Regional Standardized Uptake Value Ratios Research Articles

Exploration of neuroanatomical characteristics to differentiate prodromal Alzheimer’s disease from cognitively unimpaired amyloid-positive individuals

Differentiating clinical stages based solely on positive findings from amyloid PET is challenging. We aimed to investigate the neuroanatomical characteristics at the whole-brain level that differentiate prodromal Alzheimer’s disease (AD) from cognitively unimpaired amyloid-positive individuals (CU A+) in relation to amyloid deposition and regional atrophy. We included 45 CU A+ participants and 135 participants with amyloid-positive prodromal AD matched 1:3 by age, sex, and education. All participants underwent 18F-florbetaben positron emission tomography and 3D structural T1-weighted magnetic resonance imaging. We compared the standardized uptake value ratios (SUVRs) and volumes in 80 regions of interest (ROIs) between CU A+ and prodromal AD groups using independent t-tests, and employed the least absolute selection and shrinkage operator (LASSO) logistic regression model to identify ROIs associated with prodromal AD in relation to amyloid deposition, regional atrophy, and their interaction. After applying False Discovery Rate correction at < 0.1, there were no differences in global and regional SUVR between CU A+ and prodromal AD groups. Regional volume differences between the two groups were observed in the amygdala, hippocampus, entorhinal cortex, insula, parahippocampal gyrus, and inferior temporal and parietal cortices. LASSO logistic regression model showed significant associations between prodromal AD and atrophy in the entorhinal cortex, inferior parietal cortex, both amygdalae, and left hippocampus. The mean SUVR in the right superior parietal cortex (beta coefficient = 0.0172) and its interaction with the regional volume (0.0672) were also selected in the LASSO model. The mean SUVR in the right superior parietal cortex was associated with an increased likelihood of prodromal AD (Odds ratio [OR] 1.602, p = 0.014), particularly in participants with lower regional volume (OR 3.389, p < 0.001). Only regional volume differences, not amyloid deposition, were observed between CU A+ and prodromal AD. The reduced volume in the superior parietal cortex may play a significant role in the progression to prodromal AD through its interaction with amyloid deposition in that region.

The use of individual-based FDG-PET volume of interest in predicting conversion from mild cognitive impairment to dementia

BackgroundBased on a longitudinal cohort design, the aim of this study was to investigate whether individual-based 18F fluorodeoxyglucose positron emission tomography (18F-FDG-PET) regional signals can predict dementia conversion in patients with mild cognitive impairment (MCI).MethodsWe included 44 MCI converters (MCI-C), 38 non-converters (MCI-NC), 42 patients with Alzheimer’s disease with dementia, and 40 cognitively normal controls. Data from annual cognitive measurements, 3D T1 magnetic resonance imaging (MRI) scans, and 18F-FDG-PET scans were used for outcome analysis. An individual-based FDG-PET approach was applied using seven volumes of interest (VOIs), Z transformed using a normal FDG-PET template. Hypometabolism was defined as a Z score < -2 of regional standard uptake value ratio. For the longitudinal cognitive test scores, generalized estimating equations were used. A linear mixed-effects model was used to compare the temporal impact of cortical hypometabolism and cortical thickness degeneration.ResultsThe clinical follow-up period was 6.6 ± 3.8 years (range 3.1 to 16.0 years). The trend of cognitive decline could differentiate MCI-C from MCI-NC after 3 years of follow-up. In the baseline 18F-FDG-PET scan of the patients with MCI, medial temporal lobe (MTL; 94.7% sensitivity, 80.5% specificity) and posterior cingulate cortex (PCC; 89.5% sensitivity, 73.1% specificity) hypometabolism predicted conversion with high accuracy. 18F-FDG-PET hypometabolism preceded dementia conversion at an interval of 3.70 ± 1.68 years and was earlier than volumetric changes, with the exception of the MTL.ConclusionsOur finding supports the use of individual-based 18F-FDG-PET analysis to predict MCI conversion to dementia. Reduced FDG-PET metabolism in the MTL and PCC were strongly associated with future cognitive decline in the MCI-C group. Changes in 18F-FDG-PET occurred 1 to 8 years prior to conversion to dementia. Progressive hypometabolism in the PCC, precuneus and lateral temporal lobe, but not MTL, preceded MRI findings at the MCI stage.

Inter-scanner Aβ-PET harmonization using barrel phantom spatial resolution matching.

