Background
Following the rapid spread of the COVID‐19 virus throughout Quebec, the TRIAD cohort, a longitudinal observational study, evaluated the effects of COVID‐19 on it’s aging and vulnerable ...population and their caregivers. This study aims at investigating the behavioural and psychological effects of COVID‐19 and social isolation on the aging population. The TRIAD Assessment of Social Isolation and Cognition (TASIC) was developed to assess these effects on participants of observational trials.
Method
Pre‐pandemic data including, demographical information, Clinical Dementia Rating (CDR), Mini‐Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Montreal Cognitive Assessment (MoCA) and a Social Support Questionnaire, were collected during in‐person visits and take‐home questionnaires. Following the onset of COVID‐19, TASIC was created to include additional COVID‐19 specific scales developed by Dr. Rosa‐Neto and Dr. King that include Knowledge of COVID‐19 scale, the Montreal Assessment of Stress related to COVID‐19 (MASC), as well as the Impact of Events Scale (IESR), the Peritraumatic Distress Inventory (PDI), the Peritraumatic Dissociative Experiences Questionnaire (PDEQ) for COVID‐19. Assessments were conducted via telephone interviews with TRIAD participants (n=292) and their informants (n=243) by eight trained research assistants from April through June 2020. All participants enrolled in previous TRIAD studies, deemed eligible through detailed screening criteria were contacted.
Result
As a result of this study, and previous work done by the cohort, a culmination of information is available, with 90% of TRIAD participants having completed the COVID‐19 study also having plasma collected. 80% of participants from the COVID‐19 study have PET imaging using 18FAZD4694 and 18FMK6240 and MRI sequencing.
Conclusion
The COVID‐19 study conducted by TRIAD provides a unique opportunity to understand the effects of a global pandemic on our aging population as well as caregiver burden. This data, in conjunction with other measures available in the cohort, can make important strides in finding ways to help, and better understand those most impacted by the crisis.
Background
Individuals with cognitive/memory impairments may be more vulnerable to COVID19 due to having poor knowledge of COVID19 and how to protect themselves under current policies. Here, we aimed ...to show cognitive/memory impairment is associated with less knowledge or less anxiety change related to COVID19. We hypothesized that the effect of hippocampal volume on COVID19‐related knowledge or anxiety change during the pandemic is mediated by cognitive health.
Method
A total of 247 participants (162 cognitively normal (CN) and 85 cognitively impaired (CI)) from the Montreal TRIAD cohort underwent a structural MRI and cognition and anxiety assessments using CDRSOB and GAD score, respectively before the COVID19 pandemic. During the first wave of COVID19, the participants were assessed for anxiety using GAD score and knowledge related to COVID19. Hippocampal volume was measured using Freesurfer, and the anxiety was evaluated as the rate of change in the GAD score: (follow‐up – baseline)/time difference. Then, the effect of hippocampal volume on the rate of change in the anxiety or knowledge on COVID19 was evaluated based on a mediation analysis with CDRSOB as a mediator, 2000 bootstrapping, and age, sex, education, and APOEe4 as covariates.
Result
The CI group showed significantly less knowledge of COVID19, or less anxiety change compared to the CN group, while hippocampal volume showed a significant association with knowledge of COVID19 or the rate of change in anxiety. Upon further examination, we revealed that the effect of hippocampal volume on COVID19 knowledge or the rate of change in anxiety was significantly mediated by cognitive health, indicated by CDRSOB (Figure 1).
Conclusion
Our finding highlights the poorer knowledge of COVID19 and related risks in individuals with cognitive/memory impairments; the CDRSOB, indicative of cognitive health, significantly mediated the effect of hippocampal volume on the rate of change in anxiety or knowledge on COVID19 in our cohort. This study urges for a more effective strategy and policy about informing and educating the individual with cognitive/memory impairment on COVID19 and related risks.
Background
Tau is usually assessed through cerebrospinal fluid or Positron Emission Tomography (PET). However, those methods are expensive and not readily available. Research is now focusing on ...cost‐effective blood‐based biomarkers to assess Alzheimer’s disease (AD) pathophysiologies. A novel immunoassay for plasma pTau181 has been created, and even though there are strong associations between plasma pTau181 and PET, no study has yet investigated which cortical area better reflects plasma tau.
