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Background: The association between tau pathology and neurodegeneration (atrophy) in Alzheimer's disease (AD) is not fully understood. This study aimed to investigate whether tau pathology is associated with concurrent and longitudinal cortical thickness in individuals along the AD continuum. Method: We included 92 amyloid‐positive cognitively impaired individuals (age 65±7, 48% female, MMSE 23±4) with AD dementia (n = 73) or mild cognitive impairment due to AD (MCI, n = 19) and 61 cognitively normal individuals (CN; age 66±8, 48% female, MMSE 29±1) with subjective cognitive decline (SCD, n = 55, 19 amyloid‐positive) or healthy controls (HC, n = 6, amyloid‐status unknown). All participants underwent dynamic [18F]flortaucipir PET and structural 3T‐MRI at baseline. A subset underwent two‐year follow‐up structural 3T‐MRI (CN: n = 35, time‐interval 24±8 months; AD: n = 26; time‐interval 28±4 months). Parametric [18F]flortaucipir binding potential (BPND) images were generated using receptor parametric mapping (cerebellar gray matter reference region) to quantify tau pathology. Cortical thickness (over time) was measured using Freesurfer (version 6.0.1). Regional associations between [18F]flortaucipir BPND and cortical thickness were assessed using linear mixed models in three commonly used a priori defined regions‐of‐interest, including entorhinal, middle‐and inferior temporal, and neocortical areas. Models were adjusted for age, sex and amyloid status (in case of CN individuals). Result: For cognitively impaired individuals, higher [18F]flortaucipir BPND (in all three regions) was associated with lower concurrent cortical thickness in the entorhinal cortex [Table‐1&Fig‐1]. Higher middle‐ and inferior temporal and neocortical BPND was associated with cortical thinning over time within the same region (intra‐regionally). Higher middle‐ and inferior temporal BPND additionally showed associations with cortical thinning over time in the neocortex (inter‐regionally). For cognitively normal individuals, we found no associations between [18F]flortaucipir BPND and cortical thickness (over time) [Table‐1&Figure‐1]. Conclusion: Tau pathology is associated with both concurrent and longitudinal atrophy in a region‐specific manner in cognitively impaired individuals (MCI/AD), but not in cognitively normal individuals (HC/SCD). The regional‐specificity of these associations might suggest that there are similarities between tau‐related progression patterns and patterns of neurodegeneration. Taking into account a temporal delay between the development of region‐specific tau pathology and neurodegeneration, this potentially suggests that tau pathology is a (partial) driver of neurodegeneration in AD. [ABSTRACT FROM AUTHOR]

Background: Limited information is available on the genetic and environmental contributions to early AD pathology. Within a sample of cognitively unimpaired genetically identical older twins we aimed to assess 1) effects of amyloid‐ß pathology on [18F]flortaucipir (tau) binding and 2) spatial similarities in tau patterns within twin pairs. Method: To date, ten twin pairs (i.e. twenty twins) from the on‐going EMIF‐AD PreclinAD study underwent dynamic (0‐30min and 80‐100min) [18F]flortaucipir PET. Two twin pairs were concordant amyloid‐ß positive, four twin pairs concordant amyloid‐ß negative and four twin pairs amyloid‐ß discordant (i.e. one twin positive and co‐twin negative) based on [18F]flutemetamol visual read. [18F]flortaucipir binding potential (BPND) images were generated using receptor parametric mapping (reference region: cerebellar gray matter). First, we compared [18F]flortaucipir BPND in an early (entorhinal), intermediate (limbic) and late (neocortical) stage tau pathology region between amyloid‐ß positive and negative twins using generalized estimated equation correcting for twin dependency. Next, we examined spatial tau pattern similarities within twin pairs by correlating (Spearman) [18F]flortaucipir BPND across 46 ROIs from the Hammers template between each twin and their co‐twin for each true twin pair. Correlations were also performed for all