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Introduction: White matter hyperintensities (WMHs) are magnetic resonance imaging markers of small vessel cerebrovascular disease that are associated with cognitive decline and clinical Alzheimer disease. Previous studies have often focused on global or total WMH; less is known about associations of regional WMHs and cognitive abilities among older adults without dementia. Methods: A total of 610 older adults with normal cognition (n=302) or mild cognitive impairment (n=308) from the Alzheimer's Disease Neuroimaging Initiative underwent neuropsychological testing and magnetic resonance imaging. Linear regression models examined associations between regional WMH volumes and cognition, adjusting for age, sex, education, apolipoprotein E ε4 allele frequency, and pulse pressure. Results: Among all participants, greater regional WMH volume in all lobes was associated with poorer performance on memory and speed/executive functioning. Among participants with normal cognition, greater temporal and occipital WMH volumes were associated with poorer memory, whereas no regional WMH volumes were associated with speed/executive function. Discussion: Results show that greater regional WMH volume relates to poorer cognitive functioning—even among those with normal cognition. Together with results from previous studies, our findings raise the possibility that WMH may be a useful therapeutic target and/or important effect modifier in treatment or prevention dementia trials. [ABSTRACT FROM AUTHOR]

Importance: Low social competence is one of the most complex and resistant challenges faced by adolescents with autism spectrum disorder (ASD). Occupational therapy practitioners have recognized the potential benefits of using the arts, including training in magic tricks, as a therapeutic medium to improve and enhance clients' psychosocial well-being. Objective: To describe the efficacy of a virtual magic trick training program (MTTP) to enhance social skills and self-esteem in adolescents with ASD. Design: Pragmatic, nonrandomized, wait-list controlled trial with 1-mo follow-up. Setting: Participants' homes. Participants: Seventeen adolescents (ages 9−15 yr) with ASD participated in the MTTP, 9 in the first cohort and 8 in the second (wait-list control) cohort. Intervention: Participants received magic trick training from occupational therapy students in pairs via videoconferencing in 45-min sessions, 3 days/wk, for 3 wk. Outcomes and Measures: Participants completed the Rosenberg Self-Esteem Scale and the Social Skills Improvement System before and after participating in the program. Results: Between-cohort effect sizes (Cohen's d) were 0.58 for social skills and 0.66 for self-esteem, considered moderate effects. Combining the two cohorts revealed significant improvements in social skills and self-esteem, with gains maintained at 1-mo follow-up. Conclusions and Relevance: The results of this study support our hypothesis that adolescents with ASD who participate in the 3-wk virtual MTTP can experience enhanced social skills and self-esteem. What This Article Adds: Learning magic tricks through individual coaching from occupational therapy students in a virtual environment can enhance the social skills and self-esteem of adolescents with ASD. Adolescents with autism spectrum disorder (ASD) who participate in a virtual magic trick training program (MTTP) through individual coaching from occupational therapy students or practitioners can experience enhanced social skills and self-esteem. [ABSTRACT FROM AUTHOR]

Date Presented 03/21/24 This session will present procedures and findings of a pilot randomized controlled trial of videoconferencing acceptance and commitment therapy (ACT) for distressed family caregivers of people with dementia. Promising findings warrant a full-scale trial. Primary Author and Speaker: Areum Han Contributing Authors: Hon Yuen, Jeremy Jenkins, Lauren Edwards [ABSTRACT FROM AUTHOR]

