Cerebrospinal fluid (CSF) tau biomarkers are reliable diagnostic markers for Alzheimer's disease (AD). However, their strong association with amyloid pathology may limit their reliability as specific ...markers of tau neurofibrillary tangles. A recent study showed evidence that a ratio of CSF C-terminally truncated tau (tau368, a tangle-enriched tau species), especially in ratio with total tau (t-tau), correlates strongly with tau PET tracer uptake. In this study, we set to evaluate the performance of the tau368/t-tau ratio in capturing tangle pathology, as indexed by a high-affinity tau PET tracer, as well as its association with severity of clinical symptoms.
In total, 125 participants were evaluated cross-sectionally from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort (21 young, 60 cognitively unimpaired CU elderly 15 Aβ+, 10 Aβ+ with mild cognitive impairment MCI, 14 AD dementia patients, and 20 Aβ- individuals with non-AD cognitive disorders). All participants underwent amyloid and tau PET scanning, with
F-AZD4694 and
F-MK6240, respectively, and had CSF measurements of p-tau181, p-tau217, and t-tau. CSF concentrations of tau368 were quantified in all individuals with an in-house single molecule array assay.
CSF tau368 concentration was not significantly different across the diagnostic groups, although a modest increase was observed in all groups as compared with healthy young individuals (all P < 0.01). In contrast, the CSF tau368/t-tau ratio was the lowest in AD dementia, being significantly lower than in CU individuals (Aβ-, P < 0.001; Aβ+, P < 0.01), as well as compared to those with non-AD cognitive disorders (P < 0.001). Notably, in individuals with symptomatic AD, tau368/t-tau correlated more strongly with
F-MK6240 PET SUVR as compared to the other CSF tau biomarkers, with increasing associations being seen in brain regions associated with more advanced disease (isocortical regions > limbic regions > transentorhinal regions). Importantly, linear regression models indicated that these associations were not confounded by Aβ PET SUVr. CSF tau368/t-tau also tended to continue to become more abnormal with higher tau burden, whereas the other biomarkers plateaued after the limbic stage. Finally, the tau368/t-tau ratio correlated more strongly with cognitive performance in individuals with symptomatic AD as compared to t-tau, p-tau217 and p-tau181.
The tau368/t-tau ratio captures novel aspects of AD pathophysiology and disease severity in comparison to established CSF tau biomarkers, as it is more closely related to tau PET SUVR and cognitive performance in the symptomatic phase of the disease.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Introduction
18FAZD4694 is an amyloid beta (Aβ) imaging agent used in several observational studies and clinical trials. However, no studies have yet published data on longitudinal Aβ ...accumulation measured with 18FAZD4694.
Methods
We assessed 146 individuals who were evaluated with 18FAZD4694 at baseline and 2‐year follow‐up. We calculated annual rates of 18FAZD4694 change for clinically defined and biomarker‐defined groups
Results
Cognitively unimpaired (CU) older adults displayed subtle 18FAZD4694 standardized uptake value ratio (SUVR) accumulation over the follow‐up period. In contrast, Aβ positive CU older adults displayed higher annual 18FAZD4694 SUVR increases. 18FAZD4694 SUVR accumulation in Aβ positive mild cognitive impairment (MCI) and dementia was modest across the neocortex
Discussion
Larger increases in 18FAZD4694 SUVR were observed in CU individuals who had abnormal amyloid positron emission tomography levels at baseline. 18FAZD4694 can be used to monitor Aβ levels in therapeutic trials as well as clinical settings, particularly prior to initiating anti‐amyloid therapies.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
