| 1. |
- Binette, Alexa Pichet, et al.
(författare)
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Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Tidskriftsartikel (refereegranskat)abstract
- Background: For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, it is important to understand how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with positron emission tomography (PET) and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Method: We included 327 participants from the Swedish BioFINDER-2 cohort with cerebrospinal fluid (CSF) p-tau217, Aβ-PET, longitudinal tau-PET, and longitudinal cognition. The main groups of interest were Aβ-positive non-demented participants and AD dementia patients (Table 1 and Figure 1), and analyses were conducted separately in each group. First, we investigated how soluble p-tau217 and regional Aβ-PET were associated with tau-PET rate of change across the 200 brain parcels from the Schaefer atlas. We also tested the mediating effect of p-tau217 between Aβ-PET and tau-PET change. Second, we investigated how soluble p-tau217 and tau-PET change related to change in cognition, and mediation between these variables. Result: In early AD stages (non-demented participants), increased concentration of soluble p-tau217 was the main driver of accumulation of insoluble tau aggregates across the brain (measured as tau-PET rate of change), beyond the effect of regional Aβ-PET and baseline tau-PET (Figure 2A-C). Further, averaged across all regions, soluble p-tau217 mediated 54% of the association between Aβ and tau aggregation (Figure 2D). Higher soluble p-tau217 concentrations were also associated with cognitive decline, which was mediated by faster increase of tau aggregates (Figure 3). Repeating the same analyses in the AD dementia group, results were different. In late stage of AD, when Aβ fibrils and soluble p-tau levels have plateaued, soluble p-tau217 was not associated with accumulation of tau aggregates beyond baseline tau-PET (Figure 4A), and cognitive decline was driven by the accumulation rate of insoluble tau aggregates and not soluble p-tau217 (Figure 4B-C). Conclusion: Soluble p-tau is a main driver of tau aggregation and future cognitive decline in earlier stages of AD, whereas tau aggregation accumulation is more likely an important driver of disease in later stages. Overall, our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD.
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| 2. |
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| 3. |
- Eikelboom, Willem S., et al.
(författare)
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Evaluating the DICE method to improve early recognition and treatment of neuropsychiatric symptoms in early Alzheimer’s disease
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S8
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Tidskriftsartikel (refereegranskat)abstract
- Background: While neuropsychiatric symptoms (NPS) are common in early Alzheimer’s disease (AD), they are currently underdiagnosed and undertreated in the memory clinic. Therefore, we evaluated the effectiveness of the Describe, Investigate, Create, Evaluate (DICE™) approach to structure and standardize the care for NPS in AD in the memory clinic. Method: A total of 60 community-dwelling patients with MCI, AD dementia, or AD/VaD dementia were enrolled with their caregivers in two waves (Table-1). The first wave (n = 36) received care as usual and served as a control group, while the second wave of patients (n = 24, of which n = 20 have currently completed the study) underwent the DICE method. We applied the DICE method during two visits in which NPS were assessed, underlying causes were examined, and patients and caregivers were instructed on management strategies to deal with NPS, which were evaluated after one month. Outcomes were assessed after three and six months. Primary outcomes were quality of life of patients (QoL-AD) and caregivers (Carerqol-7D). Secondary outcomes included caregiver burden (Perseverance time), NPS prevalence and severity (NPI-Q & BEHAVE-AD), NPS-related distress (NPI-Q), competence managing NPS (additional NPI-Q item), and psychotropic drug use. We used linear mixed models to examine differences in outcomes at group-level and reliable change index to examine which participants in the intervention group showed reliable improvement in the primary outcomes. Result: We found no significant differences between the two groups in change in quality of life or any of the secondary outcomes (all p>0.05, Table-2). A proportion of the intervention group showed reliable improvement in quality of life of patients (n = 6/20) and caregivers (n = 7/20). At baseline, these patients tended to show higher NPS burden and their caregivers reported more NPS-related distress and lower feelings of competence while managing NPS compared to participants that did no show reliable improvement. Conclusion: This Stage 2 efficacy study shows no benefits of the DICE method on in early AD at group-level, but suggest that particular participants might benefit from this approach. Data will be re-analyzed when all intervention group participants have completed the study and will be extended with qualitative data investigating NPS-related knowledge and management styles of participants.
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| 4. |
- Franzmeier, Nicolai, et al.
