Tau Status Research Articles

Perivascular space enlargement accelerates in ageing and Alzheimer’s disease pathology: evidence from a three-year longitudinal multicentre study

BackgroundPerivascular space (PVS) enlargement in ageing and Alzheimer’s disease (AD) and the drivers of such a structural change in humans require longitudinal investigation. Elucidating the effects of demographic factors, hypertension, cerebrovascular dysfunction, and AD pathology on PVS dynamics could inform the role of PVS in brain health function as well as the complex pathophysiology of AD.MethodsWe studied PVS in centrum semiovale (CSO) and basal ganglia (BG) computationally over three to four annual visits in 503 participants (255 females; meanage = 70.78 ± 5.78) of the ongoing observational multicentre “DZNE Longitudinal Cognitive Impairment and Dementia Study” (DELCODE) cohort. We analysed data from subjects who were cognitively unimpaired (n = 401), had amnestic mild cognitive impairment (n = 71), or had AD (n = 31). We used linear mixed-effects modelling to test for changes of PVS volumes in relation to cross-sectional and longitudinal age, as well as sex, years of education, hypertension, white matter hyperintensities, AD diagnosis, and cerebrospinal-fluid-derived amyloid (A) and tau (T) status (available for 46.71%; A-T-/A + T-/A + T + n = 143/48/39).ResultsPVS volumes increased significantly over follow-ups (CSO: B = 0.03 [0.02, 0.05], p < 0.001; BG: B = 0.05 [0.03, 0.07], p < 0.001). PVS enlargement rates varied substantially across subjects and depended on the participant’s age, white matter hyperintensities volumes, and amyloid and tau status. PVS volumes were higher across elderly participants, regardless of region of interest (CSO: B = 0.12 [0.02, 0.21], p = 0.017; BG: B = 0.19 [0.09, 0.28], p < 0.001). Faster BG-PVS enlargement related to lower baseline white matter hyperintensities volumes (ρspearman = -0.17, pFDR = 0.001) and was more pronounced in individuals who presented with combined amyloid and tau positivity versus negativity (A + T + > A-T-, pFDR = 0.004) or who were amyloid positive but tau negative (A + T + > A + T-, pFDR = 0.07). CSO-PVS volumes increased at a faster rate with amyloid positivity as compared to amyloid negativity (A + T-/A + T + > A-T-, pFDR = 0.021).ConclusionOur longitudinal evidence supports the relevance of PVS enlargement in presumably healthy ageing as well as in AD pathology. We further discuss the region-specific involvement of white matter hyperintensities and neurotoxic waste accumulation in PVS enlargement and the possibility of additional factors contributing to PVS progression. A comprehensive understanding of PVS dynamics could facilitate the understanding of pathological cascades and might inform targeted treatment strategies.Trial registrationGerman Clinical Trials Register DRKS00007966. Registered 04.05.2015 – retrospectively registered, https://drks.de/search/en/trial/DRKS00007966.

Head-to-head comparison of leading blood tests for Alzheimer's disease pathology.

Blood tests have the potential to improve the accuracy of Alzheimer's disease (AD) clinical diagnosis, which will enable greater access to AD-specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD-related outcomes. Plasma samples from the Alzheimer's Disease Neuroimaging Initiative were assayed with AD blood tests from C2N Diagnostics, Fujirebio Diagnostics, ALZPath, Janssen, Roche Diagnostics, and Quanterix. Outcomes measures were amyloid positron emission tomography (PET), tau PET, cortical thickness, and dementia severity. Logistic regression models assessed the classification accuracies of individual or combined plasma biomarkers for binarized outcomes, and Spearman correlations evaluated continuous relationships between individual plasma biomarkers and continuous outcomes. Measures of plasma p-tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with all AD outcomes. This study identified the plasma biomarker analytes and assays that most accurately classified amyloid pathology and other AD-related outcomes. Plasma p-tau217 measures most accurately classified amyloid and tau status. Plasma Aβ42/Aβ40 had relatively low accuracy in classification of amyloid status. Plasma p-tau217 measures had higher correlations with cortical thickness than NfL. Correlations of plasma biomarkers with dementia symptoms were relatively low.

Clinical utility of diffusion MRI-derived measures of cortical microstructure in a real-world memory clinic setting.