The standardized uptake value ratio (SUVR) is used to measure amyloid beta-positron emission tomography (Aβ-PET) uptake in the brainDifferences in PET scanner technologies and image reconstruction techniques can lead to variability in PET images across scanners. This poses a challenge for Aβ-PET studies conducted in multiple centers. The aim of harmonization is to achieve consistent Aβ-PET measurements across different scanners. In this study, we proposean Aβ-PET harmonization methodof matching spatial resolution, as measured viaabarrel phantom, across PET scanners. Our approach wasvalidated using paired subject data, for whichpatients were imaged on multiple scanners. In this study, three different PET scanners were evaluated: the Siemens Biograph Vision 600, Siemens Biograph molecular computed tomography (mCT), and Philips Gemini TF64. A total of five, eight, and five subjects were each scanned twice with [18F]-NAV4694 across Vision-mCT, mCT-Philips, and Vision-Philips scanner pairs. The Vision and mCT scans were reconstructed using various iterations, subsets, and post-reconstruction Gaussian smoothing, whereas only one reconstruction configuration was used for the Philips scans. The full-width at half-maximum (FWHM) of each reconstruction configuration was calculated using [18F]-filled barrel phantom scans with the Society of Nuclear Medicine and Molecular Imaging (SNMMI) phantom analysis toolkit. Regional SUVRs were calculated from 72 brain regions using the automated anatomical labelling atlas 3 (AAL3) atlas for each subject and reconstruction configuration. Statistical similarity between SUVRs was assessed using paired (within subject) t-tests for each pair of reconstructions across scanners; the higher the p-value, the greater the similarity between the SUVRs. Vision-mCT harmonization: Vision reconstruction with FWHM=4.10mm and mCT reconstruction with FWHM=4.30mm gave the maximal statistical similarity (maximum p-value) between regional SUVRs. Philips-mCT harmonization: The FWHM of the Philips reconstruction was 8.2mm and the mCT reconstruction with the FWHM of 9.35mm, which gave the maximal statistical similarity between regional SUVRs. Philips-Vision harmonization: The Vision reconstruction with an FWHM of 9.1mm gave the maximal statistical similarity between regional SUVRs when compared with the Philips reconstruction of 8.2mm and were selected as the harmonized for each scanner pair. Based on data obtained from three sets of participants, each scanned on a pair of PET scanners, it has been verified that using reconstruction configurations that produce matched-barrel, phantom spatial resolutions results in maximally harmonized Aβ-PET quantitation between scanner pairs. This finding is encouraging for the use of PET scanners in multi-center trials or updates during longitudinal studies. Question: Does the process of matching the barrel phantom-derived spatial resolution between scanners harmonize amyloid beta-standardized uptake value ratio (Aβ-SUVR) quantitation? Pertinent findings: It has been validated that reconstruction pairs with matched barrel phantom-derived spatial resolution maximize the similarity between subjects paired Aβ-PET (positron emission tomography) SUVR values recorded on two scanners. Implications for patient care: Harmonization between scanners in multi-center trials and PET camera updates in longitudinal studies can be achieved using a simple and efficient phantom measurement procedure, beneficial for the validity of Aβ-PET quantitation measurements.

Regional glymphatic abnormality in behavioral variant frontotemporal dementia

AbstractBackgroundThe pattern of glymphatic inflow overlaps with the geographic pattern of behavioral variant frontotemporal dementia (bvFTD). The glymphatic function has not yet been explored in bvFTD. The spatial correlation between regional glymphatic function and bvFTD remain unknown.MethodA total of 60 patients with bvFTD and 61 age‐ and sex‐matched healthy controls (HCs) were selected from two independent cohorts (discovery dataset from Xuanwu Hospital and replication dataset from the Frontotemporal Lobar Degeneration Neuroimaging Initiative study). All participant underwent neuropsychological assessment. Glymphatic measures evaluated from multimodal neuroimaging data, including choroid plexus volume, diffusion along perivascular space (DTI‐ALPS) index, and coupling between blood‐oxygen‐level‐dependent signals and cerebrospinal fluid signals (BOLD‐CSF coupling), were compared between the two groups. To evaluate glymphatic regional function, DTI‐ALPS and BOLD‐CSF coupling were further divided into anterior, middle, and posterior parts. BvFTD‐related metabolic pattern was identified using spatial covariance analysis based on [l8F]‐FDG‐PET.ResultPatients with bvFTD showed higher choroid plexus volume (P &lt; 0.001); middle DTI‐ALPS (P &lt; 0.001); and weaker anterior BOLD‐CSF coupling (P &lt; 0.05) than HCs after controlling for cortical gray matter volume in both datasets. In bvFTD from the discovery dataset, the anterior DTI‐ALPS was negatively associated with the expression of the bvFTD‐related metabolic pattern (r = ‐0.51, P = 0.029) and positively related with regional standardized uptake value ratios of [l8F]‐FDG‐PET in bvFTD‐related brain regions (r = 0.44–0.60, P range: 0.008–0.039). Worse glymphatic function is associated with more severe global cognition decline, disease severity, and neuropsychiatric symptoms. In addition, anterior DTI‐ALPS was higher than posterior DTI‐ALPS (P &lt; 0.001), whereas anterior BOLD‐CSF coupling was lower than posterior BOLD‐CSF coupling (P &lt; 0.001).ConclusionOur findings reveal abnormal glymphatic function, especially in the anterior and middle regions of brain in bvFTD. Regional glymphatic dysfunction may contribute to the pathogenesis of bvFTD.