IMPORTANCE: Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of individuals with Alzheimer disease (AD). However, ...it is not known whether there are differences in blood GFAP levels across the entire AD continuum and whether its performance is similar to that of CSF GFAP. OBJECTIVE: To evaluate plasma GFAP levels throughout the entire AD continuum, from preclinical AD to AD dementia, compared with CSF GFAP. DESIGN, SETTING, AND PARTICIPANTS: This observational, cross-sectional study collected data from July 29, 2014, to January 31, 2020, from 3 centers. The Translational Biomarkers in Aging and Dementia (TRIAD) cohort (Montreal, Canada) included individuals in the entire AD continuum. Results were confirmed in the Alzheimer’s and Families (ALFA+) study (Barcelona, Spain), which included individuals with preclinical AD, and the BioCogBank Paris Lariboisière cohort (Paris, France), which included individuals with symptomatic AD. MAIN OUTCOMES AND MEASURES: Plasma and CSF GFAP levels measured with a Simoa assay were the main outcome. Other measurements included levels of CSF amyloid-β 42/40 (Aβ42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like protein 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and levels of plasma p-tau181 and NfL. Results of amyloid positron emission tomography (PET) were available in TRIAD and ALFA+, and results of tau PET were available in TRIAD. RESULTS: A total of 300 TRIAD participants (177 women 59.0%; mean SD age, 64.6 17.6 years), 384 ALFA+ participants (234 women 60.9%; mean SD age, 61.1 4.7 years), and 187 BioCogBank Paris Lariboisière participants (116 women 62.0%; mean SD age, 69.9 9.2 years) were included. Plasma GFAP levels were significantly higher in individuals with preclinical AD in comparison with cognitively unimpaired (CU) Aβ-negative individuals (TRIAD: Aβ-negative mean SD, 185.1 93.5 pg/mL, Aβ-positive mean SD, 285.0 142.6 pg/mL; ALFA+: Aβ-negative mean SD, 121.9 42.4 pg/mL, Aβ-positive mean SD, 169.9 78.5 pg/mL). Plasma GFAP levels were also higher among individuals in symptomatic stages of the AD continuum (TRIAD: CU Aβ-positive mean SD, 285.0 142.6 pg/mL, mild cognitive impairment MCI Aβ-positive mean SD, 332.5 153.6 pg/mL; AD mean SD, 388.1 152.8 pg/mL vs CU Aβ-negative mean SD, 185.1 93.5 pg/mL; Paris: MCI Aβ-positive, mean SD, 368.6 158.5 pg/mL; AD dementia, mean SD, 376.4 179.6 pg/mL vs CU Aβ-negative mean SD, 161.2 67.1 pg/mL). Plasma GFAP magnitude changes were consistently higher than those of CSF GFAP. Plasma GFAP more accurately discriminated Aβ-positive from Aβ-negative individuals than CSF GFAP (area under the curve for plasma GFAP, 0.69-0.86; area under the curve for CSF GFAP, 0.59-0.76). Moreover, plasma GFAP levels were positively associated with tau pathology only among individuals with concomitant Aβ pathology. CONCLUSIONS AND RELEVANCE: This study suggests that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and Aβ pathology even among individuals in the early stages of AD.
Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer's disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein ...(GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-β (Aβ) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for Aβ (
FAZD4694) and tau (
FMK-6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated Aβ-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not Aβ-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of Aβ and tau, respectively, on hippocampal atrophy, which was further associated with cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain Aβ and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Age‐related memory decline is well associated with hippocampal atrophy, although the specific role of hippocampal subfields in memory function has not been thoroughly investigated yet. In ...this study, we investigated the associations between hippocampal subfield volumes and free recall and recognition performances in verbal and visual memory tasks in older adults without dementia.
Method
We selected 97 right‐handed participants without dementia aged 60 to 85, 42 males, from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. From T2‐weighted MRIs with 0.7*0.7*1mm voxel size, the hippocampi were segmented five subfields: 1) DG (DG); 2) CA2 with CA3 (CA2/CA3); 3) CA1; 4) strata radiatum, lacunosum and moleculare (SRLM); and 5) subiculum by using the MAGeT‐Brain algorithm. Memory was assessed with Rey Auditory Learning test for verbal free recall (RAVLT7) and recognition (RAVLT‐R), and with Aggie Figure Learning test for visual free recall (AFLT7) and recognition (AFLT‐R). Linear models were used to test the association between hippocampal subfield volumes and memory performances with age, sex and total intracranial volume as covariates (p<0.05, corrected for false discovery rate)
Result
The volumes of bilateral CA1 and SRLM were significantly associated with RAVLT7 and RAVLT‐R. The right DG volume was significantly associated with AFLT7 and RAVLT7. AFLT7 was also associated with the volume of right CA2/CA3 while AFLT‐R was not associated with any hippocampal subfield (see Figures 1 & 2).