non‐twin "random" pairs. Correlation coefficients within true twin pairs were compared to the correlation coefficients within random pairs, correcting for age and twin amyloid‐ß status. Results: Amyloid‐ß positive twins showed higher [18F]flortaucipir BPND in entorhinal (p=0.01) and limbic (p=0.04) regions(Table‐1). Fig‐1 shows representative [18F]flortaucipir images of an amyloid‐ß concordant positive, concordant negative and discordant pair, with regional similarities observed in amyloid‐ß concordant pairs as well as dissimilarities in amyloid‐ß discordant pairs (Fig‐1;Fig‐2). Between‐twin correlations across regional [18F]flortaucipir BPND, to assess spatial tau pattern similarities, were higher for true twin pairs (r=0.71±0.17) compared to random pairs (r=0.45±0.23) (p=0.002)(Table‐2). Conclusion: In line with previous studies, amyloid‐ß positive cognitively unimpaired twins showed higher tau deposition in early and intermediate tau stage regions. Furthermore, we observed higher spatial tau pattern similarities within true twin pairs compared to random pairs, suggesting a moderate genetic contribution to mechanisms underlying tau spread. With the upcoming larger sample we aim to further assess genetic and environmental contributions to early AD pathology. [ABSTRACT FROM AUTHOR]

Background: Several studies validated R1 as a marker for relative cerebral blood flow (rCBF). However, the similarities or differences of R1 estimates obtained from different PET tracers has never been investigated. Aim: The aim of the current study was head‐to‐head comparison of R1 estimates, derived from dynamic [18F]florbetapir and [18F]flortaucipir PET scans. Method: Fifty subjects with subjective cognitive decline (Aβ‐;N = 31, Aβ+;N = 19) underwent both [18F]florbetapir and [18F]flortaucipir PET (interval: 50.6 ± 34.7 days). Receptor parametric mapping (RPM) was used to generate R1 maps with cerebellar grey matter as reference. For voxel‐wise analyses, Statistical Parametric Mapping software (SPM12) was used. Furthermore, different regions‐of‐interest were assessed (in subject‐space). Paired t‐tests, coefficients of determination (r2) and ICC were used to compare R1 estimates from [18F]florbetapir and [18F]flortaucipir PET. Results: Voxel‐wise analysis revealed only a few small significant clusters in part of the thalamus, insular gyri, midbrain and part of the cerebellum with higher R1 estimates for [18F]florbetapir and higher R1 estimates in the hippocampus, vermis, midbrain and calcarine sulcus for [18F]flortaucipir in Aβ‐ subjects (Figure 1a & 1b). In Aβ+ subjects, [18F]florbetapir showed higher R1 estimates only in part of the thalamus and [18F]flortaucipir showed higher R1 estimates in the hippocampus and striatum (Figure 1c & 1d). Despite the small amount of significant voxels, [18F]florbetapir R1 showed good correlation and excellent ICC with [18F]flortaucipir for whole brain (Aβ‐:r2 = 0.76, ICC:0.92; Aβ+:r2 = 0.60,ICC = 0.87). Conclusion: To conclude, [18F]flortaucipir and [18F]florbetapir showed similar R1 estimates in cortical regions, illustrating that R1 is a robust marker for flow independent of tracer of interest. [ABSTRACT FROM AUTHOR]

Background: The mechanisms contributing to synaptic loss in Alzheimer's disease (AD) are poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we therefore investigated associations between tau ([18F]flortaucipir PET), synaptic density (synaptic vesicle 2A [11C]UCB‐J PET) and synaptic function (MEG) in AD. Method: Seven amyloid‐positive AD subjects (age 64.3±8.2; 3/7 female; MMSE 24.1±1.8) were included from the Amsterdam Dementia Cohort. All subjects underwent dynamic 130‐min [18F]flortaucipir and 60‐min [11C]UCB‐J PET with arterial sampling. Six subjects underwent 10‐min eyes‐closed 306‐channel MEG. [18F]flortaucipir binding potential (BPND) was determined with receptor parametric mapping (reference region: cerebellar gray matter) with partial volume correction (Hypr‐IDM‐Hypr). [11C]UCB‐J distribution volume ratio (DVR, plasma input‐derived) was obtained using the centrum semi‐ovale as reference region. [18F]flortaucipir BPND, [11C]UCB‐J DVR and MEG spectral measures (total