To investigate cortical microstructural measures from diffusion MRI as "neurodegeneration" markers that could improve prognostic accuracy in mild cognitive impairment (MCI). The prognostic power of Amyloid/Tau/Neurodegeneration (ATN) biomarkers to predict progression from MCI to AD or non-AD dementia was investigated. Ninety patients underwent clinical evaluation (follow-up interval 32 ± 18 months), lumbar puncture, and MRI. Participants were grouped by clinical stage and cerebrospinal fluid Amyloid and Tau status. T1-structural and diffusion MRI scans were analyzed to calculate diffusion metrics related to cortical columnar structure (AngleR, ParlPD, PerpPD+), cortical mean diffusivity, and fractional anisotropy. Statistical tests were corrected for multiple comparisons. Prognostic power was assessed using receiver operating characteristic (ROC) analysis and related indices. A progressive increase of whole-brain cortical diffusion values was observed along the AD continuum, with all A+ groups showing significantly higher AngleR than A-T-. Investigating clinical progression to dementia, the AT biomarkers together showed good positive predictive value (with 90.91% of MCI A+T+ converting to dementia) but poor negative predictive value (with 40% of MCI A-T- progressing to a mix of AD and non-AD dementias). Adding whole-brain AngleR as an N marker, produced good differentiation between stable and converting MCI A-T- patients (0.8 area under ROC curve) and substantially improved negative predictive value (+21.25%). Results support the clinical utility of cortical microstructure to aid prognosis, especially in A-T- patients. Further work will investigate other complexities of the real-world clinical setting, including A-T+ groups. Diffusion MRI measures of neurodegeneration may complement fluid AT markers to support clinical decision-making.

Towards cascading genetic risk in Alzheimer's disease.

Alzheimer's disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (-). Over the past decades, genome-wide association studies have implicated ∼90 different loci involved with the development of late-onset Alzheimer's disease. Here, we investigate whether genetic risk for Alzheimer's disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A-T- to A+T-, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70-4.89; P < 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84-1.42; P = 0.53). Conversely, for the transition from A+T- to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05-2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27-2.36; P < 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05-6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87-3.49; P = 0.12). The genetic risk for late-onset Alzheimer's disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimer's disease, in addition to opening therapeutic windows for targeted interventions.

Clinical predictors of Alzheimer's disease-like brain atrophy in individuals with memory complaints.

The definition and assessment methods for subjective cognitive decline (SCD) vary among studies. We aimed to investigate which features or assessment methods of SCD best predict Alzheimer's disease (AD)-related structural atrophy patterns. We assessed 104 individuals aged 55+ with memory complaints but normal cognitive screening. Our research questions were as follows: To improve the prediction of AD related morphological changes, (1) Would the use of a standardized cognitive screening scale be beneficial? (2) Is conducting a thorough neuropsychological evaluation necessary instead of relying solely on cognitive screening tests? (3) Should we apply SCD-plus research criteria, and if so, which criterion would be the most effective? (4) Is it necessary to consider medical and psychiatric comorbidities, vitamin deficiencies, vascular burden on MRI, and family history? We utilized Freesurfer to analyze cortical thickness and regional brain volume meta-scores linked to AD or predicting its development. We employed multiple linear regression models for each variable, with morphology as the dependent variable. AD-like morphology was associated with subjective complaints in males, individuals with advanced age, and higher education. Later age of onset for complaints, complaints specifically related to memory, excessive deep white matter vascular lesions, and using medications that have negative implications for cognitive health (according to the Beers criteria) were predictive of AD-related morphology. The subjective cognitive memory questionnaire scores were found to be a better predictor of reduced volumes than a single-question assessment. It is important to note that not all SCD-plus criteria were evaluated in this study, particularly the APOE genotype, amyloid, and tau status, due to resource limitations. The detection of AD-related structural changes is impacted by demographics and assessment methods. Standardizing SCD assessment methods can enhance predictive accuracy.

Donanemab in Japanese Patients with Early Alzheimer's Disease: Subpopulation Analysis of the TRAILBLAZER-ALZ 2 Randomized Trial.

