GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    Phospho-tau with subthreshold tau-PET predicts increased tau accumulation rates in amyloid-positive individuals
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 4 ( 2023-04-19), p. 1580-1591
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 4 ( 2023-04-19), p. 1580-1591
    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 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 increase 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 the 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 updating the AT(N) criteria for Alzheimer’s disease biomarker classification to APT(N).
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac329
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Earlier Alzheimer's disease onset is associated with a shift of tau pathology towards brain hubs which facilitates tau spreading
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S1 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S1 ( 2022-12)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S1
    DOI: 10.1002/alz.067084
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    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
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S1 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S1 ( 2022-12)
    Abstract: 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‐tau 217 (P; 〉 110 pg/ml) and [ 18 F]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.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S1
    DOI: 10.1002/alz.065666
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Medial temporal lobe subregional atrophy patterns in early‐ and late‐onset amnestic Alzheimer’s disease
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S6 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
    Abstract: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early‐onset compared to late‐onset Alzheimer’s disease (AD). However, detailed examination of MTL subfields comparing amnestic early‐ and late‐onset AD is lacking. We investigate MTL subfield atrophy patterns in individuals with amnestic early‐ and late‐onset cognitive impairment (EOCI and LOCI). Methods Cognitively impaired (mild cognitive impairment and dementia) adults from the BioFINDER‐2 study with memory impairment ( 〉 1.5SD age‐ and education‐specific norms), amyloid‐beta (Aβ+ based on CSF Aβ42/40), and tau positivity were included (Table 1). [ 18 F]RO948‐PET standardized uptake value ratios (SUVRs) were calculated for the MTL, and tau‐PET positivity was determined from a temporal meta‐ROI. EOCI individuals were 〈 65 years, LOCI 〉 70 years of age. Self‐reported age‐of‐onset matched with EO/LO status. Two reference groups of Aβ‐ cognitively unimpaired (CU) which were age‐matched to EOCI/LOCI were included. Hippocampal subfield volumes and thickness of entorhinal cortex, Brodmann areas (BA)35/36, and parahippocampal cortex were obtained using Automated Segmentation for Hippocampal Subfields packages for T1‐ and T2‐weighted MRI. We focused particularly on BA35, region with earliest tau accumulation. Episodic memory was determined (errors on delayed word‐list recall). Results Compared to CU, LOCI showed widespread atrophy across all MTL subfields, while the atrophy pattern in EOCI was slightly more restrictive (Fig. 1). Compared to EOCI, LOCI showed more severe atrophy in hippocampal subfields and entorhinal cortex. There was no difference between EOCI and LOCI for MTL tau‐PET SUVR (Fig. 2). Zooming in on BA35, there was a trend for an association between MTL tau‐PET SUVR and BA35 atrophy in LOCI. This association was stronger for EOCI but non‐significant, likely due to limited power (Fig. 2C). In both groups, smaller BA35 was associated with worse episodic memory (Fig. 3A). In LOCI, higher MTL tau‐PET SUVR was associated with worse episodic memory (Fig. 3B). Conclusion The findings suggest that MTL tau‐PET uptake and atrophy is present in both amnestic LOCI/EOCI and is related to the observed memory impairment in these groups. The MTL atrophy pattern is more extensive in LOCI, which may be due to longer presence of tau pathology and/or the involvement of comorbid pathologies.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S6
    DOI: 10.1002/alz.066489
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
    American Medical Association (AMA) ; 2022
    In:  JAMA Neurology Vol. 79, No. 2 ( 2022-02-01), p. 149-
    Details
    In: JAMA Neurology, American Medical Association (AMA), Vol. 79, No. 2 ( 2022-02-01), p. 149-
    Type of Medium: Online Resource
    ISSN: 2168-6149
    URL: Article
    DOI: 10.1001/jamaneurol.2021.4654
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Amyloid‐associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S1 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S1 ( 2022-12)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S1
    DOI: 10.1002/alz.065080
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    Microglial activation might protect against accumulation of Aβ and tau aggregates over time in non‐demented Aβ‐positive individuals
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S6 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
