| 1. |
- Berron, David, et al.
(författare)
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Early stages of tau pathology and its associations with functional connectivity, atrophy and memory
- 2021
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:9, s. 2771-2783
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Tidskriftsartikel (refereegranskat)abstract
- In Alzheimer's disease, post-mortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with Brodmann area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior-medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance. We included 215 amyloid-β- cognitively unimpaired, 81 amyloid-β+ cognitively unimpaired and 87 amyloid-β+ individuals with mild cognitive impairment, who each underwent 18F-RO948 tau and 18F-flutemetamol amyloid PET imaging, structural T1-MRI and memory assessments as part of the Swedish BioFINDER-2 study. First, event-based modelling revealed that the entorhinal cortex and Brodmann area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, Brodmann area 36 and the parahippocampal cortex. In later stages, tau accumulation became abnormal in neocortical temporal and finally parietal brain regions. Second, in cognitively unimpaired individuals, increased tau load was related to local atrophy in the entorhinal cortex, Brodmann area 35 and the anterior hippocampus and tau load in several anterior medial temporal lobe subregions was associated with distant atrophy of the posterior hippocampus. Tau load, but not atrophy, in these regions was associated with lower memory performance. Further, tau-related reductions in functional connectivity in critical networks between the medial temporal lobe and regions in the posterior-medial system were associated with this early memory impairment. Finally, in patients with mild cognitive impairment, the association of tau load in the hippocampus with memory performance was partially mediated by posterior hippocampal atrophy. In summary, our findings highlight the progression of tau pathology across medial temporal lobe subregions and its disease stage-specific association with memory performance. While tau pathology might affect memory performance in cognitively unimpaired individuals via reduced functional connectivity in critical medial temporal lobe-cortical networks, memory impairment in mild cognitively impaired patients is associated with posterior hippocampal atrophy.
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| 2. |
- Groot, Colin, et al.
(författare)
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Phospho-tau with subthreshold tau-PET predicts increased tau accumulation rates in amyloid-positive individuals
- 2023
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 146:4, s. 1580-1591
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Tidskriftsartikel (refereegranskat)abstract
- Different tau biomarkers become abnormal at different stages of Alzheimer's disease, with CSF phospho-tau typically becoming elevated at subthreshold levels of tau-PET binding. To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we implemented an observational study design to examine longitudinal changes in Tau-PET, cortical thickness and cognitive decline in amyloid-β-positive (A+) individuals with elevated CSF P-tau levels (P+) but subthreshold Tau-PET retention (T-). To this end, individuals without dementia (i.e., cognitively unimpaired or mild cognitive impairment, N = 231) were selected from the BioFINDER-2 study. Amyloid-β-positive (A+) individuals were categorized into biomarker groups based on cut-offs for abnormal CSF P-tau217 and [18F]RO948 (Tau) PET, yielding groups of tau-concordant-negative (A + P-T-; n = 30), tau-discordant (i.e., A + P+T-; n = 48) and tau-concordant-positive (A + P+T+; n = 18) individuals. In addition, 135 amyloid-β-negative, tau-negative, cognitively unimpaired individuals served as controls. Differences in annual change in regional Tau-PET, cortical thickness and cognition between the groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures only) education. Mean follow-up time was ∼2 years. Longitudinal increase in Tau-PET was faster in the A + P+T- group than in the control and A + P-T- groups across medial temporal and neocortical regions, with the highest accumulation rates in the medial temporal lobe. The A + P+T- group showed a slower rate of increases in tau-PET compared to the A + P+T+ group, primarily in neocortical regions. We did not detect differences in yearly change in cortical thickness or in cognitive decline between the A + P+T- and A + P-T- groups. The A + P+T+ group, however, showed faster cognitive decline compared to all other groups. Altogether, these findings suggest that the A + P+T- biomarker profile in persons without dementia is associated with an isolated effect on increased Tau-PET accumulation rates but not on cortical thinning and cognitive decline. While this suggests that the tau-discordant biomarker profile is not strongly associated with short-term clinical decline, this group does represent an interesting population for monitoring effects of interventions with disease modifying agents on tau accumulation in early Alzheimer's disease, and for examining the emergence of tau aggregates in Alzheimer's disease. Further, we suggest to update the AT(N) criteria for Alzheimer's disease biomarker classification to APT(N).