Donanemab, a monoclonal antibody directed against an insoluble, modified, N-terminal truncated form of amyloid beta, demonstrated efficacy and safety in patients with early, symptomatic Alzheimer's disease (AD) in the phase 3 TRAILBLAZER-ALZ 2 trial. Here, we report clinical outcomes, biomarkers, and safety results for the Japanese subpopulation. TRAILBLAZER-ALZ 2 (N = 1736) was conducted in eight countries, including Japan (enrollment June 2020-November 2021; database lock April 2023). Participants (60-85years) with early, symptomatic AD (mild cognitive impairment/mild dementia), Mini-Mental State Examination score 20-28, and confirmed amyloid and tau pathology were randomized 1:1 (stratified by tau status) to intravenous donanemab (700mg for three doses, then 1400mg/dose) or placebo every 4weeks for 72weeks. Primary outcome was change from baseline to week 76 in integrated Alzheimer's Disease Rating Scale (iADRS) score. Other outcomes included clinical measures of cognitive and functional impairment, biomarkers, and safety. Of 88 Japanese participants (43 placebo, 45 donanemab), 7 in each group discontinued. Least-squares mean (LSM) change from baseline in iADRS score at week 76 was smaller with donanemab than with placebo in the combined (low-medium tau and high tau) and low-medium tau (N = 76) subpopulations (LSM change difference: 4.43 and 3.99, representing 38.8% and 40.2% slowing of disease progression, respectively). Slowing of AD progression with donanemab was also observed for other clinical outcomes. Marked decreases in amyloid plaque and plasma phosphorylated tau 217 were observed; amyloid clearance (< 24.1 Centiloids) was observed in 83.3% of the combined donanemab and 0% of the combined placebo groups. Amyloid-related imaging abnormalities of edema/effusions occurred in ten (22.2%) donanemab-treated participants (one [2.2%] symptomatic) and one (2.3%) placebo-treated participant. The overall efficacy and safety of donanemab in Japanese participants were similar to the global TRAILBLAZER-ALZ 2 population. ClinicalTrials.gov identifier: NCT04437511.

Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests. To determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid β (Aβ) and longitudinal change across 3 selected cohorts. This cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017-August 2021) and Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (visits February 2007-November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009-November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023. Magnetic resonance imaging, Aβ positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (Aβ42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay). Accuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status. The study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated Aβ (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal Aβ pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in Aβ-positive individuals, with the highest increase observed in those with tau positivity. This study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.

A comparison of visual assessment and semi-quantification for the diagnostic and prognostic use of [18F]flortaucipir PET in a memory clinic cohort

Purpose[18F]Flortaucipir PET is a powerful diagnostic and prognostic tool for Alzheimer’s disease (AD). Tau status definition is mainly based in the literature on semi-quantitative measures while in clinical settings visual assessment is usually preferred. We compared visual assessment with established semi-quantitative measures to classify subjects and predict the risk of cognitive decline in a memory clinic population.MethodsWe included 245 individuals from the Geneva Memory Clinic who underwent [18F]flortaucipir PET. Amyloid status was available for 207 individuals and clinical follow-up for 135. All scans were blindly evaluated by three independent raters who visually classified the scans according to Braak stages.Standardized uptake value ratio (SUVR) values were obtained from a global meta-ROI to define tau positivity, and the Simplified Temporo-Occipital Classification (STOC) was applied to obtain semi-quantitatively tau stages. The agreement between measures was tested using Cohen’s kappa (k). ROC analysis and linear mixed-effects models were applied to test the diagnostic and prognostic values of tau status and stages obtained with the visual and semi-quantitative approaches.ResultsWe found good inter-rater reliability in the visual interpretation of tau Braak stages, independently from the rater’s expertise (k>0.68, p<0.01). A good agreement was equally found between visual and SUVR-based classifications for tau status (k=0.67, p<0.01). All tau-assessment modalities significantly discriminated amyloid-positive MCI and demented subjects from others (AUC>0.80) and amyloid-positive from negative subjects (AUC>0.85). Linear mixed-effect models showed that tau-positive individuals presented a significantly faster cognitive decline than the tau-negative group (p<0.01), independently from the classification method.ConclusionOur results show that visual assessment is reliable for defining tau status and stages in a memory clinic population. The high inter-rater reliability, the substantial agreement, and the similar diagnostic and prognostic performance of visual rating and semi-quantitative methods demonstrate that [18F]flortaucipir PET can be robustly assessed visually in clinical practice.

Plasma Biomarker Strategy for Selecting Patients With Alzheimer Disease for Antiamyloid Immunotherapies