PARTIAL VOLUME CORRECTION TECHNIQUES FOR LONGITUDINAL TAU‐PET QUANTIFICATION: A COMPARISON STUDY

AbstractBackgroundThe selection of an appropriate Partial Volume Correction (PVC) is crucial for evaluating tau accumulation rates using 18F‐Flortaucipir (18F‐FTP). PVC can reduce the impact of off‐target binding, but it can also increase noise and variability. While these effects may be averaged on cross‐sectional studies, they might be of paramount importance when evaluating within‐subject longitudinal tau‐PET signal. The aim of this study is to evaluate the robustness of different PVCs for the evaluation of tau accumulation rates in longitudinal 18F‐FTP studies, as measured by their correlation with cognitive clinical progression.Method111 cognitively impaired subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with serial 18F‐FTP PET and T1 images, as well as cognitive performance evaluation available for a 2‐year follow‐up period, were included in the study. 18F‐FTP PET images were corrected by applying a traditional deconvolution PVC (Grey matter only), the reblurred Van‐Cittert (RVC) analytical PVC (grey + white matter), and 2 voxel‐based PVCs, the region‐based voxel‐wise correction (RBV) and the iterative Yang (iY). Longitudinal rates of change for the regional standard uptake value ratios (SUVR) of the temporal meta‐ROI were computed for the images corrected for the different PVCs, and their correlation with the rates of change of the ADAS‐Cog 11 cognitive performance metric was analyzed.ResultThe deconvolution PVC correction showed the strongest correlation between decreased cognitive performance and increased tau accumulation rates (p&lt;0.001, ρ = 0.38), followed closely by the RBV (p&lt;0.001, ρ = 0.36) and iY (p&lt;0.001, ρ = 0.35) corrections (Fig. 1). In contrast, the RVC results (p = 0.03, ρ = 0.20) were comparable to not applying any PVC at all (p = 0.03, ρ = 0.21).ConclusionOur findings suggest that longitudinal FTP studies might benefit from the use of PVC techniques for the evaluation of tau accumulation rates. Tau uptake rates of change tracked the observed clinical progression more accurately after certain PVC corrections were applied. Moreover, a simple deconvolution PVC has been shown to perform similarly to more complex, voxel‐wise corrections such as the RBV and iY.

Apolipoprotein E4 affects locus coeruleus functional connectivity in preclinical Alzheimer’s disease

AbstractBackgroundRecent studies have demonstrated the pivotal implications of the locus coeruleus (LC) and in the early phase of Alzheimer’s disease (AD). However, the effects of apolipoprotein E4(APOE4) carrier status on the LC functional connectivity (FC) in preclinical AD remain elusive. We aimed to demonstrate disparities in LC FC in preclinical AD with regard to APOE4 carrier status.MethodsA total of 112 patients with who were amyloid beta (Aβ) positive([18F] flutemetamol +) were recruited in the study, and they all had normal cognition. Seed to voxel analysis was conducted to measure LC FC differences between APOE4 non‐carrier and carrier. In addition, group by amyloid beta (Aβ) interactive effects on FC values were analyzed with a general linear model.ResultThe LC FC with intracalcarine cortex, lingual gyrus, occipital fusiform gyrus of the both hemispheres was reduced in APOE4 carrier. Moreover, there was a statistically significant group by regional standardized uptake value ratio interactions in LC FC with frontal, occipital cortices, the precuneus and the cerebellum.ConclusionThe aforementioned findings suggest that there are differential patterns of LC FC in APOE4 non‐carrier and carrier with preclinical AD, which interact with regional Aβ deposition.

A 2.5D residual U‐Net for improved amyloid PET harmonization preserving spatial information

AbstractBackgroundMultiple amyloid tracers with varying characteristics pose a significant challenge to standardized interpretation and quantification of amyloid PET measurements. We previously demonstrated that a deep learning based 2D residual inception encoder‐decoder network (RIED‐Net) architecture improved harmonization of florbetapir (FBP) and PiB PET. However, 2D networks fail to capture spatial information among image slices and 3D networks with more parameters require larger datasets and powerful computation for training. Here, we investigate the performance of a 2.5D approach to further improve harmonization preserving spatial information.Method92 PiB‐FBP image pairs from Open Access Series of Imaging Studies (OASIS) were processed using established pipelines to extract regional standard uptake value ratios (SUVRs), mean cortical SUVRs (mcSUVRs), and SUVR images. A 2.5D U‐Net model with residual connections was implemented to learn the nonlinear mappings from the image pairs. Input to the network is a stack of 3 adjacent FBP slices along a particular view, providing extra spatial information about volumetric data. The output of network is a stack of corresponding 3 PiB slices. Multi‐slice output avoids averaging/blurry effects common in traditional 2.5D approaches. 10‐fold cross‐validation was implemented on axial, coronal and sagittal views separately to generate synthetic PiB SUVR imaging from FBP data. The average synthetic PiB image from axial, coronal and sagittal views was used for performance evaluation. Correlation was evaluated between the virtual PiB mcSUVR derived from imputed PiB vs. the real PiB mcSUVR and voxel‐wise between the imputed vs. real PiB SUVR images.ResultThe agreement of mcSUVR improved from r = 0.90 between PiB and FBP to r = 0.95 between synthetic and real PiB SUVR images (p&lt;0.0001) in cross‐validation dataset. Additionally, imputed PiB SUVR images were visually more similar to real PiB SUVR images than FBP. Voxel‐wise correlation improved from 0.88 to 0.93 (p&lt;0.0001).ConclusionOur proposed 2.5D Residual U‐Net for synthetic imaging was able to learn voxel‐wise nonlinear associations between FBP and PiB images. The model trained in 2.5D approach with additional spatial information, was able to significantly improve agreements of amyloid burden measurement from two tracers and generate PiB SUVR images that are visually more similar to real PiB SUVR images than FBP.

