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We investigated the longitudinal changes in cortical tau accumulation and their association with cognitive decline in patients in the Alzheimer disease (AD) continuum using 2-(2-([ 18 F]fluoro)pyridin-4-yl)-9 H -pyrrolo[2,3-b:4,5c']dipyridine ([ 18 F]PI-2620) PET. Methods: We prospectively enrolled 52 participants (age, 69.7 ± 8.4 y; 18 men and 34 women): 7 with normal cognition, 28 with mild cognitive impairment, and 17 with AD. They all completed the [ 18 F]PI-2620 and [ 18 F]florbetaben PET, MRI, and neuropsychologic tests at baseline and, excepting the [ 18 F]florbetaben PET, at the 1-y follow-up. Amyloid-β (Aβ) PET images were visually scored as positive (+) or negative (-). Patients on the AD continuum, including Aβ+ mild cognitive impairment and AD, were classified into early-onset (EO+) (<65 y old) or late-onset (LO+) (≥65 y old) groups. [ 18 F]PI-2620 PET SUV ratios (SUVRs) were determined by calculating the cerebral-to-inferior cerebellar ratio. Cortical volumes were calculated using 3-dimensional T1-weighted MRI. The correlation between tau accumulation progression and cognitive decline was also investigated. Results: The global [ 18 F]PI-2620 PET SUVRs were 1.04 ± 0.07 in 15 Aβ- patients, 1.18 ± 0.21 in 20 LO+ patients (age, 76.7 ± 3.8 y), and 1.54 ± 0.38 in 17 EO+ patients (age, 63.4 ± 5.4 y; P < 0.001) at baseline. The global SUVR increased over 1 y by 0.05 ± 0.07 (3.90%) and 0.13 ± 0.22 (8.41%) in the LO+ and EO+ groups, respectively, whereas in the Aβ- groups, it remained unchanged. The EO+ group showed higher global and regional tau deposition than did the Aβ- and LO+ groups ( P < 0.05 for each) and rapid accumulation in Braak stage V (0.15 ± 0.25; 9.10% ± 12.27%; P = 0.016 and 0.008), Braak stage VI (0.08 ± 0.12; 7.16% ± 10.06%; P < 0.006 and 0.005), and global SUVR ( P = 0.013) compared with the Aβ- group. In the EO+ group, the changes in SUVR in Braak stages II-VI were strongly correlated with the baseline and changes in verbal memory ( P < 0.03). The LO+ group showed higher tau accumulation in Braak stage I-IV areas than did the Aβ- group ( P < 0.001 for each). In the LO+ group, the change in SUVR in Braak stages III and IV moderately correlated with the change in attention ( P < 0.05), and the change in SUVR in Braak stages V and VI moderately correlated with the change in visuospatial function ( P < 0.005). Conclusion: These findings suggest that [ 18 F]PI-2620 PET can be a biomarker to provide regional and chronologic information about tau pathology in the AD continuum., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Neuroinflammation is considered an important pathway associated with several diseases that result in cognitive decline. 18 F-THK5351 positron emission tomography (PET) signals might indicate the presence of neuroinflammation, as well as Alzheimer's disease-type tau aggregates. β-amyloid (Aβ)-negative (Aβ-) amnestic mild cognitive impairment (aMCI) may be associated with non-Alzheimer's disease pathophysiology. Accordingly, we investigated associations between 18 F-THK5351 PET positivity and cognitive decline among Aβ- aMCI patients., Materials and Methods: The present study included 25 amyloid PET negative aMCI patients who underwent a minimum of two follow-up neuropsychological evaluations, including clinical dementia rating-sum of boxes (CDR-SOB). The patients were classified into two groups: 18 F-THK5351-positive and -negative groups. The present study used a linear mixed effects model to estimate the effects of 18 F-THK5351 PET positivity on cognitive prognosis among Aβ- aMCI patients., Results: Among the 25 Aβ- aMCI patients, 10 (40.0%) were 18 F-THK5351 positive. The patients in the 18 F-THK5351-positive group were older than those in the 18 F-THK5351-negative group (77.4±2.2 years vs. 70.0±5.5 years; p <0.001). There was no difference between the two groups with regard to the proportion of apolipoprotein E ε4 carriers. Interestingly, however, the CDR-SOB scores of the 18 F-THK5351-positive group deteriorated at a faster rate than those of the 18 F-THK5351-negative group (B=0.003, p =0.033)., Conclusion: The results of the present study suggest that increased 18 F-THK5351 uptake might be a useful predictor of poor prognosis among Aβ- aMCI patients, which might be associated with increased neuroinflammation (ClinicalTrials.gov NCT02656498)., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2022.)