Antiamyloid immunotherapies against Alzheimer disease (AD) are emerging. Scalable, cost-effective tools will be needed to identify amyloid β (Aβ)-positive patients without an advanced stage of tau pathology who are most likely to benefit from these therapies. Blood-based biomarkers might reduce the need to use cerebrospinal fluid (CSF) or positron emission tomography (PET) for this. To evaluate plasma biomarkers for identifying Aβ positivity and stage of tau accumulation. The cohort study (BioFINDER-2) was a prospective memory-clinic and population-based study. Participants with cognitive concerns were recruited from 2017 to 2022 and divided into a training set (80% of the data) and test set (20%). Baseline values for plasma phosphorylated tau 181 (p-tau181), p-tau217, p-tau231, N-terminal tau, glial fibrillary acidic protein, and neurofilament light chain. Performance to classify participants by Aβ status (defined by Aβ-PET or CSF Aβ42/40) and tau status (tau PET). Number of hypothetically saved PET scans in a plasma biomarker-guided workflow. Of a total 912 participants, there were 499 males (54.7%) and 413 females (45.3%), and the mean (SD) age was 71.1 (8.49) years. Among the biomarkers, plasma p-tau217 was most strongly associated with Aβ positivity (test-set area under the receiver operating characteristic curve [AUC] = 0.94; 95% CI, 0.90-0.97). A 2-cut-point procedure was evaluated, where only participants with ambiguous plasma p-tau217 values (17.1% of the participants in the test set) underwent CSF or PET to assign definitive Aβ status. This procedure had an overall sensitivity of 0.94 (95% CI, 0.90-0.98) and a specificity of 0.86 (95% CI, 0.77-0.95). Next, plasma biomarkers were used to differentiate low-intermediate vs high tau-PET load among Aβ-positive participants. Plasma p-tau217 again performed best, with the test AUC = 0.92 (95% CI, 0.86-0.97), without significant improvement when adding any of the other plasma biomarkers. At a false-negative rate less than 10%, the use of plasma p-tau217 could avoid 56.9% of tau-PET scans needed to identify high tau PET among Aβ-positive participants. The results were validated in an independent cohort (n = 118). This study found that algorithms using plasma p-tau217 can accurately identify most Aβ-positive individuals, including those likely to have a high tau load who would require confirmatory tau-PET imaging. Plasma p-tau217 measurements may substantially reduce the number of invasive and costly confirmatory tests required to identify individuals who would likely benefit from antiamyloid therapies.

A multicenter validation study on the diagnostic and prognostic value of CSF Neurogranin and BACE1

AbstractBackgroundCerebrospinal fluid (CSF) biomarkers have immense diagnostic and prognostic potential for Alzheimer disease (AD). Currently, AD is still mostly diagnosed relatively late in the disease process, sometimes even years after the initial manifestation of cognitive symptoms. Disease‐modifying treatments should be most effective in the earliest stages, before amyloid plaques and neurodegeneration become prevalent. Thus, further identification of biomarkers is required that can detect AD in the predementia stage. This study aimed to assess the clinical utility of synaptic proteins neurogranin and beta‐secretase 1 (BACE1) in the diagnosis and prognosis of AD.MethodWe enrolled 530 participants from DELCODE, a multicenter prospective cohort study, including healthy controls (HC), subjective cognitive decline (SCD) subjects, mild cognitive impairment (MCI) subjects, mild AD dementia and first‐degree relatives of AD patients. Based on amyloid and tau status, we divided the participants into four groups: A−T−; A−T+; A+T−; A+T+. Neurogranin and BACE1 levels across groups were assessed by ANCOVA after adjusted for age and sex. To test the correlation of the biomarkers to cognitive performance, we used linear mixed models to model baseline biomarker levels and 7 years longitudinal MMSE and PACC5 scores.ResultRegardless of amyloid status, CSF neurogranin and BACE1 levels were significantly higher in T+ group compared with T‐ (all p &lt; 0.0001). Furthermore, for participants with negative tau status, neurogranin and BACE1 levels were lower in A+ group compared with A‐ (both p &lt; 0.0001). After adjusting for covariates (Age, Sex, Education, APOEε4), linear mixed‐effect models indicated that higher neurogranin predicts faster decline in MMSE (β = ‐0.14, p &lt; 0.01) and PACC5 (β = ‐0.03, p &lt; 0.05) over 7 years.ConclusionThis study reveals that neurogranin and BACE1 could offer insight into identifying patients at early stages of AD and improve prediction of cognitive decline.

Proteomics Analysis Identifying New Markers Related to Alzheimer’s Disease Pathology In Vivo