Background: Quantitative [18F]Flortaucipir (FTP) tau PET analysis has good discriminative accuracy for Alzheimer’s disease (AD), but visual reads are used clinically. We aimed to compare the diagnostic accuracy of FTP‐PET to amyloid PET visual reads for distinguishing AD dementia and amyloid‐positive mild cognitive impairment (MCI) from other neurodegenerative diseases and cognitively normal (CN) controls. Method: We included 661 participants studied with FTP and amyloid PET at UCSF, Lund University, and Gangnam Severance Hospital (Table 1). Amyloid PET tracers were site‐specific (UCSF, [11C]PIB; Lund, [18F]Flutemetamol; Gangnam, [18F]Florbetaben). Three visual raters interpreted amyloid PET using tracer‐specific criteria and FTP‐PET using a recently proposed method (Figure 1; Sonni et al. Alzheimer's Dement. 2020, 12:e12133. doi: 10.1002/dad2.12133). Amyloid and FTP‐PET were read in separate, randomized batches, blinded to the reads of the other physicians. The majority interpretation of each scan as amyloid positive/negative and tau positive/negative was used in the primary analysis. Diagnostic performance of FTP and amyloid PET visual reads, including sensitivity and specificity, were calculated. Kappa statistics for intra‐ and inter‐rater reliability were calculated. Result: Amyloid and FTP‐PET visual reads had similar sensitivity (92.6%, 95%‐confidence interval [88.7‐95.5%], 92.2% [88.2‐95.2%], respectively) and specificity (82.9% [78.9‐86.5%], 78.2% [73.9‐82.1%], respectively) for distinguishing AD and amyloid‐positive MCI from all other dementias and CN controls (Table 2). Amyloid PET and FTP‐PET visual reads had similar diagnostic performance for distinguishing AD or amyloid‐positive MCI from non‐AD neurodegenerative disorders or CN controls (Table 3). FTP‐PET intra‐rater reliability ranged from κ=0.80‐1.00 (p<0.0001), and inter‐rater reliability between reader pairs ranged from κ=0.78‐0.85 (p<0.0001). Amyloid PET intra‐rater reliability was κ=0.97 (p<0.0001) for each reader, and inter‐rater reliability between reader pairs ranged from κ=0.82‐0.88 (p<0.0001). Conclusion: FTP and amyloid PET visual reads have similar diagnostic performance and high intra‐ and inter‐rater reliability. Further analysis will be performed to determine if patient characteristics can predict when one PET modality will outperform the other for AD diagnosis. [ABSTRACT FROM AUTHOR]

Background: We examined the associations of white matter hyperintensities (WMH), amyloid‐PET, and tau‐PET with multi‐domain cognitive performance in symptomatic patients on the Alzheimer’s disease (AD) continuum. Method: 119 amyloid‐PET‐positive patients diagnosed with MCI or AD dementia underwent 3‐Tesla structural MRI, 18F‐flortaucipir (tau)‐PET,11C‐PIB (amyloid)‐PET, and neuropsychological assessment. Standardized uptake value ratio (SUVR) flortaucipir‐ and PIB‐PET images were created using tracer‐specific reference regions and warped to template space. Patients were split based on availability of FLAIR‐MRI (Figure 1). The exploratory sample (n=50; no FLAIR) was used to run voxelwise models to identify regions where flortaucipir‐ and PIB‐PET were associated with episodic memory, executive, language, semantic memory, and visuospatial composite scores. In the validation sample (n=69), WMH were segmented from FLAIR and T1‐MRIs using a two‐step supervised algorithm. Linear regression models assessed the independent contributions of global WMH volume (corrected for intracranial volume and log‐transformed) and cognitive domain‐specific regional PET‐SUVR (derived in the exploratory sample) to each cognitive domain. Result: The two samples had comparable demographics and clinical characteristics, with relatively young age (mean ∼65.5) and moderate impairment (mean MMSE ∼ 22, Table 1). In the exploratory sample, cognitive scores were associated with regional flortaucipir‐SUVR patterns (Figure 2); PIB‐SUVR was not robustly associated with cognition. In the validation sample, global WMH volume was inversely correlated with global PIB‐SUVR (r=‐.25, p=.04) but not global cortical flortaucipir‐SUVR (r=‐.18, p=.15). Older age predicted lower cortical flortaucipir‐SUVR (r=‐.70, p<.001) and greater WMH volume (r=.46, p<.001). Female sex was specifically associated with greater cortical flortaucipir‐SUVR (d=0.64, p=.01; psdsps Conclusion: In patients at the early clinical stages of AD, tau‐PET and global WMH volume were not associated with each other, but independently contributed to cognitive impairment. These findings emphasize the clinical relevance of cerebrovascular injury in the context of AD pathology, even in younger patients. [ABSTRACT FROM AUTHOR]