Imaging biomarkers support the diagnosis of Alzheimer's disease (AD). We aimed to determine whether combining automated brain volumetry on MRI and quantitative measurement of tau deposition on [18F] THK-5351 PET can aid discrimination of AD spectrum. From a prospective database in an IRB-approved multicenter study (NCT02656498), 113 subjects (32 healthy control, 55 mild cognitive impairment, and 26 Alzheimer disease) with baseline structural MRI and [18F] THK-5351 PET were included. Cortical volumes were quantified from FDA-approved software for automated volumetric MRI analysis (NeuroQuant). Standardized uptake value ratio (SUVR) was calculated from tau PET images for 6 composite FreeSurfer-derived regions-of-interests approximating in vivo Braak stage (Braak ROIs). On volumetric MRI analysis, stepwise logistic regression analyses identified the cingulate isthmus and inferior parietal lobule as significant regions in discriminating AD from HC and MCI. The combined model incorporating automated volumes of selected brain regions on MRI (cingulate isthmus, inferior parietal lobule, hippocampus) and SUVRs of Braak ROIs on [18F] THK-5351 PET showed higher performance than SUVRs of Braak ROIs on [18F] THK-5351 PET in discriminating AD from HC (0.98 vs 0.88, P = 0.033) but not in discriminating AD from MCI (0.85 vs 0.79, P = 0.178). The combined model showed comparable performance to automated volumes of selected brain regions on MRI in discriminating AD from HC (0.98 vs 0.94, P = 0.094) and MCI (0.85 vs 0.78; P = 0.065).

Purpose: PET is a useful tool for detecting the presence and extent of brain tau accumulation. However, most first-generation tau PET tracers are limited for high off-target binding and detection of tau in non-Alzheimer disease (AD). This study evaluated potential clinical applications of F-PI-2620 as a novel PET tracer with a high binding affinity for tau deposition in AD and non-AD tauopathies., Methods: Twenty-six participants diagnosed with either mild cognitive impairment, probable AD, frontotemporal dementia, or parkinsonism, as well as healthy controls underwent a 60- to 90-minute brain PET scan after 7 mci (259 MBq) injection of F-PI-2620. Some participants had previous PET scans using F-THK-5351 or F-FP-CIT for dopamine transporter imaging., Results: All participants showed no increase in off-target binding in basal ganglia on F-PI-2620 PET images, as noted for first-generation tau tracers. Aβ+ mild cognitive impairment or AD patients showed diverse cortical F-PI-2620 uptake in frontotemporoparietal cortex that correlated with Mini-Mental Status Examination (ρ = -0.692, P = 0.013). Aβ+ Parkinson disease with dementia and (Aβ unknown) primary progressive aphasia patients also showed increased F-PI-2620 uptakes in the frontotemporoparietal cortex. Patients with parkinsonism showed increased uptakes in the pallidum compared with Aβ- healthy controls (left: 1.41 ± 0.14 vs 1.04 ± 0.13, P = 0.014; right: 1.18 ± 0.16 vs 0.95 ± 0.07, P = 0.014)., Conclusions: F-PI-2620 PET might be a sensitive tool to detect cortical tau deposits in patients with Aβ+ AD and Aβ+ non-AD tauopathies. Furthermore, this study showed that "off-target" binding in the basal ganglia does not affect F-PI-2620.