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| 3. |
- Mattsson-Carlgren, Niklas, et al.
(författare)
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Longitudinal plasma p-tau217 is increased in early stages of Alzheimer's disease
- 2020
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 143:11, s. 3234-3241
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Tidskriftsartikel (refereegranskat)abstract
- Plasma levels of tau phosphorylated at threonine-217 (p-tau217) is a candidate tool to monitor Alzheimer's disease. We studied 150 cognitively unimpaired participants and 100 patients with mild cognitive impairment in the Swedish BioFINDER study. P-tau217 was measured repeatedly for up to 6 years (median three samples per person, median time from first to last sample, 4.3 years). Preclinical (amyloid-β-positive cognitively unimpaired, n = 62) and prodromal (amyloid-β-positive mild cognitive impairment, n = 49) Alzheimer's disease had accelerated p-tau217 compared to amyloid-β-negative cognitively unimpaired (β = 0.56, P < 0.001, using linear mixed effects models) and amyloid-β-negative mild cognitive impairment patients (β = 0.67, P < 0.001), respectively. Mild cognitive impairment patients who later converted to Alzheimer's disease dementia (n = 40) had accelerated p-tau217 compared to other mild cognitive impairment patients (β = 0.79, P < 0.001). P-tau217 did not change in amyloid-β-negative participants, or in patients with mild cognitive impairment who did not convert to Alzheimer's disease dementia. For 80% power, 109 participants per arm were required to observe a slope reduction in amyloid-β-positive cognitively unimpaired (71 participants per arm in amyloid-β-positive mild cognitive impairment). Longitudinal increases in p-tau217 correlated with longitudinal worsening of cognition and brain atrophy. In summary, plasma p-tau217 increases during early Alzheimer's disease and can be used to monitor disease progression.
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| 4. |
- Palmqvist, Sebastian, et al.
(författare)
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Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography.
- 2016
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 139:4, s. 1226-1236
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral accumulation of amyloid-β is thought to be the starting mechanism in Alzheimer's disease. Amyloid-β can be detected by analysis of cerebrospinal fluid amyloid-β42 or amyloid positron emission tomography, but it is unknown if any of the methods can identify an abnormal amyloid accumulation prior to the other. Our aim was to determine whether cerebrospinal fluid amyloid-β42 change before amyloid PET during preclinical stages of Alzheimer's disease. We included 437 non-demented subjects from the prospective, longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI) study. All underwent (18)F-florbetapir positron emission tomography and cerebrospinal fluid amyloid-β42 analysis at baseline and at least one additional positron emission tomography after a mean follow-up of 2.1 years (range 1.1-4.4 years). Group classifications were based on normal and abnormal cerebrospinal fluid and positron emission tomography results at baseline. We found that cases with isolated abnormal cerebrospinal fluid amyloid-β and normal positron emission tomography at baseline accumulated amyloid with a mean rate of 1.2%/year, which was similar to the rate in cases with both abnormal cerebrospinal fluid and positron emission tomography (1.2%/year, P = 0.86). The mean accumulation rate of those with isolated abnormal cerebrospinal fluid was more than three times that of those with both normal cerebrospinal fluid and positron emission tomography (0.35%/year, P = 0.018). The group differences were similar when analysing yearly change in standardized uptake value ratio of florbetapir instead of percentage change. Those with both abnormal cerebrospinal fluid and positron emission tomography deteriorated more in memory and hippocampal volume compared with the other groups (P < 0.001), indicating that they were closer to Alzheimer's disease dementia. The results were replicated after adjustments of different factors and when using different cut-offs for amyloid-β abnormality including a positron emission tomography classification based on the florbetapir uptake in regions where the initial amyloid-β accumulation occurs in Alzheimer's disease. This is the first study to show that individuals who have abnormal cerebrospinal amyloid-β42 but normal amyloid-β positron emission tomography have an increased cortical amyloid-β accumulation rate similar to those with both abnormal cerebrospinal fluid and positron emission tomography and higher rate than subjects where both modalities are normal. The results indicate that cerebrospinal fluid amyloid-β42 becomes abnormal in the earliest stages of Alzheimer's disease, before amyloid positron emission tomography and before neurodegeneration starts.