Deep Learning Based Estimation of Synthetic Tau PET from Amyloid PET

AbstractBackgroundAlzheimer’s disease (AD) is the most common pathological substrate for dementia. Both tau and amyloid positron emission tomography (PET) scans are valuable for evaluating innovative treatments and studying AD progression. However, tau‐PET is extremely expensive and not universally available. Estimating tau‐PET images from amyloid‐PET would mitigate these concerns. In this study, we proposed a novel application of the Conditional Generative Adversarial Network (cGAN) framework to generate high quality tau‐PET (18F‐flortaucipir) scans from the corresponding amyloid‐PET (18F‐florbetapir) scans.MethodA dataset of 475 individuals who underwent both 18F‐florbetapir and 18F‐flortaucipir scans with different clinical diagnosis (Table 1) were used in our study from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) online depository. Our cGAN model was trained for 50 epochs using real, corresponding amyloid‐tau PET pairs. The resulting model takes real amyloid‐PET images as input and outputs synthetic tau‐PET images (Figure 1.a). The similarity between synthetic and real tau‐PET images was evaluated via the structural similarity index (SSIM), peak signal to noise ratio (PSNR), and normalized root mean squared error (NRMSE). Furthermore, we extracted regional standard uptake value ratios (SUVRs) and meta‐region of interest (ROI) SUVRs from the real tau‐PET scans and synthetic tau‐PET scans. The utility of the synthetic tau‐PET meta‐ROI SUVR for identifying real tau‐PET scans that are tau positive was evaluated in terms of true positive rate (TPR), false positive rate (FPR), and the area under the receiver operating characteristic (ROC) curve (AUC).ResultOur cGAN model yielded a SSIM of 0.917, a PSNR of 27.04, and a NRSME of 0.18 on the test set. The ROC curve analysis (Figure 2) resulted in an AUC of 0.84%. By applying a cut‐off threshold corresponding to the model optimal operating point, a TPR of 90% and FPR of 28% were achieved. The SUVR analysis yielded a mean absolute percentage error of 8.3% ± 6.5% on the test dataset.ConclusionThe proposed cGAN model generated high quality 18F‐flortaucipir PET images from 18F‐florbetapir PET images (Figure 1.b). This could be highly useful in a screening paradigm to use amyloid‐PET to identify those individuals most likely to be tau positive.

Subjective cognitive impairment score associate with regional amyloid burden and brain atrophy in subjective cognitive decline subjects

AbstractBackgroundSubjective cognitive decline (SCD) is now regarded as the first preclinical stage of Alzheimer’s disease (AD) spectrum disorders. It is important to predict which patients would progress to dementia, and screening tools might be helpful. In this study, we aimed to investigate the possible correlations between AD biomarkers‐regional amyloid burden and volume changes‐and Korean Dementia Screening Questionnaire‐Cognition (KDSQ‐C) score in SCD.MethodThis study analyzed SCD data from prospective population cohort study from July 2018 to December 2020. Brain magnetic resonance imaging (MRI) volumetry, visual and standardized uptake value ratio (SUVR) analysis of 18F‐Florbetaben brain amyloid Positron Emission Tomography (PET) were performed. Demographics, physical data, social and physiological functions were also obtained.KDSQ‐C was administered to SCD subjects as part of the clinical evaluation at the 36 month follow‐up visit. KDSQ‐C included 15 questions that assess 3 dimensions: memory impairment (items 1‐5), other cognitive impairments including language impairments (items 6‐10), and the ability to perform complex tasks in daily life (items 11‐15).ResultPrevalence of subjective cognitive impairment (KDSQ‐C ≧6) among 86 subjects was 73.3%.. No significant difference was observed between groups in terms of demographic characteristics including age, sex and APOE Ɛ4 status and neuropsychological test. However, regional SUVR (amygdala, inferior temporal gyrus and precuneus) and global SUVR were significantly higher in subjectively cognitive impaired group(p&lt;0.05). There were no brain volume differences between groups.For volumetry and KDSQ‐C correlation analysis, partial correlation analysis controlled for age, sex and APOE Ɛ4 status showed significant negative correlation between left entorhinal cortex, right hippocampal volume and KDSQ‐C (r = ‐0.230, p = 0.046; r = ‐0.226, p = 0.049). Similar association was also found between KDSQ‐C memory domain score and brain volume.ConclusionKDSQ‐C can be a useful tool for screening SCD patients at a higher risk with higher amyloid deposition and brain atrophy.This study was supported by a grant from the Ministry of Health and Welfare, HI18C0530

Tau pathology is associated with neuropsychiatric symptoms in a cohort of individuals of predominantly Mexican descent at risk for autosomal‐dominant Alzheimer’s disease