Purpose: To assess the in vivo whole-brain relationship between uptake of [18F]THK-5351 on PET and cortical atrophy on structural MRI according to the presence and severity of Alzheimer's disease (AD)., Materials and Methods: Sixty-five participants (21 normal controls, 32 mild cognitive impairment [MCI] subjects, and 12 AD patients) were enrolled from a prospective multicenter clinical trial (NCT02656498). Structural MRI and [18F]THK-5351 PET were performed within a 2-month interval. Cortical volume and standardized uptake value ratios (SUVR) were calculated from MRI and PET images, respectively, for 35 FreeSurfer-derived cortical regions. Pearson's correlation coefficients between SUVR and cortical volume were calculated for the same regions, and correlated regions were compared according to disease severity and β-amyloid PET positivity., Results: No significantly correlated regions were found in the normal controls. Negative correlations between SUVR and cortical volume were found in the MCI and AD groups, mainly in limbic locations in MCI and isocortical locations in AD. The AD group exhibited stronger correlations (r = -0.576-0.781) than the MCI group (r = 0.368-0.571). Hippocampal atrophy did not show any correlation with SUVR in the β-amyloid PET-negative group, but negatively correlated with SUVR (r = -0.494, P = .012) in the β-amyloid PET-positive group., Conclusions: Regional THK-5351 uptake correlated more strongly with cortical atrophy in AD compared with MCI, thereby demonstrating a close relationship between the neuro-pathologic process and cortical atrophy. Hippocampal atrophy was associated with both β-amyloid and THK-5351 uptake, possibly reflecting an interaction between β-amyloid and tau deposition in the neurodegeneration process., Competing Interests: The authors have declared that no competing interests exist.

Tau and amyloid β (Aβ), 2 key pathogenic proteins in Alzheimer's disease (AD), reportedly spread throughout the brain as the disease progresses. Models of how these pathogenic proteins spread from affected to unaffected areas had been proposed based on the observation that these proteins could transmit to other regions either through neural fibers (transneuronal spread model) or through extracellular space (local spread model). In this study, we modeled the spread of tau and Aβ using a graph theoretical approach based on resting-state functional magnetic resonance imaging. We tested whether these models predict the distribution of tau and Aβ in the brains of AD spectrum patients. To assess the models' performance, we calculated spatial correlation between the model-predicted map and the actual map from tau and amyloid positron emission tomography. The transneuronal spread model predicted the distribution of tau and Aβ deposition with significantly higher accuracy than the local spread model. Compared with tau, the local spread model also predicted a comparable portion of Aβ deposition. These findings provide evidence of transneuronal spread of AD pathogenic proteins in a large-scale brain network and furthermore suggest different contributions of spread models for tau and Aβ in AD., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The concept of cognitive reserve (CR) originated from discrepancies between the degree of brain pathology and the severity of clinical manifestations. CR has been characterized through CR proxies, such as education and occupation complexity; however, such approaches have inherent limitations. Although several methods have been developed to overcome these limitations, they fail to reflect the entire Alzheimer's disease (AD) pathology. Meanwhile, graph theory analysis, one of most powerful and flexible approaches, have established remarkable network properties of the brain. The functional and structural brain networks are damaged in neurodegenerative diseases. Therefore, network analysis has been applied to clarify the characteristics of the disease or give insight. Here, using multimodal neuroimaging, we propose an intuitive model to estimate CR based on its original definition, and explore the neural substrates of CR from the perspective of networks and functional connectivity. A total of 87 subjects (21 AD, 32 mild cognitive impairment, and 34 normal aging) underwent tau and amyloid PET, 3D T1-weighted MR, and resting-state fMRI. We hypothesized CR as a residual of actual cognitive performance and expected performance to be related to quantitative factors, such as AD pathology, demographics, and a genetic factor. Then, we correlated this marker using education and occupation complexity as conventional CR proxies. We validated this marker by testing whether it would modulate