Method
We assessed 269 individuals from the TRIAD cohort (164 CU, 60 MCI and 45 AD) that underwent plasma pTau181 assessment, 18FMK6240 tau‐PET scan, 18FAZD4694 amyloid‐PET scan to assess their amyloid‐b (Ab) status, an MRI and a neuropsychological evaluation. We conducted statistical analyses using R, first to calculate the threshold values for positivity in both tau assessing methods and to make comparisons between the groups. SUVR values for 18FMK6240 were either based on Braak1 SUVR or temporal meta‐ROI SUVR.
Result
Using Receiver Operating Characteristic (ROC) curves, we established that the cut‐off for positivity for plasma pTau181 was 11.1060 pg/mL. When using Braak1 mask, the cut‐off for positivity was 1.040 SUVR (B1+/‐), while with temporal meta‐ROI it was 1.1827 (TMR+/‐). In both cases, we observed a majority of concordant individuals. However, we obtained 87 discordant individuals in the plasma/TMR, mostly plasma+/TMR‐, and 78 in the plasma/B1 analyses, mostly plasma‐/B1+ (Figure 1). Concomitant status of plasma/TMR was usually accompanied by a similar Ab status. However, in the Braak1 analyses, Ab status seemed to closely follow the PET status (Figure 2).
Conclusion
The cut‐off values for positivity using Braak1 mask is significantly smaller than when using temporal meta‐ROI. Using the temporal meta‐ROI mask, we had more discrepant individuals that were plasma+/TMR‐, with plasma‐/TMR+ individuals close to the threshold values. It was accurate at predicting negative biomarker statuses in CU participants, and positive in AD participants. Conversely, we had more plasma‐/B1+ individuals when using Braak1 mask, with values more spread around the plot. Due to low threshold values, portion of CU and MCI individuals were categorized as positive to both biomarkers. Finally, B1 status seemed to follow closely the Ab levels. Plasma pTau181 thus seems to reflect better temporal meta‐ROI tau.
Background
Assessments of tau usually come from cerebrospinal fluid or Positron Emission Tomography (PET). However, those methods are expensive and not readily available. Current research is focusing ...on cost‐effective blood‐based biomarkers, and a novel immunoassay for plasma pTau181 has been created. Even though there are strong associations between plasma pTau181 and PET, no study has yet investigated whether plasma pTau181 can be used to detect early AD‐pathology. Does the status of plasma pTau181 always correlate with tau‐PET status?
Method
We assessed 269 individuals from the TRIAD cohort (164 CU, 60 MCI and 45 AD) that underwent plasma pTau181 assessment, 18FMK6240 tau‐PET scan, 18FAZD4694 amyloid‐PET scan to assess their amyloid status, an MRI and a neuropsychological evaluation. We conducted statistical analyses using R, first to calculate the threshold values for positivity in both tau assessing methods and to make comparisons between the groups. For tau‐PET, we used 18FMK6240 SUVR in the temporal meta‐ROI.
Result
Using Receiver Operating Characteristic (ROC) curves, we established that the cut‐off for positivity for plasma pTau181 was 11.1060 pg/mL, while for tau‐PET, it was 1.1827 SUVR. 182 individuals had concordant statuses for both plasma pTau181 and tau‐PET, while 87 were discrepant. 64 were plasma+/PET‐, with a majority cognitively unimpaired (CU) and 23 were plasma‐/PET+, with values close to the thresholds, and mostly MCI or AD (Figure1). Moreover, concomitant plasma/PET statuses were usually accompanied by a similar Ab status (Figure2). CU Ab+ individuals were found in high proportion in the plasma+/PET‐ group (Figure3).
Conclusion
Most of the participants had concordant statuses for plasma pTau181 and tau‐PET, which correlate well with memory scores and diagnoses. However, there was a significant portion of discordant individuals, which were predominantly plasma+/PET‐. This corroborates findings from comparisons between CSF pTau181 and tau‐PET, with CSF positivity coming before PET. Plasma pTau181 is also a great tool to assess Ab status, even before the onset of tau‐PET abnormalities. Assessing tau through plasma or PET is thought to suggest different stages of pathological progression.