AbstractBackgroundNeuropsychiatric symptoms are common in Alzheimer’s disease (AD), causing significant suffering and diminished quality of life for both individuals and caregivers. The goal of this study was to investigate the relationship between tau pathology in vivo and neuropsychiatric symptoms within a cohort of individuals of predominantly Mexican ancestry at risk for fully penetrant autosomal dominant AD (ADAD) caused by mutations in PSEN1 and APP genes (Figure 1).MethodParticipants from the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) cohort were selected based on availability of demographic variables, mutation carrier status, tau PET scans (flortaucipir), and completion of the neuropsychiatric inventory (NPI). Linear regression models were used to investigate whether regional tau PET standard uptake value ratio (SUVR) predicted total score on the NPI. Models were adjusted for age, sex, and mutation carrier status. Participants were characterized as carriers if they possessed one of the following ADAD mutations: PSEN1 A431E, PSEN1 I180F, or APP V717I. Analyses were done with and without outliers. The 12‐item total NPI score was used for all analyses. The primary brain regions of interest (i.e., medial orbitofrontal, caudal anterior cingulate, rostral anterior cingulate, parahippocampal, precuneus, and lateral occipital) were selected based on previous findings. Additional analyses were conducted only on individuals who were carriers of 1 of the ADAD mutations.ResultThe sample consisted of 31 participants (45% women, mean age±SD = 37.1±11.7 years, 71% ADAD mutation carriers [81% PSEN1 A431E, 16% PSEN1 I180F, and 3% APP V717I carriers]). A significant relationship was found between regional tau pathology and neuropsychiatric symptoms for all six brain regions (Table 1), all p’s &lt; 0.01. Within all regression models, regional tau pathology explained between 24% to 49% of the variance in neuropsychiatric symptoms. Sub‐set analyses completed on the ADAD mutation carriers sample exhibited similar results (Table 2). No significant results were found for non‐carriers.ConclusionRegional tau pathology within six distinct brain regions is strongly associated with neuropsychiatric symptoms in a cohort of individuals of predominantly Mexican ancestry at risk for fully penetrant ADAD caused by mutations in PSEN1 and APP genes.

Tau pathology is associated with neuropsychiatric symptoms in a cohort of individuals of predominantly Mexican descent at risk for autosomal‐dominant Alzheimer’s disease

AbstractBackgroundNeuropsychiatric symptoms are common in Alzheimer’s disease (AD), causing significant suffering and diminished quality of life for both individuals and caregivers. The goal of this study was to investigate the relationship between tau pathology in vivo and neuropsychiatric symptoms within a cohort of individuals of predominantly Mexican ancestry at risk for fully penetrant autosomal dominant AD (ADAD) caused by mutations in PSEN1 and APP genes (Figure 1).MethodParticipants from the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) cohort were selected based on availability of demographic variables, mutation carrier status, tau PET scans (flortaucipir), and completion of the neuropsychiatric inventory (NPI). Linear regression models were used to investigate whether regional tau PET standard uptake value ratio (SUVR) predicted total score on the NPI. Models were adjusted for age, sex, and mutation carrier status. Participants were characterized as carriers if they possessed one of the following ADAD mutations: PSEN1 A431E, PSEN1 I180F, or APP V717I. Analyses were done with and without outliers. The 12‐item total NPI score was used for all analyses. The primary brain regions of interest (i.e., medial orbitofrontal, caudal anterior cingulate, rostral anterior cingulate, parahippocampal, precuneus, and lateral occipital) were selected based on previous findings. Additional analyses were conducted only on individuals who were carriers of 1 of the ADAD mutations.ResultThe sample consisted of 31 participants (45% women, mean age±SD = 37.1±11.7 years, 71% ADAD mutation carriers [81% PSEN1 A431E, 16% PSEN1 I180F, and 3% APP V717I carriers]). A significant relationship was found between regional tau pathology and neuropsychiatric symptoms for all six brain regions (Table 1), all p’s &lt; 0.01. Within all regression models, regional tau pathology explained between 24% to 49% of the variance in neuropsychiatric symptoms. Sub‐set analyses completed on the ADAD mutation carriers sample exhibited similar results (Table 2). No significant results were found for non‐carriers.ConclusionRegional tau pathology within six distinct brain regions is strongly associated with neuropsychiatric symptoms in a cohort of individuals of predominantly Mexican ancestry at risk for fully penetrant ADAD caused by mutations in PSEN1 and APP genes.

The aftermath of boxing: Longitudinal changes of cerebral retention patterns of 18F‐florzolotau (18F‐APN‐1607) in the former professional boxers

AbstractBackgroundChronic traumatic encephalopathy (CTE), formerly known as “boxer’s encephalopathy” is a neurodegenerative disease associated with mild‐repetitive TBI. CTE is characterized by the deposition of hyperphosphorylated tau as neurofibrillary tangles around small blood vessels of the cortex, typically at the sulcal depths. Although tau PET studies on American football players reported findings consistent with neuropathological changes identified by postmortem brains, there are no reports of tau PET studies in boxers, and longitudinal changes of tau depositions following boxing remains unknown. The present study was aimed to characterize cerebral retention patterns of 18F‐florzolotau (18F‐APN‐1607) in the former professional boxers.MethodTwenty‐nine former boxers (43.4 ± 10.3 years) and 27 age‐matched healthy control (HC) subjects underwent PET scans with 18F‐florzolotau and 11C‐PiB. Eleven former boxers underwent a second tau PET scan (average interval: 874days). Standard uptake value ratio (SUVR) with the optimized reference tissue was calculated. Regions of interest were defined on brain regions of the gray matter (GM), white matter (WM) and the gray‐white matter boundary (GWB). Association of regional SUVR values with neurocognitive symptoms and various indexes related boxing was investigated.ResultOne boxer was [11C]PiB positive. Former boxers showed higher 18F‐florzolotau retentions than HC subjects in the bilateral frontal GM, right parietal GM, bilateral frontal WM, right parietal WM (P &lt; 0.001). There was a significant correlation between SUVR values in the whole GM and the total number of bouts (p = 0.07,r = 0.40). Subtyping using z‐score heatmap with predetermined criteria revealed heterogeneity in 18F‐florzolotau retention patterns in boxers. Of the 29 boxers, (1) 10 showed increased retention of 18F‐florzolotau in GM (GM dominant), (2) 4 showed increased accumulation mainly in WM (WM dominant), (3) 5 showed increased accumulation in GWB (GWB dominant), and (4) 10 showed no significant increased accumulation in the brain (No tau). These types vary in longitudinal changes of 18F‐florzolotau retention patterns, as well as in clinical features.ConclusionThe present study not only supports pathological heterogeneity of late‐sequalae of professional boxing, but also suggests utility of 18F‐florzolotau PET in detection of late‐life neurodegenerative diseases following mild‐repetitive TBI.