the effect of brain pathology on memory function. To examine the neural substrates associated with CR, we performed graph analysis to investigate the association between the CR marker and network measures at different granularities in total subjects, AD spectrum and normal aging, respectively. The CR marker from our model was well associated with education and occupation complexity. More directly, the CR marker was revealed to modify the relationship between brain pathology and memory function among AD spectrum. The CR marker was correlated with the global efficiency of the entire network, nodal clustering coefficient, and local efficiency of the right middle-temporal pole. In connectivity analysis, one cluster of edges centered on right middle-temporal pole was significantly correlated with the CR marker. In subgroup analysis, the network measures of right middle-temporal pole still correlated with the CR marker among AD spectrum. However, right precentral gyrus was revealed to be associated with the CR marker in normal aging. This study demonstrates that our intuitive model using multimodal neuroimaging and network perspective adequately and comprehensively captures CR. From a network perspective, CR is associated with the capacity to process information efficiently in the brain. The right middle-temporal pole was revealed to be a pivotal neural substrate of CR in AD spectrum. These findings foster understanding of AD and will be useful to help identify individuals with vulnerability or resistance to AD pathology, and characterize patients for intervention or drug trials., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Tau accumulation is a core pathologic change in various neurodegenerative diseases including Alzheimer's disease and frontotemporal lobar degeneration-tau. Recently, tau positron emission tomography tracers such as [ 18 F] AV-1451 and [ 18 F] THK5351 have been developed to detect tau deposition in vivo. In the present study, we performed a head to head comparison of these two tracers in Alzheimer's disease and frontotemporal dementia cases and aimed to investigate which tracers are better suited to image tau in these disorders., Methods: A cross-sectional study was conducted using a hospital-based sample at a tertiary referral center. We recruited eight participants (two Alzheimer's disease, four frontotemporal dementia and two normal controls) who underwent magnetic resonance image, amyloid positron emission tomography with [ 18 F]-Florbetaben and tau positron emission tomography with both THK5351 and AV-1451. To measure regional AV1451 and THK5351 uptakes, we used the standardized uptake value ratios by dividing mean activity in target volume of interest by mean activity in the cerebellar hemispheric gray matter., Results: Although THK5351 and AV-1451 uptakes were highly correlated, cortical uptake of AV-1451 was more striking in Alzheimer's disease, while cortical uptake of THK5351 was more prominent in frontotemporal dementia. THK5351 showed higher off-target binding than AV-1451 in the white matter, midbrain, thalamus, and basal ganglia., Conclusions: AV-1451 is more sensitive and specific to Alzheimer's disease type tau and shows lower off-target binding, while THK5351 may mirror non-specific neurodegeneration.

Objective: Spatial normalization of C-Pittsburgh Compound B (PiB) images is challenging for an automatic quantitative analysis without magnetic resonance imaging (MRI) because of different distribution patterns between amyloid positive and negative images. To overcome this issue, we evaluated a selective positron emission tomography template (SPT) method., Materials and Methods: Three sets of single positron emission tomography templates were created: PiB negative template, PiB positive template, and mixed template. Sixty-one patients with dementia were enrolled as the validation cohort. Magnetic resonance imaging-aided normalization method was used as a reference. The SPT method was based on visual classification (positive, negative, and equivocal). The optimal templates for each visual group were determined by correlation values and average percent errors (APEs) with MRI-aided normalization. The results of the SPT and the single template methods were compared with those of MRI-aided normalization in terms of correlation values, APEs, and concordance rates., Results: The SPT (PiB negative template for the negative and equivocal groups and PiB positive template for the positive group) showed higher correlations and concordance rate and lower APEs with MRI-aided normalization than did the single template., Conclusions: Use of the SPT provides accurate normalization of amyloid images without MRI.