AbstractBackgroundTo better understand the pathophysiological processes in Alzheimer’s disease (AD), we need to broaden our knowledge on molecular pathways and discover molecular markers that co‐occur with, precipitate and follow the accumulation beta‐amyloid (Aβ) and tau pathology. Using high‐throughput proteomics, we investigated how a wide array of proteins relate to AD pathology in a large cohort spanning the AD continuum.MethodWe included 949 BioFINDER‐2 participants with cerebrospinal fluid (CSF) measurements of 2943 proteins (Olink Explore 3072 assay), and CSF and/or PET measurements of Aβ and tau. We compared CSF proteins between groups based on their Aβ (A) and tau (T) status, defined respectively from CSF Aβ42/40 ratio and tau‐PET RO948 in the temporal meta‐ROI (i.e. A‐T‐ vs. A+T‐ and A+T‐ vs. A+T+). We also compared A+T+ vs. non‐AD neurodegenerative diseases. Then, among the significant proteins identified across all three comparisons, we evaluated their associations with Aβ‐ (flutemetamol) and tau‐PET, both cross‐sectionally and longitudinally (based on rate of change). These latter analyses were restricted to cognitively unimpaired and patients with MCI, who all had Aβ‐ and tau‐PET available (n = 548).ResultAcross all AT comparisons, 85 proteins were significantly different between groups (pFDR&lt;0.05; Fig.1). More advanced pathology was associated with higher protein levels, except ApoE levels that were decreased. The A+T‐ vs. A+T+ comparison revealed most protein differences (n = 74; Fig.1B), compared to A‐T‐ vs. A+T‐ or A+T+ vs. non‐AD neurodegenerative diseases. In cross‐sectional analyses, 32/85 proteins (38%) were significantly associated with Aβ‐ and tau‐PET load, with the strongest ones being microtubule‐associated protein tau (MAPT), neurogranin (NRGN), ITGAM, ITGB2 and SMOC1. When putting both pathologies in the same model, all proteins remained associated with Aβ only, except for ENO2 and GPI, which remained associated with tau only (Table 1). In longitudinal analyses, 19 proteins were associated with greater tau‐PET rate of change (the top five being MAPT, NRGN, ITGB2, FABP3 and CHIT1), whereas only SMOC1 and ITGAM were associated with greater Aβ‐PET rate of change (Table 1).ConclusionThrough comprehensive proteomics analysis, we identified novel proteins associated with AD pathology, many of which are involved innate immunity, intracellular transport and extracellular matrix binding.

Longitudinal Locus Coeruleus Imaging across the Alzheimer’s Spectrum

AbstractBackgroundNoradrenergic neurons of the locus coeruleus (LC) may play a critical role in the pathophysiology of Alzheimer’s Disease (AD). LC imaging with MRI is a promising in vivo method to study the role of this system in AD. Here we investigate longitudinal change in LC integrity across the AD spectrum.MethodThis study included 291 participants from the TRIAD cohort at the McGill Research Center for Studies in Aging (cognitively normal: n = 166, mild cognitive impairment: n = 79, AD: n = 46). Follow‐up data was available for 123 participants. All participants underwent MR imaging including a turbo spin echo (TSE) sequence for LC imaging, tau positron emission tomography (using [18F]MK6240), and clinical and cognitive assessment including the Mini Mental State Exam (MMSE). LC signal contrast was assessed relative to a pontine reference region. Linear regression analyses related LC signal to clinical measures.ResultConsistent with prior work in an earlier version of this sample, at baseline, LC signal was reduced in tau positive participants (t(285) = ‐4.56, p&lt;0.0001) and negatively correlated to AD severity (Braak stage: t(253) = ‐4.79, p&lt;0.0001; MMSE score: t(254) = 4.30, p&lt;0.0001). There was no significant change in LC signal over time (t(122) = 1.36, p = 0.18) and no significant impact of tau status on LC change (t(119) = 0.39, p = 0.70). Counterintuitively, there was evidence of increasing LC signal in the most severe participants, as those with low MMSE score (&lt;27) showed a significant signal increase over time (t(16) = 2.16, p = 0.046). Moreover, increasing LC signal in tau positive participants was correlated to reduction in MMSE performance over time (t(35) = ‐2.13, p = 0.040). In contrast, tau negative participants showed the opposite trend (t(52) = 1.97, p = 0.054).ConclusionWhile cross‐sectional analyses found the expected negative correlation between LC signal and AD severity, longitudinal analyses obtained the surprising result that increasing signal correlated to worsening AD severity. This finding could suggest that the LC imaging sequence used (TSE) may imperfectly capture LC degeneration and signal increases could be driven by other factors occuring simultaneously with LC degeneration (perhaps elevated neuromelanin or tau deposition). Future work could determine if different types of LC sequence (TSE versus magnetization transfer) differ in their ability to capture degeneration and provide complementary information.