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| 5. |
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| 6. |
- Pereira, Joana B., et al.
(författare)
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Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer's disease
- 2021
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:11, s. 3505-3516
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Tidskriftsartikel (refereegranskat)abstract
- Although recent clinical trials targeting amyloid-β in Alzheimer's disease have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with amyloid-β metabolism and amyloid pathology might be important to halt the clinical deterioration. In particular, there is evidence supporting a critical role of astroglial activation and astrocytosis in Alzheimer's disease. However, so far, no studies have assessed whether astrocytosis is independently related to either amyloid-β or tau pathology in vivo. To address this question, we determined the levels of the astrocytic marker GFAP in plasma and CSF of 217 amyloid-β-negative cognitively unimpaired individuals, 71 amyloid-β-positive cognitively unimpaired individuals, 78 amyloid-β-positive cognitively impaired individuals, 63 amyloid-β-negative cognitively impaired individuals and 75 patients with a non-Alzheimer's disease neurodegenerative disorder from the Swedish BioFINDER-2 study. Participants underwent longitudinal amyloid-β (18F-flutemetamol) and tau (18F-RO948) PET as well as cognitive testing. We found that plasma GFAP concentration was significantly increased in all amyloid-β-positive groups compared with participants without amyloid-β pathology (P < 0.01). In addition, there were significant associations between plasma GFAP with higher amyloid-β-PET signal in all amyloid-β-positive groups, but also in cognitively normal individuals with normal amyloid-β values (P < 0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict amyloid-β-PET positivity with an area under the curve of 0.76, which was greater than the performance achieved by CSF GFAP (0.69) and other glial markers (CSF YKL-40: 0.64, soluble TREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for amyloid-β-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-Alzheimer's disease patients compared to other groups (P < 0.05) and correlated with amyloid-β-PET only in amyloid-β-positive cognitively impaired individuals (P = 0.005). Finally, plasma GFAP was associated with both longitudinal amyloid-β-PET and cognitive decline, and mediated the effect of amyloid-β-PET on tau-PET burden, suggesting that astrocytosis secondary to amyloid-β aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain amyloid-β pathology but not tau aggregation, even in cognitively normal individuals with a normal amyloid-β status. This suggests that plasma GFAP should be incorporated in current hypothetical models of Alzheimer's disease pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to amyloid-β pathology.
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| 7. |
- Pereira, Joana B., et al.
(författare)
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Plasma markers predict changes in amyloid, tau, atrophy and cognition in non-demented subjects
- 2021
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:9, s. 2826-2836
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Tidskriftsartikel (refereegranskat)abstract
- It is currently unclear whether plasma biomarkers can be used as independent prognostic tools to predict changes associated with early Alzheimer's disease. In this study, we sought to address this question by assessing whether plasma biomarkers can predict changes in amyloid load, tau accumulation, brain atrophy and cognition in non-demented individuals. To achieve this, plasma amyloid-β 42/40 (Aβ42/40), phosphorylated-tau181, phosphorylated-tau217 and neurofilament light were determined in 159 non-demented individuals, 123 patients with Alzheimer's disease dementia and 35 patients with a non-Alzheimer's dementia from the Swedish BioFINDER-2 study, who underwent longitudinal amyloid (18F-flutemetamol) and tau (18F-RO948) PET, structural MRI (T1-weighted) and cognitive testing. Our univariate linear mixed effect models showed there were several significant associations between the plasma biomarkers with imaging and cognitive measures. However, when all biomarkers were included in the same multivariate linear mixed effect models, we found that increased longitudinal amyloid-PET signals were independently predicted by low baseline plasma Aβ42/40 (P = 0.012), whereas increased tau-PET signals, brain atrophy and worse cognition were independently predicted by high plasma phosphorylated-tau217 (P < 0.004). These biomarkers performed equally well or better than the corresponding biomarkers measured in the CSF. In addition, they showed a similar performance to binary plasma biomarker values defined using the Youden index, which can be more easily implemented in the clinic. In addition, plasma Aβ42/40 and phosphorylated-tau217 did not predict longitudinal changes in patients with a non-Alzheimer's neurodegenerative disorder. In conclusion, our findings indicate that plasma Aβ42/40 and phosphorylated-tau217 could be useful in clinical practice, research and drug development as prognostic markers of future Alzheimer's disease pathology.