Objective: Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment., Methods: We included 226 patients: 89 with Alzheimer disease-related cognitive impairment (ADCI) and 137 with subcortical vascular cognitive impairment (SVCI). All subjects underwent amyloid imaging with [(11) C] Pittsburgh compound B (PiB) positron emission tomography, and MRI to detect CMBs and markers of subcortical SVD, including the volume of white matter hyperintensities (WMH) and the number of lacunes., Results: Parietal and occipital lobar CMBs counts were higher in PiB(+) ADCI with moderate WMH than PiB(+) ADCI with minimal WMH, whereas PiB(-) patients with SVCI (ie, "pure" SVCI) showed both lobar and deep CMBs. In multivariate analyses of the whole cohort, WMH volume and lacuna counts were positively associated with both lobar and deep CMBs, whereas amyloid burden (PiB) was only associated with lobar CMBs. There was an interaction between lacuna burden and PiB retention on lobar (but not deep) CMBs (p<0.001)., Interpretation: Our findings suggest that although deep CMBs are mainly linked to subcortical SVD, both subcortical SVD and amyloid-related pathologies (eg, CAA) contribute to the pathogenesis of lobar CMBs, at least in subjects with mixed lobar and deep CMBs. Furthermore, subcortical SVD and amyloid-related pathologies interact to increase the risk of lobar CMBs., (Copyright © 2012 American Neurological Association.)

Objectives: Despite many neuropsychological studies to differentiate subcortical vascular dementia (SVaD) from Alzheimer disease (AD), previous studies did not eliminate confounding effects of mixed Alzheimer and vascular pathology. We aimed to investigate neuropsychological differences between patients with Pittsburgh compound B (PiB)-negative SVaD and those with PiB-positive AD., Methods: We recruited patients who were clinically diagnosed with SVaD or AD and underwent an 11C-PiB-PET scan. All patients with SVaD fulfilled DSM-IV criteria for vascular dementia and had severe white matter hyperintensities. The diagnosis of AD was made on the basis of criteria for probable AD proposed by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association., Results: The final patient sample consisted of 44/67 (65.7%) patients with SVaD who tested negative for PiB retention [PiB- SVaD] and 61/68 (89.7%) patients with AD who tested positive for PiB retention [PiB(+) AD]. Patients with PiB- SVaD performed better than patients with PiB(+) AD on both verbal and visual memory tests including delayed recalls of the Seoul verbal learning test and Rey complex figure test. Patients with PiB- SVaD were worse than patients with PiB(+) AD on phonemic fluency of the Controlled Oral Word Association Test and Stroop color test., Conclusions: Patients with PiB- SVaD were better at memory but worse at frontal function than patients with PiB(+) AD. The differences in memory/frontal functions observed between the 2 groups, however, could not differentiate all individual data due to some overlap in the cutoff threshold.

PurposeTau accumulation is a core pathologic change in various neurodegenerative diseases including Alzheimer's disease and frontotemporal lobar degeneration-tau. Recently, tau positron emission tomography tracers such as [18F] AV-1451 and [18F] THK5351 have been developed to detect tau deposition in vivo. In the present study, we performed a head to head comparison of these two tracers in Alzheimer's disease and frontotemporal dementia cases and aimed to investigate which tracers are better suited to image tau in these disorders.MethodsA cross-sectional study was conducted using a hospital-based sample at a tertiary referral center. We recruited eight participants (two Alzheimer's disease, four frontotemporal dementia and two normal controls) who underwent magnetic resonance image, amyloid positron emission tomography with [18F]-Florbetaben and tau positron emission tomography with both THK5351 and AV-1451. To measure regional AV1451 and THK5351 uptakes, we used the standardized uptake value ratios by dividing mean activity in target volume of interest by mean activity in the cerebellar hemispheric gray matter.ResultsAlthough THK5351 and AV-1451 uptakes were highly correlated, cortical uptake of AV-1451 was more striking in Alzheimer's disease, while cortical uptake of THK5351 was more prominent in frontotemporal dementia. THK5351 showed higher off-target binding than AV-1451 in the white matter, midbrain, thalamus, and basal ganglia.ConclusionsAV-1451 is more sensitive and specific to Alzheimer's disease type tau and shows lower off-target binding, while THK5351 may mirror non-specific neurodegeneration.