Introduction Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very ...early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears. Methods We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta (formula omitted) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages. Results 14-3-3 formula omitted was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 formula omitted correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss. Conclusions Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation. Keywords: Alzheimer's disease, sTREM2, Microglia, Neuroinflammation, Synaptic loss
Abstract
Introduction
Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer’s disease (AD). However, synaptic damage happens early in AD at ...the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears.
Methods
We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta (
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) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages.
Results
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was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3
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correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss.
Conclusions
Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation.
INTRODUCTION
We set out to identify tau PET‐positive (A+T+) individuals among amyloid‐beta (Aβ) positive participants using plasma biomarkers.
METHODS
In this cross‐sectional study we assessed 234 ...participants across the AD continuum who were evaluated by amyloid PET with 18FAZD4694 and tau‐PET with 18FMK6240 and measured plasma levels of total tau, pTau‐181, pTau‐217, pTau‐231, and N‐terminal tau (NTA‐tau). We evaluated the performances of plasma biomarkers to predict tau positivity in Aβ+ individuals.
RESULTS
Highest associations with tau positivity in Aβ+ individuals were found for plasma pTau‐217 (AUC CI95% = 0.89 0.82, 0.96) and NTA‐tau (AUC CI95% = 0.88 0.91, 0.95). Combining pTau‐217 and NTA‐tau resulted in the strongest agreement (Cohen's Kappa = 0.74, CI95% = 0.57/0.90, sensitivity = 92%, specificity = 81%) with PET for classifying tau positivity.
DISCUSSION
The potential for identifying tau accumulation in later Braak stages will be useful for patient stratification and prognostication in treatment trials and in clinical practice.
Highlights
We found that in a cohort without pre‐selection pTau‐181, pTau‐217, and NTA‐tau showed the highest association with tau PET positivity.
We found that in Aβ+ individuals pTau‐217 and NTA‐tau showed the highest association with tau PET positivity.
Combining pTau‐217 and NTA‐tau resulted in the strongest agreement with the tau PET‐based classification.
Background
Astrocyte reactivity is a common finding in individuals across the Alzheimer’s disease (AD) continuum. Recently, we demonstrated that individuals with higher levels of plasma glial ...fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, present a stronger association between amyloid‐β (Aβ) and tau pathologies in preclinical AD. Because cohort studies and clinical trials show sex differences in AD biomarkers, we investigated whether the effects of astrocyte reactivity on the association between Aβ and tau differs in men and women
Method
We assessed 1,016 CU individuals from three cohorts with available Aβ (plasma/PET), plasma p‐tau181 and GFAP measures. A subset of individuals also has plasma p‐tau217 available (n = 136).Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP of younger Aβ‐ individuals.Linear regressions accounting for age and sex were used to evaluate the association between plasma p‐tau epitopes and Aβ burden.An interaction between term between Aβ*sex was also added to the models.Voxel‐wise associations between biomarkers were tested using linear regressions accounting for age, sex, and adjusting for multiple comparisons.
Result
We found that Aβ burden was associated with plasma p‐tau in Ast+ but not in Ast‐ . Men in the Ast+ group presented a much increased association between Aβ with plasma p‐tau181 (β = 0.71,p<0.0001,Fig.1a) or p‐tau217 (β = 1.23,p = 0.00086,Fig.1b) compared to women. Similarly, a significant interaction between Aβ and sex on plasma p‐tau181 (β = 0.47,p = 0.005,Fig1a) and p‐tau217 (β = 1.01,p = 0.002,Fig.1b) was observed only in the Ast+ individuals. Voxel‐wise analysis showed the differences in the topographical association between Aβ and plasma p‐tau epitopes between men and women. In men but not women, Aβ‐PET associates with plasma p‐tau181 (Fig.2) and plasma p‐tau217 (Fig.3) in important AD regions such as precuneus, posterior cingulate and orbitofrontal cortex.