Distinct associations between tau PET and cognitive impairment across brain regions and cognitive domains in Alzheimer’s disease

AbstractBackgroundCompared with biofluid‐biomarkers, tau‐PET shows stronger association with cognitive impairment (Ossenkoppele,R‐2021) and decline, and better detects Alzheimer’s disease (AD) pathology (Coomans,EM‐2022; Smith,R‐2022). Conventionally, tau‐cognition relationship has been evaluated between global cortical tau‐PET and composite cognitive scores. However, tau‐PET binding patterns are heterogenous, with regional binding showing strong correlations with domain‐specific cognitive performance and decline. The goal of this study was to evaluate domain‐specific patterns of tau‐PET at baseline and in change‐from‐baseline (CFB) in symptomatic AD patients.MethodAmyloid‐positive participants (n = 172) with a clinical diagnosis of mild‐cognitive‐impairment (n = 97) or dementia due to AD (n = 76) and amyloid‐negative healthy‐controls (n = 68) underwent a 18Flortaucipir tau‐PET and neuropsychological testing (AV1451‐A05:NCT02016560) at baseline and 18months. Observed cognitive scores in impaired patients were normalized to age‐adjusted outcomes in healthy‐controls at baseline and 18months (Ossenkoppele,R‐2015). These scores were subsequently averaged within the episodic‐memory, semantic‐memory, language, visuospatial, and executive function cognitive domains (Malpetti,M‐2022). Standardized uptake value ratio (SUVr) in automated‐anatomical‐labelling regions (Tzourio‐Mazoyer,M‐2002) and AD‐specific region (MUBADA; Devous,M‐2017) was calculated in reference to cerebellum‐crus. The CFB (18months‐baseline) in SUVr and domain‐specific sub‐scores were calculated for all participants. Correlations between global SUVr versus composite cognitive score and regional SUVr versus domain‐specific scores at baseline and CFB were calculated.ResultDifferential cross‐sectional tau‐PET patterns showed significant negative associations with domain‐specific cognitive performance (Fig.1A). When evaluated longitudinally, higher global CFB in tau‐PET SUVr showed no‐to‐modest correlation with cognitive decline (Fig.2: ADAS‐Cog11 = 0.012, FAQ = ‐0.015, MMSE = ‐0.210, CDR‐SB = 0.014), however, heterogeneous associations were observed at the regional‐ and voxel‐level (Fig.1B,Fig.3), ranging from maximum of r = ‐0.45 (p&lt;0.001; frontal‐inferior and visuospatial) to minimum of r = ‐0.002 (p&lt;0.1; lingual and episodic). Increase in tau‐PET signal was associated with greater cognitive decline (i.e. visuospatial function: predominantly frontal; executive function: parietal and prefrontal; semantic‐memory: superior temporal region). An extensive and asymmetric tau‐PET pattern (L&gt;R) in frontal and occipital regions was related to language.ConclusionWe found associations between patterns of tau accumulation and domain‐specific cognitive decline in MCI and AD dementia. After validations using larger datasets, these relationships can supplement widely used associations between global tau‐PET and composite cognitive scores and, therefore, enhance tau PET‐guided and patient‐centered staging, prognosis, and response assessment.

The interplay between White Matter Hyperintensities and regional β‐Amyloid on Defaults Mode Network

AbstractBackgroundCerebral small vessel ischemic disease (SVID) has been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Yet, the mechanistic role of SVID in potentially contributing to AD pathology is unclear. The main objective of this study was to test the hypothesis that axonal SVID influences amyloid β (Aβ) levels within connected default mode network (DMN) tracts and cortical regions in cognitively unimpaired older adults.MethodRegional Standard Uptake Value ratios (SUVr) from Aβ‐PET, and white matter hyperintensity (WMH) volumes from 3D MRI FLAIR images were analyzed across a sample of 72 clinically‐unimpaired (Mini‐Mental State Examination (MMSE) ≥ 26), aged participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI3). The association of WMH volumes in major fiber tracts projecting from cortical DMN regions and Aβ‐PET SUVr in the connected cortical DMN regions were analyzed using linear regression models adjusted for age, sex, ApoE and total brain volumes.ResultThe regression analyses demonstrate that increased WMH volumes in the superior longitudinal fasciculus (SLF) was associated with increased regional SUVr in the inferior parietal lobule (IPL) (p = 0.011).ConclusionThe findings suggest that the relation between Aβ parietal cortex is partially driven by SVID in downstream axonal pathways in pAD. The biological relationships and interplay between Aβ and white matter microstructure alterations that precede overt WMH development across the continuum of AD progression warrants further study.