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| 8. |
- Schöll, Michael, et al.
(författare)
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Distinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer's disease
- 2017
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 140:9, s. 2286-2294
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Tidskriftsartikel (refereegranskat)abstract
- Patients with Alzheimer's disease can present with different clinical phenotypes. Individuals with late-onset Alzheimer's disease (465 years) typically present with medial temporal lobe neurodegeneration and predominantly amnestic symptomatology, while patients with early-onset Alzheimer's disease (565 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early-onset Alzheimer's disease, 21 with late-onset Alzheimer's disease, three with prodromal early-onset Alzheimer's disease and 13 with prodromal late-onset Alzheimer's disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F-AV-1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early- and late-onset Alzheimer's disease exhibit differential regional tau pathology and atrophy patterns. Strong associations of lower age at symptom onset with higher 18F-AV-1451 uptake were observed in several neocortical regions, while higher age did not yield positive associations in neither patient group. Comparing patients with early-onset Alzheimer's disease with controls resulted in significantly higher 18F-AV-1451 retention throughout the neocortex, while comparing healthy controls with late-onset Alzheimer's disease patients yielded a distinct pattern of higher 18F-AV-1451 retention, predominantly confined to temporal lobe regions. When compared against each other, the early-onset Alzheimer's disease group exhibited greater uptake than the late-onset group in prefrontal and premotor, as well as in inferior parietal cortex. These preliminary findings indicate that age may constitute an important contributor to Alzheimer's disease heterogeneity highlighting the potential of tau positron emission tomography to capture phenotypic variation across patients with Alzheimer's disease.
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| 9. |
- Smith, Ruben, et al.
(författare)
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The accumulation rate of tau aggregates is higher in females and younger amyloid-positive subjects
- 2020
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:12, s. 3805-3815
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Tidskriftsartikel (refereegranskat)abstract
- The development of tau-PET allows paired helical filament tau pathology to be visualized in vivo. Increased knowledge about conditions affecting the rate of tau accumulation could guide the development of therapies halting the progression of Alzheimer's disease. However, the factors modifying the rate of tau accumulation over time in Alzheimer's disease are still largely unknown. Large-scale longitudinal cohort studies, adjusting for baseline tau load, are needed to establish such risk factors. In the present longitudinal study, 419 participants from four cohorts in the USA (Avid 05e, n = 157; Expedition-3, n = 82; ADNI, n = 123) and Sweden (BioFINDER, n = 57) were scanned repeatedly with tau-PET. The study participants were cognitively unimpaired (n = 153), or patients with mild cognitive impairment (n = 139) or Alzheimer's disease dementia (n = 127). Participants underwent two to four tau-PET (18F-flortaucipir) scans with a mean (± standard deviation) of 537 (±163) days between the first and last scan. The change in tau-PET signal was estimated in temporal meta- and neocortical regions of interest. Subject specific tau-PET slopes were predicted simultaneously by age, sex, amyloid status (determined by amyloid-β PET), APOE ϵ4 genotype, study cohort, diagnosis and baseline tau load. We found that accelerated increase in tau-PET signal was observed in amyloid-β-positive mild cognitive impairment (3.0 ± 5.3%) and Alzheimer's disease dementia (2.9 ± 5.7%), respectively, when compared to either amyloid-β-negative cognitively unimpaired (0.4 ± 2.7%), amyloid-β-negative mild cognitive impairment (-0.4 ± 2.3%) or amyloid-β-positive cognitively unimpaired (1.2 ± 2.8%). Tau-PET uptake was accelerated in