Background: In Alzheimer's disease (AD), cognitive symptoms have varying associations with tau, amyloid and neurodegeneration. Patients with early‐onset AD (EOAD, age<65) have more non‐amnestic symptoms, greater AD pathological burden, and less co‐pathologies than late‐onset AD (LOAD, age≥65). It is unknown whether the association between cognitive symptoms and Alzheimer's disease biomarkers differs with age, and this has implications for clinical trials. The goal of this study was (1) to evaluate the association between domain‐specific cognitive performance and PET‐based pathology in AD, and (2) to compare whether theses associations differ in EOAD versus LOAD. Method: Amyloid‐positive patients meeting criteria for mild cognitive impairment or AD dementia (Total n=71; EOAD n=33, mean age 58±4, MMSE 20±7, 61% female; LOAD n=38, mean age 74±6, MMSE 24±5, 45% female) underwent neuropsychological testing, 18F‐flortaucipir (FTP‐PET), 11C‐PIB‐PET (PIB‐PET), and a subset underwent 18F‐fluorodeoxyglucose‐PET (FDG‐PET, n=57). Composite scores were calculated for episodic memory, semantic memory, language, executive function and visuospatial domains. Voxelwise regressions (thresholded at uncorrected p<0.001 voxel‐level, FWE p<0.05 cluster‐level) evaluated PET/cognition correlations, and EOAD versus LOAD differences were tested with a PET*group interaction. Mediation analyses assessed direct and FDG‐PET‐mediated associations between FTP‐PET and cognitive performance in regions‐of‐interest based on the voxelwise regressions. Results: FTP‐PET and FDG‐PET (lesser extent), but not PIB‐PET, showed significant domain‐specific voxelwise associations with cognitive performance that aligned with known brain‐behavior relationships (episodic memory/medial temporal lobe, semantic memory/anterior temporal, language/perisylvian, executive/frontal, visuospatial/occipital) (Figures 1‐3). There were no significant interactions between age and PET correlations across all modalities. Mediation analysis revealed that FDG‐PET mediated the relationship between FTP‐PET and cognition in all domains except episodic memory (Table 1). FTP‐PET also had a direct effect on executive function (p<0.001) and visuospatial (p=0.02) performance. Conclusion: In AD, cognitive performance correlated with tau and neurodegeneration, but not amyloid, in similar patterns across the age spectrum. The relationship between tau and cognition was in part mediated by glucose metabolism. These findings provide support for inclusion of EOAD patients in clinical trials, for tau PET as a biomarker that captures molecular specificity and aligns with clinical performance, and for the shared potential of disease‐modifying therapies across the AD age spectrum. [ABSTRACT FROM AUTHOR]

Background: Most theoretical frameworks for Alzheimer's disease (AD) pathogenesis propose amyloid as the primary pathologic process, whereas tau in the absence of amyloid (A‐/T+) is considered a "non‐AD pathologic change" (Jack et al., 2018). Previous research has demonstrated AD‐like characteristics of the A‐/T+ biomarker profile, including poorer memory and language performance and entorhinal thinning (Weigand et al., 2022; Yoon et al., 2022). Assessment of domain‐specific longitudinal cognitive decline in this group, however, has not yet been addressed. Our study sought to evaluate 1‐year memory, language, and attention/executive function trajectories of A‐/T+ older adults. Method: We included 756 older adults at baseline across the AD clinical continuum from the Alzheimer's Disease Neuroimaging Initiative (ADNI), of whom 359 had 1‐year follow‐up cognitive data. Four A/T groups were classified based on cortical amyloid‐beta and medial temporal tau positron emission tomography positivity. Linear mixed effects models examined 1‐year trajectories of each baseline A/T group