Conclusion
Our results are consistent with the view that hippocampal subfields contribute differently to memory traces: CA1 for recollection that requires contextual information; the DG for pattern separation (creating new distinct representations of each stimulus); and CA3 for pattern completion (the recollection of a stimulus from a partial memory). Contextual information is more important when recollecting known words, while distinct and efficient encoding may be especially useful for search strategies inherent to free recall. Pattern completion could be particularly useful to efficiently recollect visual figures based on visual features during free recall. Overall, this shows that hippocampal subfield segmentation offers a better understanding of their distinctive roles in cognition.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Age‐related memory decline is well associated with hippocampal atrophy, although the specific role of hippocampal subfields in memory function has not been thoroughly investigated yet. In ...this study, we investigated the associations between hippocampal subfield volumes and free recall and recognition performances in verbal and visual memory tasks in older adults without dementia.
Method
We selected 97 right‐handed participants without dementia aged 60 to 85, 42 males, from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. From T2‐weighted MRIs with 0.7*0.7*1mm voxel size, the hippocampi were segmented five subfields: 1) DG (DG); 2) CA2 with CA3 (CA2/CA3); 3) CA1; 4) strata radiatum, lacunosum and moleculare (SRLM); and 5) subiculum by using the MAGeT‐Brain algorithm. Memory was assessed with Rey Auditory Learning test for verbal free recall (RAVLT7) and recognition (RAVLT‐R), and with Aggie Figure Learning test for visual free recall (AFLT7) and recognition (AFLT‐R). Linear models were used to test the association between hippocampal subfield volumes and memory performances with age, sex and total intracranial volume as covariates (p<0.05, corrected for false discovery rate).
Result
The volumes of bilateral CA1 and SRLM were significantly associated with RAVLT7 and RAVLT‐R. The right DG volume was significantly associated with AFLT7 and RAVLT7. AFLT7 was also associated with the volume of right CA2/CA3 while AFLT‐R was not associated with any hippocampal subfield (see Figures 1 & 2).
Conclusion
Our results are consistent with the view that hippocampal subfields contribute differently to memory traces: CA1 for recollection that requires contextual information; the DG for pattern separation (creating new distinct representations of each stimulus); and CA3 for pattern completion (the recollection of a stimulus from a partial memory). Contextual information is more important when recollecting known words, while distinct and efficient encoding may be especially useful for search strategies inherent to free recall. Pattern completion could be particularly useful to efficiently recollect visual figures based on visual features during free recall. Overall, this shows that hippocampal subfield segmentation offers a better understanding of their distinctive roles in cognition.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
The Translational Biomarkers in Aging and Dementia (TRIAD) is a longitudinal, biomarker‐based cohort designed to study interactions between the pathophysiological processes driving to ...dementia. Currently, 50 million people worldwide have dementia 1. PET and MRI imaging have been widely used to assess disease stage, though expensive and not readily accessible 2. More recently though, breakthroughs in blood‐based biomarkers have proven a useful, available, and more cost‐effective way of evaluating amyloid and tau positivity. The TRIAD Biobank provides a unique framework to study disease stage using blood‐based biomarkers in conjunction with PET and CSF studies. Our cohort allows for validation of novel biomarkers as we simultaneously acquire gold standard second generation imaging acquisitions with full spectrum fluid biomarkers (CSF, saliva, plasma, urine). Importantly, the data acquired is integrated in a database compliant to multi‐dimensional biomarker analysis.
Method
Figure 1 depicts the cohort's banked fluids by diagnostic group. Figure 2 depicts the cohort's banked fluids by sex grouping.
Result
The TRIAD Biobank stores 1,034 blood samples from 655 participants, 658 of these being follow‐up collections. Additionally, cerebrospinal fluid has been collected from 381 individuals accounting for 520 collections in the bank, 812 urine collections from 662 individuals and 591 saliva samples from 432 individuals.
Additionally, the cohort has collected 761 tau PET scans using 18FMK6240, 644 amyloid PET scans using 18FAZD4694 and 804 MRI using 3 Tesla.
Conclusion
With dementia being one of the leading, most costly causes of death, the need for early detection, more affordable, less invasive, and more readily available ways to determine disease stage is apparent 2. The TRIAD multi‐dimensional biobank provides a wealth of resources to discover affordable biomarkers needed for early diagnosis and Alzheimer’s disease prevention.