(författare)
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Earlier Alzheimer's disease onset is associated with a shift of tau pathology towards brain hubs which facilitates tau spreading
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Tidskriftsartikel (refereegranskat)abstract
- Background: In Alzheimer’s disease (AD), younger symptom onset is associated accelerated cognitive decline and tau spreading, yet the drivers of faster disease manifestation in patients with earlier symptom onset are unknown. Earlier symptom onset is associated with stronger tau pathology in fronto-parietal regions which typically harbor globally connected hubs that are central for cognition. Since tau spreads across connected regions, globally connected hubs may accelerate tau spreading due to their large number of connections to other brain regions. Thus, we hypothesized that a pattern shift of tau pathology towards globally connected brain hubs may facilitate tau spreading and earlier symptom manifestation in AD. Method: We included two independent samples with longitudinal Flortaucipir tau-PET covering the AD spectrum (ADNI: n(controls/AD-preclinical/AD-symptomatic)=93/60/89, BioFINDER, n(controls/AD-preclinical/AD-symptomatic)=16/16/25). In addition, we included resting-state fMRI from human connectome project participants (n=1000), applying a 200-ROI brain atlas to obtain a global connectivity map for assessing brain hubs (Fig.1A-D). Applying the same atlas to tau-PET we transformed SUVRs to tau positivities using a pre-established gaussian-mixture modeling approach (Fig.1E-F). By mapping tau-PET positivities to the fMRI-derived global connectivity map (Fig.1G-L), we assessed the degree to which subject specific tau-PET patterns were shifted towards globally connected hubs or non-hubs, while adjusting for global tau levels. Using linear regression, we then tested whether a stronger shift of tau towards hubs was associated with earlier symptom manifestation and faster longitudinal tau accumulation. Result: In symptomatic AD patients, younger age was associated with a stronger shift of tau-PET towards globally connected brain hubs (p[ADNI/BiOFINDER]=0.024/0.018, Fig.2A&B), and with higher global connectivity of epicenters with highest tau pathology (p[ADNI/BiOFINDER]<0.001/0.001, Fig.2C&D). In symptomatic AD, younger age (p[ADNI/BiOFINDER]=0.009/0.001) and a stronger shift of tau-PET towards hubs predicted faster subsequent tau accumulation (p[ADNI/BiOFINDER]=0.004/0.002), supporting the view that that hubs facilitate tau spreading (Fig.3). Further, a stronger shift of tau-PET towards globally connected brain hubs mediated the association between younger age and faster tau accumulation in symptomatic AD patients (p[ADNI/BiOFINDER]=0.039/0.046). Conclusion: Younger AD symptom onset is associated with stronger tau pathology in globally connected brain hubs, which facilitates faster tau spreading.
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| 5. |
- Franzmeier, Nicolai, et al.
(författare)
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The BIN1 rs744373 Alzheimer's disease risk SNP is associated with faster Aβ-associated tau accumulation and cognitive decline
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:1, s. 103-115
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The BIN1 rs744373 single nucleotide polymorphism (SNP) is a key genetic risk locus for Alzheimer's disease (AD) associated with tau pathology. Because tau typically accumulates in response to amyloid beta (Aβ), we tested whether BIN1 rs744373 accelerates Aβ-related tau accumulation. Methods: We included two samples (Alzheimer's Disease Neuroimaging Initiative [ADNI], n = 153; Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably [BioFINDER], n = 63) with longitudinal 18F-Flortaucipir positron emission tomography (PET), Aβ biomarkers, and longitudinal cognitive assessments. We assessed whether BIN1 rs744373 was associated with faster tau-PET accumulation at a given level of Aβ and whether faster BIN1 rs744373-associated tau-PET accumulation mediated cognitive decline. Results: BIN1 rs744373 risk-allele carriers showed faster global tau-PET accumulation (ADNI/BioFINDER, P <.001/P <.001). We found significant Aβ by rs744373 interactions on global tau-PET change (ADNI: β/standard error [SE] = 0.42/0.14, P = 0.002; BioFINDER: β/SE = –0.35/0.15, P =.021), BIN1 risk-allele carriers showed accelerated tau-PET accumulation at higher Aβ levels. In ADNI, rs744373 effects on cognitive decline were mediated by faster global tau-PET accumulation (β/SE = 0.20/0.07, P =.005). Discussion: BIN1-associated AD risk is potentially driven by accelerated tau accumulation in the face of Aβ.
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| 6. |
- Groot, Colin, et al.