    Abstract: The past years have seen a turning point in the view of the impact of microglia in Alzheimer’s disease (AD). In particular, the activation of soluble TAM receptors and the TREM‐2 dependent transition from a homeostatic to a disease‐associated microglia stage 2 state (DAM2) seem to play relevant roles in AD. However, a comprehensive analysis of microglial‐associated biomarkers and their associations with longitudinal accumulation of amyloid‐β (Aβ) and tau aggregates in humans has not been performed yet. Method We determined the baseline levels of DAM2‐associated biomarkers (sTREM2, LPL, CST7, SPP1, CSF1), TAM receptors (AXL, Mer) and their ligand (Gas6) in the cerebrospinal fluid (CSF) of non‐demented individuals from the Swedish BioFINDER‐2 cohort. All subjects underwent longitudinal Aβ (18F‐flutemetamol) and tau (18F‐RO948) positron emission tomography (PET). Linear mixed effects models were employed to test whether the microglial markers predicted longitudinal amyloid and tau PET changes, while adjusting for relevant covariates and multiple comparisons. Result Higher levels of DAM2 markers, TAM receptors and their ligand were associated with slower global Aβ‐PET accumulation over time in Aβ‐positive participants (p 〈 0.05), in contrast to SPP1, which was associated with faster Aβ‐PET deposition (p=0.012). Moreover, higher levels markers associated with TAM receptors and DAM2 microglia were associated with slower longitudinal tau‐PET accumulation in the neocortex (p 〈 0.01) in Aβ‐positive subjects with evidence of tau pathology. The associations with longitudinal tau remained significant after adjusting for Aβ‐PET changes indicating they were independent of amyloid. Conclusion These findings suggest that markers associated with DAM2 and TAM might mitigate the accumulation of amyloid and tau aggregates in individuals with Aβ as well as both Aβ and tau pathology, respectively. These findings have important implications for future clinical trials using microglial drugs in isolation or in combination with anti‐Aβ and anti‐tau therapies for AD.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S6
    DOI: 10.1002/alz.067765
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Age‐related tau‐PET uptake and its downstream effects extend beyond the medial temporal lobe in cognitively normal older adults
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S6 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
    Abstract: Amyloid‐beta (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe (MTL). However, there is evidence that age‐related Aβ‐independent tau pathology is present outside the MTL (Kaufman et al., Acta Neuropathol, 2018). We examine tau deposition determined by positron emission tomography (PET) in regions typically involved earlier/later in AD and downstream effects on neurodegeneration and cognition in cognitively unimpaired older adults and a low‐Aβ subgroup. Methods We included 488 adults (40‐91 years; low‐Aβ: n=355, 65.2±11.5 years) from the BioFINDER‐2 study. MTL volumes (dentate gyrus, subiculum (SUB), cornu ammonis 1) and thickness (entorhinal cortex, Brodmann areas (BA)35/36, and parahippocampal cortex) were obtained, using Automated Segmentation for Hippocampal Subfields packages for T1‐ and T2‐weighted magnetic resonance images. Thickness of early/late neocortical AD‐regions (anterior cingulate, precuneus/posterior cingulate (PPC), orbitofrontal, inferior parietal cortex; and middle frontal, lateral occipital, and precentral/postcentral gyrus) was determined using FreeSurfer. [ 18 F]RO948‐ and [ 18 F]flutemetamol‐PET standardized uptake value ratios (SUVRs) were calculated for local tau and global/local Aβ. Aβ status was determined using Aβ‐PET or cerebrospinal fluid Aβ‐42/40 ratio. Global cognition was measured using delayed word‐list recall, trail making test B, and animal fluency. Results Increasing age was associated with higher tau‐PET SUVRs primarily in MTL/frontal/parietal regions. A significant association between age and local tau‐PET remained even when including Aβ‐PET as a mediator (Fig. 1). Age and local tau‐PET, but not Aβ‐PET, where negatively associated with structure in most examined regions (Figs. 2‐3). Age‐structure associations were serially mediated via tau‐PET in regions with early AD pathology (SUB/BA35/PPC). Also, in the low‐Aβ subgroup, tau‐PET mediated the age‐structure (SUB/BA35/PPC) associations (Fig. 3D). Finally, the age‐global cognition relationship was serially mediated via MTL tau‐PET and subiculum volume, even when including global Aβ‐PET as additional mediator (Fig. 4). Conclusion We observe partially Aβ‐independent associations between age and tau‐PET signal across the neocortex. Interestingly, partially Aβ‐independent tau‐PET signal appears to mediate the age‐structure associations in and outside the MTL (PPC), also in the low‐Aβ group, and the age‐MTL structure‐cognition associations. This potentially provides in vivo support for Primary Age‐related Tauopathy downstream effects on structure, beyond the MTL, and cognition.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S6
    DOI: 10.1002/alz.066545
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Earlier Alzheimer’s disease onset is associated with tau pathology in brain hub regions and facilitated tau spreading
    Springer Science and Business Media LLC ; 2022