Plasma ALZpath p‐tau217 for the identification of amyloid and tau positivity

AbstractBackgroundIn the last 5 years, immunoassays for the quantification of phosphorylated tau (p‐tau) in blood have proven to accurately identify Alzheimer’s disease (AD) pathology with important implications for primary care management and therapeutic trials. Comparisons of p‐tau epitopes (p‐tau181, p‐tau217, p‐tau231) show small differences in diagnostic accuracy, however, often p‐tau217 is preferred, citing its larger fold‐change in symptomatic patients and lower rate of false positives in amyloid‐negative individuals. This study describes the performance of a novel Single molecule array (Simoa) for p‐tau217 (p‐tau217ALZpath)MethodWe included 355 participants from Translational Biomarkers in Aging and Dementia (TRIAD) participants, which was representative of the AD continuum. Further, 425 cognitively unimpaired individuals, with longitudinal plasma measures (≤8 years), were included from Wisconsin Registry for Alzheimer’s Prevention (WRAP). All plasma samples were measured for ALZpath p‐tau217ALZpath, a validated Simoa assay at the University of Gothenburg, Sweden. In TRIAD, amyloid positivity (A+) was defined as [18F]AZD‐4694 SUVR &gt;1.5 or CSF Aβ42/40 &lt;0.068. In WRAP, A+ was defined by [11C]PiB &gt;1.16. 18F‐MK‐6240 determined tau status (T+) both cohorts (TRIAD, &gt;1.24 SUVR; WRAP, &gt;1.3).ResultIn TRIAD, p‐tau217ALZpath determined A+ (AUC = 0.957, 0.935‐978) and T+ (AUC = 0.952, 0.929–0.976) individuals with high accuracy. A sensitivity analysis, including only participants with imaging (amyloid and tau) and CSF biomarkers (p‐tau181, p‐tau205, p‐tau217, Aβ42/40), p‐tau217ALZpath demonstrated equivalent accuracies in determining A+ (Figure 1A) and T+ (Figure 1B) than these high‐performing modalities. In addition, plasma p‐tau217AlzPATH demonstrated a good accuracy to identify T+ from all A+ participants (AUC = 0.839, 0.767‐910). Concentration cut‐points derived in WRAP to identify A+ (&gt;0.676 pg/mL; PPV = 87.2%) and A– (&lt;0.235 pg/mL; NPV = 98.2%) were directly tested in TRIAD with high accuracy (&gt;0.676 pg/mL, PPV = 98.8%; &lt;0.235 pg/mL, NPV = 95.1%. In WRAP, longitudinal analysis (Figure 2) demonstrated that over 8‐years, p‐tau217AlzPATH increased only in A+ individuals and more steeply in A+T+ participants (βestimate = 0.1 pg/mL per year; P&lt;0.0001) compared to A+T‐ (βestimate = 0.022 pg/mL per year, P = 0.0008).ConclusionThe novel p‐tau217ALZpath immunoassay demonstrates high accuracy to determine amyloid and tau pathology across all stages of AD continuum. Clinical cut‐points to identify A+ or A– with high PPV and NPV are directly transferable across cohorts.

Longitudinal Locus Coeruleus Imaging across the Alzheimer’s Spectrum

AbstractBackgroundNoradrenergic neurons of the locus coeruleus (LC) may play a critical role in the pathophysiology of Alzheimer’s Disease (AD). LC imaging with MRI is a promising in vivo method to study the role of this system in AD. Here we investigate longitudinal change in LC integrity across the AD spectrum.MethodThis study included 291 participants from the TRIAD cohort at the McGill Research Center for Studies in Aging (cognitively normal: n = 166, mild cognitive impairment: n = 79, AD: n = 46). Follow‐up data was available for 123 participants. All participants underwent MR imaging including a turbo spin echo (TSE) sequence for LC imaging, tau positron emission tomography (using [18F]MK6240), and clinical and cognitive assessment including the Mini Mental State Exam (MMSE). LC signal contrast was assessed relative to a pontine reference region. Linear regression analyses related LC signal to clinical measures.ResultConsistent with prior work in an earlier version of this sample, at baseline, LC signal was reduced in tau positive participants (t(285) = ‐4.56, p&lt;0.0001) and negatively correlated to AD severity (Braak stage: t(253) = ‐4.79, p&lt;0.0001; MMSE score: t(254) = 4.30, p&lt;0.0001). There was no significant change in LC signal over time (t(122) = 1.36, p = 0.18) and no significant impact of tau status on LC change (t(119) = 0.39, p = 0.70). Counterintuitively, there was evidence of increasing LC signal in the most severe participants, as those with low MMSE score (&lt;27) showed a significant signal increase over time (t(16) = 2.16, p = 0.046). Moreover, increasing LC signal in tau positive participants was correlated to reduction in MMSE performance over time (t(35) = ‐2.13, p = 0.040). In contrast, tau negative participants showed the opposite trend (t(52) = 1.97, p = 0.054).ConclusionWhile cross‐sectional analyses found the expected negative correlation between LC signal and AD severity, longitudinal analyses obtained the surprising result that increasing signal correlated to worsening AD severity. This finding could suggest that the LC imaging sequence used (TSE) may imperfectly capture LC degeneration and signal increases could be driven by other factors occuring simultaneously with LC degeneration (perhaps elevated neuromelanin or tau deposition). Future work could determine if different types of LC sequence (TSE versus magnetization transfer) differ in their ability to capture degeneration and provide complementary information.

