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We developed a novel quantification method named "shape feature" by combining the features of amyloid positron emission tomography (PET) and brain magnetic resonance imaging (MRI) and evaluated its significance in predicting the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. From the ADNI database, 334 patients with MCI were included. The brain amyloid smoothing score (AV45_BASS) and brain atrophy index (MR_BAI) were calculated using the surface area and volume of the region of interest in AV45 PET and MRI. During the 48-month follow-up period, 108 (32.3%) patients converted from MCI to AD. Age, Mini-Mental State Examination (MMSE), cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), apolipoprotein E (APOE), standardized uptake value ratio (SUVR), AV45_BASS, MR_BAI, and shape feature were significantly different between converters and non-converters. Univariate analysis showed that age, MMSE, ADAS-cog, APOE, SUVR, AV45_BASS, MR_BAI, and shape feature were correlated with the conversion to AD. In multivariate analyses, high shape feature, SUVR, and ADAS-cog values were associated with an increased risk of conversion to AD. In patients with MCI in the ADNI cohort, our quantification method was the strongest prognostic factor for predicting their conversion to AD. [ABSTRACT FROM AUTHOR]

The recent advance of positron emission tomography (PET) tracers as biomarkers in Alzheimer's disease (AD) provides more insight into pathophysiology, preclinical diagnosis, and further therapeutic strategies. However, synergistic processes or interactions between amyloid and tau deposits are still poorly understood. To better understand their relationship in focal brain changes with clinical phenotypes, we focused on region-specific or atypical AD characterized by focal clinical presentations: Posterior cortical atrophy (PCA) and logopenic variant of primary progressive aphasia (lpvPPA). We compared three different PET images with 18F–THK–5351 (tau), 18F–Florbetaben (amyloid beta, Aβ), and 18F–Fluorodeoxyglucose (glucose metabolism) to investigate potential interactions among pathologies and clinical findings. Whereas the amyloid accumulations were widespread throughout the neocortex, tau retentions and glucose hypometabolism showed focal changes corresponding to the clinical features. The distinctly localized patterns were more prominent in tau PET imaging. These findings suggest that tau pathology correlates more closely to the clinical symptoms and the neurodegenerative processes than Aβ pathology in AD. [ABSTRACT FROM AUTHOR]

Purpose: Although most deep learning (DL) studies have reported excellent classification accuracy, these studies usually target typical Alzheimer's disease (AD) and normal cognition (NC) for which conventional visual assessment performs well. A clinically relevant issue is the selection of high-risk subjects who need active surveillance among equivocal cases. We validated the clinical feasibility of DL compared with visual rating or quantitative measurement for assessing the diagnosis and prognosis of subjects with equivocal amyloid scans. Methods: 18F-florbetaben scans of 430 cases (85 NC, 233 mild cognitive impairment, and 112 AD) were assessed through visual rating-based, quantification-based, and DL-based methods. DL was trained using 280 two-dimensional PET images (80%) and tested by randomly assigning the remaining (70 cases, 20%) cases and a clinical validation set of 54 equivocal cases. In the equivocal cases, we assessed the agreement among the visual rating, quantification, and DL and compared the clinical outcome according to each modality-based amyloid status. Results: The visual reading was positive in 175 cases, equivocal in 54 cases, and negative in 201 cases. The composite SUVR cutoff value was 1.32 (AUC 0.99). The subject-level performance of DL using the test set was 100%. Among the 54 equivocal cases, 37 cases were classified as positive (Eq(deep+)) by DL, 40 cases were classified by a second-round visual assessment, and 40 cases were classified by quantification. The DL- and quantification-based classifications showed good agreement (83%, κ = 0.59). The composite SUVRs differed between Eq(deep+) (1.47 [0.13]) and Eq(deep−) (1.29 [0.10]; P < 0.001). DL, but not the visual rating, showed a significant difference in the Mini-Mental Status Examination score change during the follow-up between Eq(deep+) (− 4.21 [0.57]) and Eq(deep−) (− 1.74 [0.76]; P = 0.023) (mean duration, 1.76 years). Conclusions: In visually equivocal scans, DL was more related to quantification than to visual assessment, and the negative cases selected by DL showed no decline in cognitive outcome. DL is useful for clinical diagnosis and prognosis assessment in subjects with visually equivocal amyloid scans. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the regional distribution of 18F-THK5351 uptake in gray (GM) and white matter (WM) in patients with behavioral-variant frontotemporal dementia (bvFTD) and compared it with that in patients with Alzheimer's disease (AD) or semantic dementia (SD).Methods: 18F-THK-5351 positron emission tomography (PET), 18F-florbetaben PET, magnetic resonance imaging, and neuropsychological testing were performed in 103 subjects including 30, 24, 9, and 8 patients with mild cognitive impairment, AD, bvFTD, and SD, respectively, and 32 normal subjects. Standardized uptake value ratios (SUVRs) of 18F-THK-5351 PET images were measured from six GM and WM regions using cerebellar GM as reference. GM and WM SUVRs and WM/GM ratios, the relationship between GM SUVR and WM/GM ratio, and correlation between SUVR and cognitive function were compared.Results: In AD, both parietal GM (p < 0.001) and WM (p < 0.001) SUVRs were higher than in bvFTD. In AD and SD, the WM/GM ratio decreased as the GM SUVR increased, regardless of lobar region. In AD, memory function correlated with parietal GM (ρ = −0.74, p < 0.001) and WM (ρ = −0.53, p < 0.001) SUVR. In SD, language function correlated with temporal GM SUVR (ρ = −0.69, p = 0.006). The frontal WM SUVR was higher in bvFTD than in AD (p = 0.003) or SD (p = 0.017). The frontal WM/GM ratio was higher in bvFTD than in AD (p < 0.001). In bvFTD, the WM/GM ratio increased more prominently than the GM SUVR only in the frontal lobe (R2 = 0.026). In bvFTD, executive function correlated with frontal WM SUVR (ρ = −0.64, p = 0.014).Conclusions: Frontal WM 18F-THK5351 uptake was higher in bvFTD than in other dementias. The increase in frontal WM uptake was greater than the increase in GM uptake and correlated with executive function. This suggests that frontal lobe WM 18F-THK5351 uptake reflects neuropathological differences between bvFTD and other dementias. [ABSTRACT FROM AUTHOR]