females (temporal region of interest: t = 2.86, P = 0.005; neocortical region of interest: t = 2.90, P = 0.004), younger individuals (temporal region of interest: t = -2.49, P = 0.013), and individuals with higher baseline tau-PET signal (temporal region of interest: t = 3.83, P < 0.001; neocortical region of interest: t = 5.01, P < 0.001). Tau-PET slopes decreased with age in amyloid-β-positive subjects, but were stable by age in amyloid-β-negative subjects (age × amyloid-β status interaction: t = -2.39, P = 0.018). There were no effects of study cohort or APOE ϵ4 positivity. In a similar analysis on longitudinal amyloid-β-PET (in ADNI subjects only, n = 639), we found significant associations between the rate of amyloid-β accumulation and APOE ϵ4 positivity, older age and baseline amyloid-β positivity, but no effect of sex. In conclusion, in this longitudinal PET study comprising four cohorts, we found that the tau accumulation rate is greater in females and younger amyloid-β-positive individuals, while amyloid-β accumulation is greater in APOE ϵ4 carriers and older individuals. These findings are important considerations for the design of clinical trials, and might improve our understanding of factors associated with faster tau aggregation and spread.
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| 10. |
- Wuestefeld, Anika, et al.
(författare)
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Age-related and amyloid-beta-independent tau deposition and its downstream effects
- 2023
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Ingår i: Brain : a journal of neurology. - 1460-2156. ; 146:8, s. 3192-3205
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-β (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of Aβ, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related Aβ-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures. We included 545 cognitively unimpaired adults (40-92 years) from the BioFINDER-2 study (in vivo) and 639 (64-108 years) from the Rush Alzheimer's Disease Center cohorts (ex vivo). 18F-RO948- and 18F-flutemetamol-PET standardized uptake value ratios were calculated for regional tau and global/regional Aβ in vivo. Immunohistochemistry was used to estimate Aβ load and tangle density ex vivo. In vivo medial temporal lobe volumes (subiculum, cornu ammonis 1) and cortical thickness (entorhinal cortex, Brodmann area 35) were obtained using Automated Segmentation for Hippocampal Subfields packages. Thickness of early and late neocortical Alzheimer's disease regions was determined using FreeSurfer. Global cognition and episodic memory were estimated to quantify cognitive functioning. In vivo age-related tau deposition was observed in the medial temporal lobe and in frontal and parietal cortical regions, which was statistically significant when adjusting for Aβ. This was also observed in individuals with low Aβ load. Tau deposition was negatively associated with cortical volumes and thickness in temporal and parietal regions independently of Aβ. The associations between age and cortical volume or thickness were partially mediated via tau in regions with early Alzheimer's disease pathology, i.e. early tau and/or Aβ pathology (subiculum/Brodmann area 35/precuneus/posterior cingulate). Finally, the associations between age and cognition were partially mediated via tau in Brodmann area 35, even when including Aβ-PET as covariate. Results were validated in the ex vivo cohort showing age-related and Aβ-independent increases in tau aggregates in and outside the medial temporal lobe. Ex vivo age-cognition associations were mediated by medial and inferior temporal tau tangle density, while correcting for Aβ density. Taken together, our study provides support for primary age-related tauopathy even outside the medial temporal lobe in vivo and ex vivo, with downstream effects on structure and cognition. These results have implications for our understanding of the spreading of tau outside the medial temporal lobe, also in the context of Alzheimer's disease. Moreover, this study suggests the potential utility of tau-targeting treatments in primary age-related tauopathy, likely already in preclinical stages in individuals with low Aβ pathology.
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