(författare)
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A biomarker profile of elevated CSF p-tau with normal tau PET is associated with increased tau accumulation rates on PET in early Alzheimer’s disease
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Different tau biomarkers become abnormal at different stages of Alzheimer’s disease (AD), with CSF p-tau typically being 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 selected a group of amyloid-β-positive (A+) individuals with elevated CSF p-tau levels but negative tau-PET scans and assessed longitudinal changes in tau-PET, cortical thickness and cognitive decline. Method: Individuals without dementia (i.e., cognitively unimpaired (CU) or mild cognitive impairment, n=231) were selected from the BioFINDER-2 study. These subjects were categorized into biomarker groups based on Gaussian mixture modelling to determine cut-offs for abnormal CSF Aβ42/40 (A; <0.078), CSF p-tau217 (P; >110 pg/ml) and [18F]RO948 tau-PET SUVR within a temporal meta-ROI (T; SUVR >1.40). Resulting groups were: A+P-T- (concordant, n=30), A+P+T- (discordant, n=48) and A+P+T+ (concordant, n=18). We additionally used 135 A- CU individuals (A- CU) as a reference group (Tables 1 and 2). Differences in annual change in regional tau-PET SUVR, cortical thickness and cognition between the A+P+T- group and the other groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures) education. Result: Longitudinal change in tau-PET was faster in the A+P+T- group than in the A- CU and A+P-T- groups across medial temporal and neocortical regions, with the medial temporal increases being more pronounced. The A+P+T- group showed slower rate of increases in tau-PET compared to the A+P+T+ group, primarily in neocortical regions (Figures 1 and 2). We did not detect differences in yearly change in cortical thickness (Figure 3) or in cognitive decline (Figure 3) 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. Conclusion: These findings suggest that the A+P+T- biomarker profile is associated with early tau accumulation, and with relative sparing of cortical thinning and cognitive decline compared to A+P+T+ individuals. Therefore, the A+P+T- group represents an interesting target-group for early anti-tau interventions and for examining the emergence of tau aggregates in early AD.
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| 7. |
- Janssen, O., et al.
(författare)
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Characteristics of subjective cognitive decline associated with amyloid positivity
- 2022
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:10, s. 1832-1845
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Tidskriftsartikel (refereegranskat)abstract
- Introduction The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. Methods In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns, feelings of worse performance) demographics, setting, apolipoprotein E gene (APOE) epsilon 4 carriership, and neuropsychiatric symptoms with amyloid positivity. Results Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Only older age, clinical setting, and APOE epsilon 4 carriership showed univariate associations with increased amyloid positivity. After adjusting for these, lower education was also associated with increased amyloid positivity. Only within a research setting, informant-confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. Discussion Next to age, setting, and APOE epsilon 4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals.
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| 8. |
- Leijenaar, Jolien F., et al.
(författare)
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Comorbid amyloid-β pathology affects clinical and imaging features in VCD
- 2020
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 16:2, s. 354-364
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: To date, the clinical relevance of comorbid amyloid-β (Aβ) pathology in patients with vascular cognitive disorders (VCD) is largely unknown. Methods: We included 218 VCD patients with available cerebrospinal fluid Aβ42 levels. Patients were divided into Aβ+ mild-VCD (n = 84), Aβ− mild-VCD (n = 68), Aβ+ major-VCD (n = 31), and Aβ− major-VCD (n = 35). We measured depression with the Geriatric Depression Scale, cognition with a neuropsychological test battery and derived white matter hyperintensities (WMH) and gray matter atrophy from MRI. Results: Aβ− patients showed more depressive symptoms than Aβ+. In the major-VCD group, Aβ− patients performed worse on attention (P =.02) and executive functioning (P =.008) than Aβ+. We found no cognitive differences in patients with mild VCD. In the mild-VCD group, Aβ− patients had more WMH than Aβ+ patients, whereas conversely, in the major-VCD group, Aβ+ patients had more WMH. Atrophy patterns did not differ between Aβ+ and Aβ− VCD group. Discussion: Comorbid Aβ pathology affects the manifestation of VCD, but effects differ by severity of VCD.
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| 9. |
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| 10. |
- Mattsson, Niklas, et al.
(författare)
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Predicting diagnosis and cognition with 18F-AV-1451 tau PET and structural MRI in Alzheimer's disease
- 2019
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:4, s. 570-580
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The relative importance of structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) to predict diagnosis and cognition in Alzheimer's disease (AD) is unclear. Methods: We tested 56 cognitively unimpaired controls (including 27 preclinical AD), 32 patients with prodromal AD, and 39 patients with AD dementia. Optimal classifiers were constructed using the least absolute shrinkage and selection operator with 18F-AV-1451 (tau) PET and structural MRI data (regional cortical thickness and subcortical volumes). Results: 18F-AV-1451 in the amygdala, entorhinal cortex, parahippocampal gyrus, fusiform, and inferior parietal lobule had 93% diagnostic accuracy for AD (prodromal or dementia). The MRI classifier involved partly the same regions plus the hippocampus, with 83% accuracy, but did not improve upon the tau classifier. 18F-AV-1451 retention and MRI were independently associated with cognition. Discussion: Optimized tau PET classifiers may diagnose AD with high accuracy, but both tau PET and structural brain MRI capture partly unique information relevant for the clinical deterioration in AD.
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