in domains of memory, language, and attention/executive function. Both statistical significance and effect size estimates were evaluated. Result: The following proportions of A/T groups were observed at baseline: 47.0% A‐/T‐, 13.2% A‐/T+, 13.4% A+/T‐, and 26.4% A+/T+. Only the A+/T+ group exhibited a statistically significant decline in language and attention/executive function domains relative to the A‐/T‐ group. Examination of effect sizes, however, revealed that the A‐/T+ group had a quantitatively similar degree of decline as the A+/T+ group in memory (A‐/T+ and A+/T+ bs = ‐0.13), and an intermediate degree of decline between the A‐/T‐ and A+/T+ groups for language (A‐/T+ b = ‐0.17) and attention/executive function (A‐/T+ b = ‐0.19). Similar patterns were observed when examining cognitively unimpaired participants only. Conclusion: Older adults with the A‐/T+ biomarker profile demonstrate a degree of cognitive decline across multiple domains consistent with a possible AD trajectory. The systematic exclusion of these individuals from AD clinical trials may hinder early intervention efforts to attenuate the cognitive decline observed in this biomarker group, and an expansion of our conceptualization of the AD continuum to include A‐/T+ individuals may offer improved insight into the pathologic and cognitive changes that occur in the context of preclinical AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease clinical expression is highly heterogeneous: cognitive and anatomical variations exist on a multi‐axis spectrum with well‐described variants like posterior cortical atrophy (PCA) or logopenic variant of primary progressive aphasia (lvPPA) representing extreme phenotypes of so‐called "atypical" AD. Here, we provide an overview of our investigations of PCA and lvPPA using structural MRI and amyloid/tau‐PET imaging, emphasizing both the differences and the similarities between these phenotypes and more typical presentations of AD. Method: We investigated 97 amyloid‐positive patients with a clinical diagnosis of AD (MCI or dementia stage), including 18 patients with PCA and 19 with lvPPA; the remaining patients are referred to as typical (tAD; Table 1). Patients received 3‐tesla MRI and PET with [11C]PIB and [18F]Flortaucipir. Standardized Uptake Value Ratio (SUVR) images were created using specific reference regions. Mean SUVR or cortical thickness values were extracted from 72 FreeSurfer regions, and cortical asymmetry indices were calculated. Result: Atypical variants tended to be younger and less likely to carry APOE4 than tAD (Table1). Global amyloid burden did not vary across phenotypes or with any clinical measure (Figure 1A). The cortical distribution of PIB was widespread and only showed minor differences between variants (Figure 2A). In contrast, global Flortaucipir‐SUVR was higher in atypical groups compared to tAD, and was lower in older patients across phenotypes (Figure 1A). Flortaucipir was consistently elevated in temporo‐parietal regions but also showed strong between‐variant regional differences (Figure 2B) that mirrored differences in cortical volume (Figure 3B). Flortaucipir and MRI asymmetries were strongly inter‐related and very common across all AD phenotypes rather than specific to atypical variants (Figure 3). However, asymmetry was systematic in lvPPA (84‐95% left‐predominant, 5% right‐predominant) and PCA (33% left‐predominant, 66% right‐predominant) Conclusion: Atypical phenotypes share various features with tAD: i) widespread cortical amyloid deposition, ii) tau pathology in the temporo‐parietal areas, iii) higher tau burden associated with earlier disease onset, iv) a strong negative relationship between tau and local cortical volume. The main between‐phenotype differences were related to the distribution of tau and associated atrophy that were more left‐predominant and perisylvian in lvPPA, and more occipital and asymmetric in PCA. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease clinical expression is highly heterogeneous: cognitive and anatomical variations exist on a multi‐axis spectrum with well‐described variants like posterior cortical atrophy (PCA) or logopenic variant of primary progressive aphasia (lvPPA) representing extreme phenotypes of so‐called "atypical" AD. Here, we provide an overview of our investigations of PCA and lvPPA using structural MRI and amyloid/tau‐PET imaging, emphasizing both the differences and the similarities between these phenotypes and more typical presentations of AD. Method: We investigated 97 amyloid‐positive patients with a clinical diagnosis of AD (MCI or dementia stage), including 18 patients with PCA and 19 with lvPPA; the remaining patients are referred to as typical (tAD; Table 1). Patients received 3‐tesla MRI and PET with [11C]PIB and [18F]Flortaucipir. Standardized Uptake Value Ratio (SUVR) images were created using specific reference regions. Mean SUVR or cortical thickness values were extracted from 72 FreeSurfer regions, and cortical asymmetry indices were calculated. Result: Atypical variants tended to be younger and less likely to carry APOE4 than tAD (Table1). Global amyloid burden did not vary across phenotypes or with any clinical measure (Figure 1A). The cortical distribution of PIB was widespread and only showed minor differences between variants (Figure 2A). In contrast, global Flortaucipir‐SUVR was higher in atypical groups compared to tAD, and was lower in older patients across phenotypes (Figure 1A). Flortaucipir was consistently elevated in temporo‐parietal regions but also showed strong between‐variant regional differences (Figure 2B) that mirrored differences in cortical volume (Figure 3B). Flortaucipir and MRI asymmetries were strongly inter‐related and very common across all AD phenotypes rather than specific to atypical variants (Figure 3). However, asymmetry was systematic in lvPPA (84‐95% left‐predominant, 5% right‐predominant) and PCA (33% left‐predominant, 66% right‐predominant) Conclusion: Atypical phenotypes share various features with tAD: i) widespread cortical amyloid deposition, ii) tau pathology in the temporo‐parietal areas, iii) higher tau burden associated with earlier disease onset, iv) a strong negative relationship between tau and local cortical volume. The main between‐phenotype differences were related to the distribution of tau and associated atrophy that were more left‐predominant and perisylvian in lvPPA, and more occipital and asymmetric in PCA. [ABSTRACT FROM AUTHOR]

Background: Tau‐PET is included in the AT(N) research framework to define T‐status. However, no consensus exists as to how to classify patients as T+ or T‐ with this modality. We aim to compare T‐status derived from 18F‐Flortaucipir (FTP) PET visual assessment, 18F‐FTP SUVR quantification, and CSF pTau. Methods: 278 subjects who underwent 18F‐FTP PET and CSF analysis within 1 year were included from UCSF and ADNI. The cohort consisted of a continuum from cognitively normal controls (CN) to Alzheimer's disease dementia (AD), and non‐Alzheimer's disorders (clinical diagnoses, Table 1). T‐status was derived from: (1) 18F‐FTP consensus between two readers performing blinded visual assessment based on a priori criteria (Figure 1, inter‐rater k=0.68, 95%CI 0.59‐0.76; Provost et al, HAI Conference, 2020); (2) 18F‐FTP SUVR quantification of from a temporal meta‐ROI using a previously validated threshold (SUVR >1.27, Ossenkoppele et al. 2018); (3) Elecsys® Phospho‐Tau (181P) CSF (Roche Diagnostics) applying a ROC‐based threshold derived from an external ADNI cohort comparing amyloid‐positive AD vs. healthy controls (pTau >24.5 pg/mL). Results: T+ was assigned in a higher proportion of AD, MCI and amyloid‐positive CN with 18F‐FTP visual assessment compared to 18F‐FTP SUVR and CSF pTau (Table 2). However, visual ratings also yielded the highest proportion of T+ in amyloid‐negative CN and MCI. Contrasting amyloid‐positive AD/MCI with other groups, sensitivity was highest for 18F‐FTP visual assessment, while specificity was highest for 18F‐FTP SUVR (Table 3). In a subset of patients with autopsy (n=11), T‐status derived from 18F‐FTP visual assessment had an accuracy of 100%, compared to 82% for SUVR quantification and 64% for CSF pTau. Overall agreement between the 3 classification criteria ranged from 68% to 76% in the whole cohort (Figure 2) and was highest in patients with AD (94%). Patients with concordant T‐status across all three modalities were significantly younger, had higher CSF pTau, higher 18F‐FTP SUVR (Figure 3), and were more likely to be amyloid positive. Conclusions: Concordance of T‐status derived from 18F‐FTP visual assessment, SUVR quantification and CSF pTau varies across disease stage, being highest in AD. 18F‐FTP visual assessment offers highest sensitivity, while SUVR threshold maximizes specificity. [ABSTRACT FROM AUTHOR]