power (0.5‐48Hz), peak frequency, and relative delta (0.5‐4Hz), theta (4‐8Hz), alpha (8‐13Hz) power) were calculated in 12 bilateral a priori defined temporal, parietal, frontal and occipital region‐of‐interests (ROIs). We used generalized estimating equations (GEE), correcting for multiple ROIs per subject, to investigate associations between [18F]flortaucipir, [11C]UCB‐J and spectral MEG. GEE analyses with MEG were performed separately per brain lobe. Additionally, within‐subject regional correlations (Spearman) between [18F]flortaucipir and [11C]UCB‐J were performed. Result: Higher [18F]flortaucipir BPND was associated with lower [11C]UCB‐J DVR (β=‐0.35, p<0.001) (Figure 1A,B). Within subjects, negative associations were observed when neocortical tau was high, while positive associations were observed when neocortical tau was low (Figure 1C). Additionally, higher [18F]flortaucipir was strongly associated with oscillatory slowing, reflected by negative associations with peak frequency and alpha power, and positive associations with delta or theta power (Table 1). In contrast, lower [11C]UCB‐J binding was associated with lower peak frequency and alpha power, and higher delta power, most clearly in the occipital lobe (Table 1). Conclusion: Across subjects, higher regional tau pathology was associated with synaptic loss, while within subjects, this association depended on subjects' neocortical tau levels. Moreover, higher tau pathology and synaptic loss were associated with oscillatory slowing. This suggests that tau is associated with synaptic loss and reduced synaptic activity, yet that a tau‐threshold may need to be reached before regional synaptic loss occurs. [ABSTRACT FROM AUTHOR]

Background: Tau pathology can be assessed by [18F]flortaucipir positron emission tomography (PET). Dynamic PET protocols allow for accurate quantification of [18F]flortaucipir specific binding. However, dynamic acquisitions can be challenging or burdensome to patients given the long required scan duration of 130 min, especially in persons with cognitive impairment due to Alzheimer's disease (AD). Therefore, the current study assessed the effect of shorter scan protocols for [18F]flortaucipir PET on its quantitative accuracy. Method: For this study, two study samples were used: 10 Alzheimer disease (AD) patients and 10 healthy controls (HC) with arterial blood sampling, and 8 AD patients and 6 HCs with a test‐retest scan protocol but without arterial sampling. All subjects underwent a 130‐minute dynamic [18F]flortaucipir PET scan with a 20 min break after 60 minutes. First, the second part of the scan was shortened to 80‐120, 80‐110 and 80‐100 minutes p.i.. Second, the first part of the scan was shortened to 0‐50, 0‐40, and 0‐30 min p.i.. To fill the gap of missing time frames in the reference region (i.e. grey matter cerebellum) time activity curves, four different interpolation methods were tested: 2T4k_VB model using population‐based input‐function (2T4k_POP‐IP), cubic, linear and exponential interpolations. Regional BPND values estimated using SRTM and/or RPM and different scan protocols were compared to the respective values estimated using the original scan acquisition. In addition, test‐retest repeatability (TRT) of the RPM BPND values estimated using the optimal shortest scan duration was assessed. Result: RPM BPND values obtained using a shortened second part of the PET scan had negligible effect on the accuracy of parameter estimates (Table 1). The RPM BPND values using 0‐30/80‐100 min with 2T4k_POP‐IP interpolation had the best correlation with original DVR‐1, SRTM and RPM BPND (r2=0.95, slope=0.91; r2=0.97, slope=0.88; r2=0.99, slope=0.96). The TRT remained similar using the shortest scan duration (Figure 1). Conclusion: The current study demonstrated that accurate [18F]flortaucipir quantification can be obtained using a scan protocol of 0‐30/80‐100 min p.i.. With this reduction in total scan duration the scan will be less burdensome while remaining quantitatively accurate. [ABSTRACT FROM AUTHOR]