    In:  Nature Communications Vol. 13, No. 1 ( 2022-08-20)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-08-20)
    Abstract: In Alzheimer’s disease (AD), younger symptom onset is associated with accelerated disease progression and tau spreading, yet the mechanisms underlying faster disease manifestation are unknown. To address this, we combined resting-state fMRI and longitudinal tau-PET in two independent samples of controls and biomarker-confirmed AD patients (ADNI/BioFINDER, n  = 240/57). Consistent across both samples, we found that younger symptomatic AD patients showed stronger tau-PET in globally connected fronto-parietal hubs, i.e., regions that are critical for maintaining cognition in AD. Stronger tau-PET in hubs predicted faster subsequent tau accumulation, suggesting that tau in globally connected regions facilitates connectivity-mediated tau spreading. Further, stronger tau-PET in hubs mediated the association between younger age and faster tau accumulation in symptomatic AD patients, which predicted faster cognitive decline. These independently validated findings suggest that younger AD symptom onset is associated with stronger tau pathology in brain hubs, and accelerated tau spreading throughout connected brain regions and cognitive decline.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-022-32592-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2553671-0
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    Comparison of Group-Level and Individualized Brain Regions for Measuring Change in Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
    American Medical Association (AMA) ; 2023
    In:  JAMA Neurology Vol. 80, No. 6 ( 2023-06-01), p. 614-
    Details
    In: JAMA Neurology, American Medical Association (AMA), Vol. 80, No. 6 ( 2023-06-01), p. 614-
    Abstract: Longitudinal tau positron emission tomography (PET) is a relevant outcome in clinical trials evaluating disease-modifying therapies in Alzheimer disease (AD). A key unanswered question is whether the use of participant-specific (individualized) regions of interest (ROIs) is superior to conventional approaches where the same ROI (group-level) is used for each participant. Objective To compare group- and participant-level ROIs in participants at different stages of the AD clinical continuum in terms of annual percentage change in tau-PET standardized uptake value ratio (SUVR) and sample size requirements. Design, Setting, and Participants This was a longitudinal cohort study with consecutive participant enrollment between September 18, 2017, and November 15, 2021. Included in the analysis were participants with mild cognitive impairment and AD dementia from the prospective and longitudinal Swedish Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably 2 (BioFINDER-2) study; in addition, a validation sample (the AVID 05e, Expedition-3, Alzheimer’s Disease Neuroimaging Initiative [ADNI], and BioFINDER-1 study cohorts) was also included. Exposures Tau PET (BioFINDER-2, [ 18 F]RO948; validation sample, [ 18 F]flortaucipir), 7 group-level (5 data-driven stages, meta-temporal, whole brain), and 5 individualized ROIs. Main Outcomes and Measures Annual percentage change in tau-PET SUVR across ROIs. Sample size requirements in simulated clinical trials using tau PET as an outcome were also calculated. Results A total of 215 participants (mean [SD] age, 71.4 (7.5) years; 111 male [51.6%] ) from the BioFINDER-2 study were included in this analysis: 97 amyloid-β (Aβ)–positive cognitively unimpaired (CU) individuals, 77 with Aβ-positive mild cognitive impairment (MCI), and 41 with AD dementia. In the validation sample were 137 Aβ-positive CU participants, 144 with Aβ-positive MCI, and 125 with AD dementia. Mean (SD) follow-up time was 1.8 (0.3) years. Using group-level ROIs, the largest annual percentage increase in tau-PET SUVR in Aβ-positive CU individuals was seen in a composite ROI combining the entorhinal cortex, hippocampus, and amygdala (4.29%; 95% CI, 3.42%-5.16%). In individuals with Aβ-positive MCI, the greatest change was seen in the temporal cortical regions (5.82%; 95% CI, 4.67%-6.97%), whereas in those with AD dementia, the greatest change was seen in the parietal regions (5.22%; 95% CI, 3.95%-6.49%). Significantly higher estimates of annual percentage change were found using several of the participant-specific ROIs. Importantly, the simplest participant-specific approach, where change in tau PET was calculated in an ROI that best matched the participant’s data-driven disease stage, performed best in all 3 subgroups. For the power analysis, sample size reductions for the participant-specific ROIs ranged from 15.94% (95% CI, 8.14%-23.74%) to 72.10% (95% CI, 67.10%-77.20%) compared with the best-performing group-level ROIs. Findings were replicated using [ 18 F]flortaucipir. Conclusions and Relevance Finding suggest that certain individualized ROIs carry an advantage over group-level ROIs for assessing longitudinal tau changes and increase the power to detect treatment effects in AD clinical trials using longitudinal tau PET as an outcome.
    Type of Medium: Online Resource
    ISSN: 2168-6149
    URL: Article
    DOI: 10.1001/jamaneurol.2023.1067
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...