Introduction: We investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early‐onset versus late‐onset Alzheimer's disease (EOAD and LOAD). Methods: Plasma was analyzed using ultra‐sensitive immuno‐based assays from 33 EOAD, 30 LOAD, and 36 functionally normal older adults. Results: Principle component analyses identified 3 factors: trophic (BDNF, VEGF, TGFβ), degenerative (GFAP, NfL), and inflammatory (TNFα, IL‐6, IP‐10, IL‐10). Trophic factor was elevated in both AD groups and associated with cognition and gray matter volumes. Degenerative factor was elevated in EOAD, with higher levels associated with worse functioning in this group. Biomarkers of inflammation were not significantly different between groups and were only associated with age. Disucssion: Plasma proteomic biomarkers provide novel means of investigating molecular processes in vivo and their contributions to clinical outcomes. We present initial investigations of several of these fluid biomarkers, capturing aspects of astrocytopathy, neuronal injury, cellular plasticity, and inflammation in EOAD versus LOAD. [ABSTRACT FROM AUTHOR]

The representation of women in faculty roles within universities broadly and within public affairs departments specifically has been evolving over the past three decades. However, diversifying gender representation in public affairs faculties is not sufficient. Barriers for success remain for women in public affairs departments. Bias exists in hiring and promotion decisions, imbalanced expectations of institutional norms and expectations persist, and fault lines emerge through the diversification of departments. Inclusion is the necessary next step to make representation more meaningful implementation of diversity. The article provides suggestions on how public affairs departments can promote more inclusive climates to elicit the positive effects of gender diversity and alleviate the negative consequences of more diverse faculties. [ABSTRACT FROM AUTHOR]

Background: Few studies have evaluated the relationship between in vivo [18F]Flortaucipir (FTP) PET and post‐mortem pathology. Method: We sought to compare antemortem FTP‐PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative diseases. 80‐100 min FTP‐PET standardized uptake value ratio (SUVR) images were created using an inferior cerebellar gray matter reference. W‐score maps were generated to highlight areas of increased tracer retention compared to cognitively normal controls, adjusting for age as a covariate. Autopsies were performed blinded to PET results. Mean SUVRs were calculated for Braak stage regions of interest (ROIs), and these values were compared to SUVRs derived from young, non‐autopsy, cognitively normal controls used as a standard for tau negativity. Result: Nineteen patients were included (mean age at PET 61 [range 34‐76]; 8 female; mean PET‐to‐autopsy time of 30 months [range 4‐59 months]; Table 1). Eight patients had primary Alzheimer's disease (AD) pathology, 9 had non‐AD tauopathies (progressive supranuclear palsy [PSP], corticobasal degeneration [CBD], argyrophilic grain disease [AGD], and frontotemporal lobar degeneration [FTLD] with tau inclusions), 2 patients had non‐tau related FTLD. There was excellent correspondence between areas of FTP retention and neurofibrillary tangle (NFT) distribution in patients with primary AD neuropathology. Patients with non‐AD tauopathies showed a range of tracer retention that was less than AD and more than age‐matched, cognitively normal controls, with CBD and FTLD due to MAPT mutations showing the most extensive and distinct binding patterns (Figure 1). Patients with non‐tau