Perfusion Imaging and Inflammation Biomarkers Provide Complementary Information in Alzheimer's Disease.

Single photon emission tomography (SPECT) can detect early changes in brain perfusion to support the diagnosis of dementia. Inflammation is a driver for dementia progression and measures of inflammation may further support dementia diagnosis. In this study, we assessed whether combining imaging with markers of inflammation improves prediction of the likelihood of Alzheimer's disease (AD). We analyzed 91 participants datasets (Institutional Ethics Approval 20/NW/0222). AD biomarkers and markers of inflammation were measured in cerebrospinal fluid. Statistical parametric mapping was used to quantify brain perfusion differences in perfusion SPECT images. Logistic regression models were trained to evaluate the ability of imaging and inflammation markers, both individually and combined, to predict AD. Regional perfusion reduction in the precuneus and medial temporal regions predicted Aβ42 status. Increase in inflammation markers predicted tau and neurodegeneration. Matrix metalloproteneinase-10, a marker of blood-brain barrier regulation, was associated with perfusion reduction in the right temporal lobe. Adenosine deaminase, an enzyme involved in sleep homeostasis and inflammation, was the strongest predictor of neurodegeneration with an odds ratio of 10.3. The area under the receiver operator characteristic curve for the logistic regression model was 0.76 for imaging and 0.76 for inflammation. Combining inflammation and imaging markers yielded an area under the curve of 0.85. Study results showed that markers of brain perfusion imaging and markers of inflammation provide complementary information in AD evaluation. Inflammation markers better predict tau status while perfusion imaging measures represent amyloid status. Combining imaging and inflammation improves AD prediction.

Symposium 04: Innovative Ways of Applying Digital Technology in Neuropsychology - A Sneak Peak into the Future

Summary Abstract:The explosion of digital technology in the past decade has led to unprecedented possibilities towards improving cognitive assessment and understanding brain health. Digital technology encompasses using a multitude of devices, such as laptops, smartphones, etc, to collect health-related data. The settings can be varied to include in-clinic, remote/virtual, or a combination of hybrid models for data collection. Data can be collected at a single time point or over a continued period of time. Furthermore, the unique combination of devices used, settings, and methods of collecting digital data can become even more exclusive against the backdrop of the 'purpose’ for conducting the digital study. This symposium, consisting of four abstracts, brings together the unique combination of digital studies with exclusive devices, methodologies, settings, and purposes. The topics range from how smartphone-based assessments can be applied to understand the interaction between day-to-day variability in sleep and cognition, to the use of computerized testing to investigate the associations between cognitive performance and markers of brain pathology (e.g. amyloid and tau status), to understanding cognition from an open-source smartphone application to passively and continuously capture sensor data including global positioning system trajectories, to the development and validation of an online simulated money management credit card task, and to determining the effects of cognitive rehabilitation via digital technology on cognition, neuropsychiatric symptoms, and memory strategies.

Criterion Validation of Tau PET Staging Schemes in Relation to Cognitive Outcomes.

Utilization of NIA-AA Research Framework requires dichotomization of tau pathology. However, due to the novelty of tau-PET imaging, there is no consensus on methods to categorize scans into "positive" or "negative" (T+ or T-). In response, some tau topographical pathologic staging schemes have been developed. The aim of the current study is to establish criterion validity to support these recently-developed staging schemes. Tau-PET data from 465 participants from the Alzheimer's Disease Neuroimaging Initiative (aged 55 to 90) were classified as T+ or T- using decision rules for the Temporal-Occipital Classification (TOC), Simplified TOC (STOC), and Lobar Classification (LC) tau pathologic schemes of Schwarz, and Chen staging scheme. Subsequent dichotomization was analyzed in comparison to memory and learning slope performances, and diagnostic accuracy using actuarial diagnostic methods. Tau positivity was associated with worse cognitive performance across all staging schemes. Cognitive measures were nearly all categorized as having "fair" sensitivity at classifying tau status using TOC, STOC, and LC schemes. Results were comparable between Schwarz schemes, though ease of use and better data fit preferred the STOC and LC schemes. While some evidence was supportive for Chen's scheme, validity lagged behind others-likely due to elevated false positive rates. Tau-PET staging schemes appear to be valuable for Alzheimer's disease diagnosis, tracking, and screening for clinical trials. Their validation provides support as options for tau pathologic dichotomization, as necessary for use of NIA-AA Research Framework. Future research should consider other staging schemes and validation with other outcome benchmarks.

Biostatistical Estimation of Tau Threshold Hallmarks (BETTH) Algorithm for Human Tau PET Imaging Studies.