36 Regional Amyloid and Memory in Amyloid Positive and Negative Older Adults

Objective:Alzheimer’s disease (AD) pathophysiology, including β-amyloid (Aβ), can be appreciated with molecular PET imaging. Among older adults, the distribution of Aβ standard uptake value ratios (SUVR) is typically bimodal and a diagnostic cut is applied to define those who are amyloid ‘positive’ and ‘negative’. However, it is unclear whether the dynamic range of SUVRs in amyloid positive and negative individuals is meaningful and associated with cognition. Previous work by Insel and colleagues (2020) used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) trial to demonstrate subtle associations between a cortical summary SUVR and cognition, particularly on the Free and Cued Selective Reminding Test (FCSRT). We followed up this study to determine the extent to which regional SUVR is associated with performance on the FCSRT in amyloid positive and negative participants screened for participation in the A4 study.Participants and Methods:We accessed regional Aβ SUVR, including anterior cingulate, posterior cingulate, parietal, precuneus, temporal, and medial/orbital frontal regions, along with FCSRT15 and demographic data from 4492 A4 participants at screening. Participants were coded as amyloid positive (n=1329; 30%) or amyloid negative (n=3169; 70%) based on a summary SUVR of greater than or equal to 1.15. We used separate general linear models to examine the association of total or regional SUVR, amyloid positivity status, and the interaction of SUVR and amyloid status with FCSRT scores. We compared model fits across regions with the Akaike Information Criterion (AIC). We ran post hoc correlational analyses examining the relationship between SUVR and FCSRT scores stratified by amyloid status in the case of significant interactions. Results were similar with and without demographic adjustment.Results:There was a significant interaction of summary and all regional SUVR with FCSRT scores in addition to main effects of amyloid positivity. In all models, there were small negative associations between SUVR and memory in amyloid positive individuals. For amyloid negative individuals, there was a significant and very small negative association between SUVR and FCSRT scores only in the parietal lobes and precuneus regions. Model fits were generally similar across the different analyses.Conclusions:In this sample of individuals screened for a secondary prevention trial of AD, there were consistent associations between Aβ SUVR in all regions and memory for those considered amyloid positive. However, for individuals considered amyloid negative, there were only very small associations between SUVR and memory in parietal and precuneus regions. We conclude that the dynamic range of amyloid may be relevant among those with diagnostic evidence of amyloidosis, but that subtle Aβ accumulation in posterior regions may relate to declining memory in “subthreshold” states.

Sex-Related Disparities in the Resting State Functional Connectivity of the Locus Coeruelus and Salience Network in Preclinical Alzheimer's Disease.

Recent studies have demonstrated the pivotal role of locus coeruleus (LC) and salience network (SN) resting state functional connectivity (rsFC) changes in the early stage of Alzheimer's disease (AD). Moreover, sex has been a crucial point of discussion in understanding AD pathology. We aimed to demonstrate the sex-related disparities in the functional connectivity (FC) of the SN and LC in preclinical AD. A total of 89 cognitively normal patients with evidence of amyloid beta (Aβ) accumulation ([18F] flutemetamol +) were recruited in the study. A seed-to-voxel analysis was conducted to measure the LC and SN rsFC differences between sexes. In addition, sex by Aβ interactive effects on FC values were analyzed with a general linear model. There were statistically significant sex by regional standardized uptake value ratio (SUVR) interactions in the LC FC with the parietal, frontal, and occipital cortices. Moreover, there was a significant sex by global SUVR interaction in the SN FC with the temporal cortex. The findings suggest that there are differential patterns of LC FC and SN FC in males and females with preclinical AD, which interact with regional Aβ deposition.

Generative Adversarial Network-Enhanced Ultra-Low-Dose [18F]-PI-2620 τ PET/MRI in Aging and Neurodegenerative Populations.

With the utility of hybrid τ PET/MR imaging in the screening, diagnosis, and follow-up of individuals with neurodegenerative diseases, we investigated whether deep learning techniques can be used in enhancing ultra-low-dose [18F]-PI-2620 τ PET/MR images to produce diagnostic-quality images. Forty-four healthy aging participants and patients with neurodegenerative diseases were recruited for this study, and [18F]-PI-2620 τ PET/MR data were simultaneously acquired. A generative adversarial network was trained to enhance ultra-low-dose τ images, which were reconstructed from a random sampling of 1/20 (approximately 5% of original count level) of the original full-dose data. MR images were also used as additional input channels. Region-based analyses as well as a reader study were conducted to assess the image quality of the enhanced images compared with their full-dose counterparts. The enhanced ultra-low-dose τ images showed apparent noise reduction compared with the ultra-low-dose images. The regional standard uptake value ratios showed that while, in general, there is an underestimation for both image types, especially in regions with higher uptake, when focusing on the healthy-but-amyloid-positive population (with relatively lower τ uptake), this bias was reduced in the enhanced ultra-low-dose images. The radiotracer uptake patterns in the enhanced images were read accurately compared with their full-dose counterparts. The clinical readings of deep learning-enhanced ultra-low-dose τ PET images were consistent with those performed with full-dose imaging, suggesting the possibility of reducing the dose and enabling more frequent examinations for dementia monitoring.

