation and a positive correlation indicates that base and apex rotate in the same direction. In patients, LV pressure was measured invasively during biventricular stimulation. Acute response to CRT was defined by >10% increase in dP/dt(max) relative to baseline. LV volume was determined at baseline and 8 months follow-up using echocardiography. The base-apex rotation correlation (BARC) was significantly higher in acute responders (n=22) than in nonresponders (n=12) and controls (0.64+/-0.51, -0.23+/-0.67, and -0.68+/-0.22, respectively; P=.001). The sensitivity and specificity for prediction of acute response were 82% and 83%, respectively, at a cutoff value of 0.5. At follow-up, volumes could be analyzed in 18 patients. In the group with BARC >0.5, end-diastolic volume decreased by 7% (NS), end-systolic volume by 16%, and ejection fraction increased by 28% (both P=.02), whereas in the group with BARC <0.5, no significant changes were observed. CONCLUSIONS: The loss of opposite base-apex rotation in patients eligible for CRT is an excellent predictor of acute response and is associated with LV reverse remodeling.

Comparison of 2D and 3D calculation of left ventricular torsion as circumferential-longitudinal shear angle using cardiovascular magnetic resonance tagging.

PURPOSE: To compare left ventricular (LV) torsion represented as the circumferential-longitudinal (CL) shear angle between 2D and 3D quantification, using cardiovascular magnetic resonance (CMR). METHODS: CMR tagging was performed in six healthy volunteers. From this, LV torsion was calculated using a 2D and a 3D method. The cross-correlation between both methods was evaluated and comparisons were made using Bland-Altman analysis. RESULTS: The cross-correlation between the curves was r2 = 0.97 +/- 0.02. No significant time-delay was observed between the curves. Bland-Altman analysis revealed a significant positive linear relationship between the difference and the average value of both analysis methods, with the 2D results showing larger values than the 3D. The difference between both methods can be explained by the definition of the 2D method. CONCLUSION: LV torsion represented as CL shear quantified by the 2D and 3D analysis methods are strongly related. Therefore, it is suggested to use the faster 2D method for torsion calculation.

Quantitative comparison of 2D and 3D circumferential strain using MRI tagging in normal and LBBB hearts.

The response to cardiac resynchronization therapy (CRT), which is applied to patients with heart failure (HF) and left bundle-branch block (LBBB), can be predicted from the mechanical dyssynchrony measured on circumferential strain. Circumferential strain can be assessed by either 2D or 3D strain analysis. In this study was evaluated the difference between 2D and 3D circumferential strain using MR tagging with high temporal resolution (14 ms). Six healthy volunteers and five patients with LBBB were evaluated. We compared the 2D and 3D circumferential strains by computing the mechanical dyssynchrony and the cross correlation (r) between 2D and 3D strain curves, and by quantifying the differences in peak circumferential shortening, time to onset, and time to peak of shortening. The obtained maximum r(2) values were 0.97 +/- 0.03 and 0.87 +/- 0.16 for the healthy and LBBB populations, respectively, and thus showed a good similarity between 2D and 3D strain curves. No significant difference was observed between 2D and 3D in time to onset, time to peak, or peak circumferential shortening. Thus, to measure dyssynchrony, 2D strain analysis will suffice. Since 2D analysis is easier to implement than 3D analysis, this finding brings the application of MRI tagging and strain analysis closer to the clinical routine.

Extended harmonic phase tracking of myocardial motion: improved coverage of myocardium and its effect on strain results.

PURPOSE: To extend the harmonic phase (HARP) tracking method in order to track the myocardial tissue that appears near the epicardial contour during systole and reappears near the endocardial contour during diastole, due to the longitudinal motion and conical shape of the heart. MATERIALS AND METHODS: A mathematical model of myocardial deformation was used to quantify the accuracy of the extended HARP tracking and of the strain computation. For six healthy volunteers, the number of tracked points and the two-dimensional strain components were computed with the extended and with the original HARP tracking version. RESULTS: High accuracy was obtained for the circumferential strain (maximum error is 0.5% relative to analytical strain). The extended version tracked 22 +/- 7%, 51 +/- 19%, and 67 +/- 20% more points than the original version on the basal, mid, and apical slices, respectively (P < or = 0.001 for each slice), and yielded a decreased circumferential shortening (relative decrease: 2 +/- 4%, 9 +/- 4%, and 12 +/- 5% for the three slices; P < 0.005 for mid and apex), at end systole. These differences in circumferential strain were related to the more complete coverage of the myocardial wall with tracked points. CONCLUSION: The extended HARP tracking also provides strain values from myocardial regions that were not covered by the original HARP tracking.