1 Patterson, C. 2018. World Alzheimer Report 2018: The state of the art of dementia research, new frontiers. London, England: Alzheimer's Disease International.
2 Gauthier S, Rosa‐Neto P, Morais JA, & Webster C. 2021. World Alzheimer Report 2021: Journey through the diagnosis of dementia. London, England: Alzheimer’s Disease International.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
The Translational Biomarkers in Aging and Dementia (TRIAD) is a longitudinal, biomarker‐based cohort designed to study interactions between the pathophysiological processes driving to ...dementia. Currently, 50 million people worldwide have dementia 1. PET and MRI imaging have been widely used to assess disease stage, though expensive and not readily accessible 2. More recently though, breakthroughs in blood‐based biomarkers have proven a useful, available, and more cost‐effective way of evaluating amyloid and tau positivity. The TRIAD Biobank provides a unique framework to study disease stage using blood‐based biomarkers in conjunction with PET and CSF studies. Our cohort allows for validation of novel biomarkers as we simultaneously acquire gold standard second generation imaging acquisitions with full spectrum fluid biomarkers (CSF, saliva, plasma, urine). Importantly, the data acquired is integrated in a database compliant to multi‐dimensional biomarker analysis.
Method
Figure 1 depicts the cohort's banked fluids by diagnostic group. Figure 2 depicts the cohort's banked fluids by sex grouping.
Result
The TRIAD Biobank stores 1,034 blood samples from 655 participants, 658 of these being follow‐up collections. Additionally, cerebrospinal fluid has been collected from 381 individuals accounting for 520 collections in the bank, 812 urine collections from 662 individuals and 591 saliva samples from 432 individuals.
Additionally, the cohort has collected 761 tau PET scans using 18FMK6240, 644 amyloid PET scans using 18FAZD4694 and 804 MRI using 3 Tesla.
Conclusion
With dementia being one of the leading, most costly causes of death, the need for early detection, more affordable, less invasive, and more readily available ways to determine disease stage is apparent 2. The TRIAD multi‐dimensional biobank provides a wealth of resources to discover affordable biomarkers needed for early diagnosis and Alzheimer’s disease prevention.
1 Patterson, C. 2018. World Alzheimer Report 2018: The state of the art of dementia research, new frontiers. London, England: Alzheimer's Disease International
2 Gauthier S, Rosa‐Neto P, Morais JA, & Webster C. 2021. World Alzheimer Report 2021: Journey through the diagnosis of dementia. London, England: Alzheimer’s Disease International.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Tau in Alzheimer's disease (AD) is assessed via cerebrospinal fluid (CSF) and Positron emission tomography (PET). Novel methods to detect phosphorylated tau (pTau) in blood have been recently ...developed. We aim to investigate agreement of tau status as determined by 18FMK6240 tau-PET, plasma pTau181 and pTau231.
We assessed cognitively unimpaired young, cognitively unimpaired, mild cognitive impairment and AD individuals with 18FMK6240, plasma pTau181, pTau 231, 18FAZD4694 amyloid-PET and MRI. A subset underwent CSF assessment.
We conducted ROC curves to obtain cut-off values for plasma pTau epitopes. Individuals were categorized as positive or negative in all biomarkers. We then compared the distribution among concordant and discordant groups in relation to diagnosis, Aβ status, APOEε4 status, 18FAZD4694 global SUVR, hippocampal volume and CSF pTau181.
The threshold for positivity was 15.085 pg/mL for plasma pTau181 and 17.652 pg/mL for plasma pTau231. Most individuals had concordant statuses, however, 18% of plasma181/PET, 26% of plasma231/PET and 25% of the pTau231/pTau181 were discordant. Positivity to at least one biomarker was often accompanied by diagnosis of cognitive impairment, Aβ positivity, APOEε4 carriership, higher levels of 18FAZD4694 global SUVR, hippocampal atrophy and CSF pTau181.
Plasma pTau181, pTau231 and 18FMK6240 seem to reflect different stages of tau progression. Plasma biomarkers can be useful in the context of diagnostic information and clinical trials, to evaluate the disease stage. Moreover, they seem to confidently evaluate tau-PET positivity.
Moreover, this study was supported by Weston Brain Institute, Canadian Institute of Health Research and Fonds de Recherche du Québec.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