White matter hyperintensities influence distal cortical β-amyloid accumulation in default mode network pathways.

Cerebral small vessel disease (SVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Yet, the role of SVD in potentially contributing to AD pathology is unclear. The main objective of this study was to test the hypothesis that WMHs influence amyloid β (Aβ) levels within connected default mode network (DMN) tracts and cortical regions in cognitively unimpaired older adults. Regional standard uptake value ratios (SUVr) from Aβ-PET and white matter hyperintensity (WMH) volumes from three-dimensional magnetic resonance imaging FLAIR images were analyzed across a sample of 72 clinically unimpaired (mini-mental state examination ≥26), older adults (mean age 74.96 and standard deviation 8.13) from the Alzheimer's Disease Neuroimaging Initiative (ADNI3). The association of WMH volumes in major fiber tracts projecting from cortical DMN regions and Aβ-PET SUVr in the connected cortical DMN regions was analyzed using linear regression models adjusted for age, sex, ApoE, and total brain volumes. The regression analyses demonstrate that increased WMH volumes in the superior longitudinal fasciculus were associated with increased regional SUVr in the inferior parietal lobule (p=.011). The findings suggest that the relation between Aβ in parietal cortex is associated with SVD in downstream white matter (WM) pathways in preclinical AD. The biological relationships and interplay between Aβ and WM microstructure alterations that precede overt WMH development across the continuum of AD progression warrant further study.

Regional Glymphatic Abnormality in Behavioral Variant Frontotemporal Dementia.

Glymphatic function has not yet been explored in behavioral variant frontotemporal dementia (bvFTD). The spatial correlation between regional glymphatic function and bvFTD remains unknown. A total of 74 patients with bvFTD and 67 age- and sex-matched healthy controls (HCs) were selected from discovery dataset and replication dataset. All participants underwent neuropsychological assessment. Glymphatic measures including choroid plexus (CP) volume, diffusion tensor imaging along the perivascular (DTI-ALPS) index, and coupling between blood-oxygen-level-dependent signals and cerebrospinal fluid signals (BOLD-CSF coupling), were compared between the two groups. Regional glymphatic function was evaluated by dividing DTI-ALPS and BOLD-CSF coupling into anterior, middle, and posterior regions. The bvFTD-related metabolic pattern was identified using spatial covariance analysis based on l8 F-FDG-PET. Patients with bvFTD showed higher CP volume (p < 0.001); anterior and middle DTI-ALPS (p < 0.001); and weaker anterior BOLD-CSF coupling (p < 0.05) than HCs after controlling for cortical gray matter volume in both datasets. In bvFTD from the discovery dataset, the anterior DTI-ALPS was negatively associated with the expression of the bvFTD-related metabolic pattern (r = -0.52, p = 0.034) and positively related with regional standardized uptake value ratios of l8 F-FDG-PET in bvFTD-related brain regions (r range: 0.49 to 0.62, p range: 0.017 to 0.047). Anterior and middle glymphatic functions were related to global cognition and disease severity. Our findings reveal abnormal glymphatic function, especially in the anterior and middle regions of brain in bvFTD. Regional glymphatic dysfunction may contribute to the pathogenesis of bvFTD. ANN NEUROL 2023;94:442-456.

The combined effect of β ‐amyloid and white matter hyperintensities on present and future executive function performance in cognitively normal older adults

AbstractBackgroundβ‐amyloid (Aβ) and White matter hyperintensities (WMH) are key drivers of cognitive decline in healthy older adults and both are considered biomarkers of preclinical dementia. Deficit in executive function (EF) linked to WMHs and Aβ burden, have been shown to predict the development of dementia. The present study aimed to explore the interactions of regional and global Aβ with WMH on baseline and longitudinal performance in EF in cognitively normal (CN) older adults.MethodGlobal and regional Standard Uptake Value ratios (SUVr) from Aβ‐PET, WMH volumes from MRI FLAIR images, and composite scores of EF at baseline and after approximately 2 years were analyzed across a sample of 714 clinically‐normal (Mini‐Mental State Examination (MMSE) ≥ 26), aged participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI2). We used multiple regression models including the interaction tem and main effects for Aβ and WMH to investigate the independent and combined associations of these pathologies with EF. Age, ApoE, education, baseline EF score, and time to follow up EF testing were entered as covariates in the regression models.ResultThe moderation regression analysis showed that additive effects on Aβ burden and WMH in relation to baseline EF with p value for the interaction term between the two pathologies 0.07, and significant interaction effects of global, frontal and cingulate Aβ burden, and WMH in relation to longitudinal EF performance with p values of 0.037, 0.03, and 0.032 respectively. The main effect from regression analysis demonstrated that baseline EF performance was predicted by the combination of Aβ burden and WMH, while Aβ burden was the only predictor for longitudinal EF performance.ConclusionThese data demonstrated that baseline Aβ and WMHs have both independent effects on EF scores at baseline and synergistic effects on longitudinal EF performance. The biological relationships and interplay between Ab and WMH responsible for the synergistic effects seen on longitudinal EF performance warrants further study.