Background: Carotid occlusive disease (COD) is a risk factor for cognitive decline. One of the proposed underlying mechanisms is that cerebral hypoperfusion may result in accelerated accumulation of amyloid‐β in the brain. We hypothesized that patients with longstanding, unilateral COD have an asymmetrical burden of cerebral amyloid‐β, with more amyloid‐β in the hemisphere ipsilateral to the COD than in the contralateral hemisphere. Method: The AMYCODE study is a cross‐sectional observational study. Inclusion criterion is a unilateral occlusion of the internal carotid artery. Exclusion criteria are: a contralateral stenosis of > 70% and a history of vascular reconstructive surgery. All patients underwent a neuropsychological assessment, MRI‐scan and dynamic 18F Florbetaben positron emission tomography scan (PET). Global relative perfusion (R1) and binding potential (BPND) were determined from the PET‐images using PMOD and a simplified reference tissue model with the cerebellar grey matter as reference region. Distribution Volume ratio (DVR) was calculated as BPND + 1. We performed Wilcoxon signed‐rank tests to examine differences between hemispheres within subjects. Result: To date, we included eight participants (seven males, age 66.1±7.3 years, MMSE score 28.1±2.0; inclusion ongoing, target n = 20). Mean global DVR was 1.03±0.03 in the ipsilateral hemisphere (i.e. side of the occlusion) and 1.04±0.02 in the contralateral hemisphere (p = 0.064). Mean global R1 was 0.89±0.06 in the ipsilateral hemisphere and 0.91±0.05 in the contralateral hemisphere (p = 0.033). Conclusion: Preliminary analyses suggest that patients with unilateral COD had similar amyloid‐β distribution, despite lower cerebral perfusion in the hemisphere ipsilateral to the COD than in the contralateral hemisphere. [ABSTRACT FROM AUTHOR]

Background: Dynamic [18F]flortaucipir PET imaging allows for more accurate quantification of specific binding compared to static imaging in Alzheimer’s disease (AD). Besides, with dynamic imaging flow is taken into account, which is especially important in longitudinal studies, because disease progression or drug intervention may lead to flow changes. We aimed to compare semi‐quantitative (SUVr) and quantitative (BPND) parameters for [18F]flortaucipir PET in a longitudinal study. Method: We included subjects with subjective cognitive decline (SCD; n=38) and AD patients (n=24). All subjects underwent baseline (BL) and 2‐year follow‐up (FU) dynamic [18F]flortaucipir PET. BPND and R1 (relative cerebral blood flow) were calculated (RPM; reference region cerebellar gray). SUVr was derived 80‐100 min p.i.. (Trans)entorhinal, limbic and neocortical regions‐of‐interest (ROIs) were assessed. For each parameter %change was calculated (100*(FU‐BL)/BL). Regional SUVr was compared against respective DVR (BPND+1) using paired T‐tests. Additionally, simulations were performed to model effects of flow changes on BPND and SUVr in high, medium or low binding categories. For each category, R1 values were varied to mimic 5‐25% increase or decrease in flow. Thereafter, %bias for SUVr with respect to underlying binding and its association with respect to change in flow were evaluated. Result: In SCD, there was a significant difference between %change in DVR (2.56%) and SUVr (1.85%) in the (trans)entorhinal ROI (p<0.05) only. In AD, differences in %change were found in the limbic ROI (DVR 6.61% vs. SUVr 7.52%; p<0.05) only. R1 changes were small (+0.7% in SCD and ‐1.6% in AD). Simulations showed varying %bias in SUVr depending on underlying binding. With increasing flow a decreased bias in low binding conditions was observed, whereas in high binding conditions an increased bias was seen. DVR remained relatively stable under different flow conditions, irrespective of underlying binding. Conclusion: Compared to BPND, SUVr provided a good estimate of specific binding for [18F]flortaucipir over a two‐year follow‐up. However, simulations showed that [18F]flortaucipir SUVr is subject to variable bias in case of larger flow changes, which seemed to be depending on underlying tau load. Therefore, BPND should be preferred over SUVr, especially in the context of pharmacotherapeutic interventions that could induce significant changes in flow. [ABSTRACT FROM AUTHOR]