A methodology for determining tau PET thresholds is needed to confidently detect early tau deposition. We compared multiple threshold-determining methods in participants who underwent either 18F-flortaucipir or 18F-MK-6240 PET scans. Methods: 18F-flortaucipir (n = 798) and 18F-MK-6240 (n = 216) scans were processed and sampled to obtain regional SUV ratios. Subsamples of the cohorts were based on participant diagnosis, age, amyloid-β status (positive or negative), and neurodegeneration status (positive or negative), creating older-adult (age ≥ 55 y) cognitively unimpaired (amyloid-β-negative, neurodegeneration-negative) and cognitively impaired (mild cognitive impairment/Alzheimer disease, amyloid-β-positive, neurodegeneration-positive) groups, and then were further subsampled via matching to reduce significant differences in diagnostic prevalence, age, and Mini-Mental State Examination score. We used the biostatistical estimation of tau threshold hallmarks (BETTH) algorithm to determine sensitivity and specificity in 6 composite regions. Results: Parametric double receiver operating characteristic analysis yielded the greatest joint sensitivity in 5 of the 6 regions, whereas hierarchic clustering, gaussian mixture modeling, and k-means clustering all yielded perfect joint specificity (2.00) in all regions. Conclusion: When 18F-flortaucipir and 18F-MK-6240 are used, Alzheimer disease-related tau status is best assessed using 2 thresholds, a sensitivity one based on parametric double receiver operating characteristic analysis and a specificity one based on gaussian mixture modeling, delimiting an uncertainty zone indicating participants who may require further evaluation.

Structural Network Topology Reveals Higher Brain Resilience in Individuals with Preclinical Alzheimer's Disease.

Introduction: The diagnosis of Alzheimer's disease (AD) requires the presence of amyloid and tau pathology, but it remains unclear how they affect the structural network in the pre-clinical stage. We aimed to assess differences in topological properties in cognitively normal (CN) individuals with varying levels of amyloid and tau pathology, as well as their association with AD pathology burden. Methods: A total of 68 CN individuals were included and stratified by normal/abnormal (-/+) amyloid (A) and tau (T) status based on positron emission tomography results, yielding three groups: A-T- (n = 19), A+T- (n = 28), and A+T+ (n = 21). Topological properties were measured from structural connectivity. Group differences and correlations with A and T were evaluated. Results: Compared with the A-T- group, the A+T+ group exhibited changes in the structural network topology. At the global level, higher assortativity was shown in the A+T+ group and was correlated with greater tau burden (r = 0.29, p = 0.02), while no difference in global efficiency was found across the three groups. At the local level, the A+T+ group showed disrupted topological properties in the left hippocampus compared with the A-T- group, characterized by lower local efficiency (p < 0.01) and a lower clustering coefficient (p = 0.014). Conclusions: The increased linkage in the higher level architecture of the white matter network reflected by assortativity may indicate increased brain resilience in the early pathological state. Our results encourage further investigation of the topological properties of the structural network in pre-clinical AD.

Diffusion Changes in Hippocampal Cingulum in Early Biologically Defined Alzheimer's Disease.

Diagnosis of Alzheimer's disease (AD) was recently shifted from clinical to biological construct to reflect underlying neuropathological status, where amyloid deposition designated patients to the Alzheimer's continuum, and additional tau positivity represented AD. To investigate white matter (WM) alteration in the brain of patients in the Alzheimer's continuum. A total of 236 subjects across the clinical and biological spectra of AD were included and stratified by normal/abnormal (-/+) amyloid (A) and tau (T) status based on positron emission tomography results, yielding five groups: A-T-cognitively normal (CN), A+T-CN, A+T+ CN, A+T+ mild cognitive impairment, and A+T+ AD. WM alteration was measured by diffusion tensor imaging (DTI). Group differences, correlation of DTI measures with amyloid and tau, and diagnostic performance of such measures were evaluated. Compared with A-T-CN, widespread WM alteration was observed in the Alzheimer's continuum, including hippocampal cingulum (CGH), cingulum of the cingulate gyrus, and uncinate fasciculus. Diffusion changes measured by regional mean fractional anisotropy (FA) in the bilateral CGH were first detected in the A+T+ CN group and associated with tau burden in the Alzheimer's continuum (p < 0.001). For discrimination between A+T+ CN and A-T-CN groups, CGH FA achieved accuracy, sensitivity, and specificity of 74%, 58%, and 78% for right CGH and 57%, 83%, and 47% respectively for left CGH. WM alteration is widespread in the Alzheimer's continuum. Diffusion alteration in CGH occurred early and was correlated with tau pathology, thus may be a promising biomarker in preclinical AD.