Background: About 40–50% of patients with amnestic mild cognitive impairment (MCI) are found to have no significant Alzheimer's pathology based on amyloid PET positivity. Notably, conversion to dementia in this population is known to occur much less often than in amyloid-positive MCI. However, the relationship between MCI and brain amyloid deposition remains largely unknown. Therefore, we investigated the influence of subthreshold levels of amyloid deposition on conversion to dementia in amnestic MCI patients with negative amyloid PET scans. Methods: This study was a retrospective cohort study of patients with amyloid-negative amnestic MCI who visited the memory clinic of Asan Medical Center. All participants underwent detailed neuropsychological testing, brain magnetic resonance imaging, and [18F]-florbetaben (FBB) positron emission tomography scan (PET). Conversion to dementia was determined by a neurologist based on a clinical interview with a detailed neuropsychological test or a decline in the Korean version of the Mini-Mental State Examination score of more than 4 points per year combined with impaired activities of daily living. Regional cortical amyloid levels were calculated, and a receiver operating characteristic (ROC) curve for conversion to dementia was obtained. To increase the reliability of the results of the study, we analyzed the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset together. Results: During the follow-up period, 36% (39/107) of patients converted to dementia from amnestic MCI. The dementia converter group displayed increased standardized uptake value ratio (SUVR) values of FBB on PET in the bilateral temporal, parietal, posterior cingulate, occipital, and left precuneus cortices as well as increased global SUVR. Among volume of interests, the left parietal SUVR predicted conversion to dementia with the highest accuracy in the ROC analysis (area under the curve [AUC] = 0.762, P < 0.001). The combination of precuneus, parietal cortex, and FBB composite SUVRs also showed a higher accuracy in predicting conversion to dementia than other models (AUC = 0.763). Of the results of ADNI data, the SUVR of the left precuneus SUVR showed the highest AUC (AUC = 0.596, P = 0.006). Conclusion: Our findings suggest that subthreshold amyloid levels may contribute to conversion to dementia in patients with amyloid-negative amnestic MCI. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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. Highlights • We generated an equation to quantify cognitive reserve (CR) reflecting overall AD neuropathology using multimodal neuroimaging techniques. • CR was proved to modify the relationship between brain pathology and memory function in AD spectrum. • CR was associated with global network efficiency and nodal clustering coefficient and local efficiency of the right middle-temporal pole. • Graph parameters of right middle-temporal pole was revealed to modulate the effect of brain atrophy on cognition in AD spectrum. [ABSTRACT FROM AUTHOR]

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 [F] AV-1451 and [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 [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. [ABSTRACT FROM AUTHOR]