Conclusion
A sex effect was observed in the association between Aβ burden and plasma p‐tau epitopes in individuals with increased astrocyte reactivity, with the association being stronger in men than women. The greater effect of Aβ on tau phosphorylation in the presence of Ast+ in men than in women may have implications for interpretation of biomarkers in clinical trials testing as anti‐Aβ therapies already showed different effects between men and women.
Background
Aβ accumulation precedes tau pathology in cognitively unimpaired (CU) individuals, which is an event closely related to the development of cognitive symptoms. However, Aβ leads to tau ...pathology in some individuals, but not in others, suggesting the presence of other processes triggering the deleterious effects of Aβ in the early Alzheimer’s disease (AD) stages. It was already demonstrated that glial fibrillary acidic protein (GFAP)‐positive astrocytes can internalize tau and might contribute to its propagation. Here we investigated whether astrocyte reactivity is a key element to determining the longitudinal accumulation and spreading of tau pathology in CU individuals.
Method
We assessed 147 CU individuals from the TRIAD cohort with available baseline Aβ‐ and Tau‐PET, plasma p‐tau181 and GFAP. Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP levels of younger Aβ‐ individuals. Longitudinal analysis included 71 CU individuals with Tau‐PET (mean follow‐up:2.3 years).Voxel‐wise associations between biomarkers were tested using linear regressions accounting for age, sex, and adjusting for multiple comparisons. We measured the annual rate of progression in Tau uptake as the difference between follow‐up and baseline uptakes divided by the time between scans. To assess individuals’ percentage of abnormal regions, we used composite brain regions corresponding to Braak histopathological stages.
Result
Tau‐PET deposition occurred as a function of Aβ burden only in CU Ast+ and in regions expected to present the earliest tau deposition (Fig.1a). In the longitudinal analysis, we observed that the annual rate of tau‐PET accumulation was higher in the CU Ast+ group (Fig.2a) and predicted by baseline Aβ burden only in CU Ast+ (Fig.2b). Interestingly, while the baseline association was confined to the mesial temporal cortex, the longitudinal tau‐PET accumulation as a function of Aβ/Ast presented initial tau spread over the neocortex in Braak III‐IV regions (Fig.2c).
Conclusion
We observed that Tau‐PET accumulation was highest in CU Ast+ individuals, with astrocyte reactivity being necessary for the spreading of tau over the neocortex. Our findings suggest that astrocyte reactivity is an important upstream event to unleash tau accumulation and spread in CU individuals, which might have implications for selecting individuals for early preventive clinical trials.
Background
Biomarkers of astrocyte reactivity have the potential to improve diagnostic precision, disease monitoring, and treatment efficacy. Glial fibrillary acidic protein (GFAP) protein is ...expressed in astrocytes, which is important to synaptic plasticity, cell communication, and reactive gliosis.
Method
Cerebrospinal fluid (CSF) biomarkers were measured in participants of the McGill TRIAD cohort. 75 individuals (>50 years old, 44 cognitively unimpaired (CU), and 31 with cognitive impairment (CI)), had available Aß and tau‐PET. We measured CSF GFAP and synaptic markers (growth‐associated protein 43 (GAP‐43), neurogranin (Ng), synaptotagmin 1 (SYT1), presynaptic protein synaptosomal‐associated protein 25 (SNAP‐25)). Linear regressions adjusted for age, sex, clinical diagnosis, and Aß/tau‐PET were used to test the associations between astrocyte reactivity and synaptic function.
Result
Demographic information is shown in Table 1. We found an association between CSF GFAP and presynaptic markers (GAP‐43: p<0.0001, ß = 0.1076; SYT1: p<0.0001, ß = 0.0024; SNAP‐25 long: p<0.0001, ß = 0.0008) as well as postsynaptic markers (Ng: p<0.05, ß = 0.0066) independently of Aß and tau burden (Figure 1).
Conclusion
Our biomarker results support experimental literature suggesting that astrocyte reactivity plays a role in downstream synaptic dysfunction independent of the brain levels of Aß and tau tangles pathologies. This supports in vitro literature suggesting that therapeutic interventions targeting astrocyte reactivity can contribute to halting AD progression.
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