related FTLD also showed small areas of tracer retention (Figure 1). Overall, binding across both tau‐positive and tau‐negative non‐AD disorders did not reliably correspond with post‐mortem tau pathology. Quantification of FTP‐PET SUVR images at Braak stage ROIs reliably detected high Alzheimer's Disease Neuropathologic Change (Braak VI) pathology. However, patients with earlier Braak stages did not show elevated tracer uptake in these regions compared to young, tau‐negative controls (Figure 2). Conclusion: In summary, PET‐to‐autopsy correlations confirm that FTP‐PET is a reliable biomarker of advanced tau pathology in AD. The tracer cannot reliably differentiate non‐AD tauopathies and may not detect early Braak stages of NFT pathology. [ABSTRACT FROM AUTHOR]

Background: The high cognitive and anatomical heterogeneity in phenotypical variants of Alzheimer's Disease imposes a formidable challenge for biomarker‐based discriminatory models. Motivated by recent findings (La Joie, 2020) suggesting a causal relationship between regional tau accumulation and future atrophy development, we used Machine Learning techniques to test whether colocalization of these two biomarkers could improve clinical differentiation of AD phenotypical variants. Method: We investigated 85 amyloid‐positive patients with a clinical diagnosis of AD (MCI or dementia stage), including 17 patients with PCA, 16 with lvPPA, and 52 typical cases (tAD, Table 1). Patients received 3‐tesla MRI and PET with [11C]PIB and [18F]Flortaucipir. Thickness measurements were turned into age and sex adjusted z‐scores (Potvin, 2017). Standardized Uptake Value Ratio (SUVR) images were created using reference regions. Mean SUVR or cortical thickness values were extracted from 72 FreeSurfer regions (Figure 1). Random Forest (RF) and Support Vector Machines (SVM) were used for supervised classification of patients into one of the three diagnosis above. Four distinct models were compared: based on amyloid, atrophy, tau, or on the product between atrophy and tau (hence capturing the colocalization of these two biomarkers). Selected ROIs were acquired using SVM feature importance and used in a second SVM method (SVM‐ROIs). Result: Figure 2a shows the accuracy of the classification models as a function of the used input features. As a general trend: i) amyloid‐based models had the poorest classification accuracy; ii) tau‐based SVM models outperformed atrophy‐based predictions; iii) the product of atrophy and tau significantly improved accuracy; and iv) in SVM models, selection of a subset of regions consistently improved classifications over those models using all brain regions. Figure 2b shows the confusion matrix for the most accurate model (SVM on selected ROIs). Conclusion: In the cohort used in this study, the product of atrophy and tau provides a better classification feature than each feature considered in isolation. Our results suggest that the colocalization of these two biomarkers represent a valuable instrument for clinical decision‐making in phenotypical variants of AD. References: La Joie, et al. Science Translational Medicine (2020). Potvin, et al. Neuroimage (2017). [ABSTRACT FROM AUTHOR]

Background: We assessed the relative contributions of four potential mechanisms associated with [18F]‐Fluorodeoxyglucose (FDG)‐PET hypometabolism in the posterior cingulate cortex (PCC) and inferior parietal (IP) lobe, two primary regions of hypometabolism in AD: 1) local (amyloid and tau) pathology and atrophy, 2) pathology in functionally connected regions, 3) deafferentation from the degenerating medial temporal lobe (MTL), and 4) vascular injury in the white matter (Figure 1). Method: Eighty‐five patients with MCI or AD dementia underwent MRI and PET with FDG for glucose metabolism, [11C]‐Pittsburgh Compound B (PIB) for amyloid, and [18F]‐Flortaucipir (FTP) for tau within one year (Table 1). SUVR were calculated using tracer‐specific reference regions: pons for FDG, cerebellar cortex for PIB, and inferior cerebellar cortex for FTP. ROIs and volume of white matter hyperintensities (WMH) were defined in native space using FreeSurfer. Regions with high or low connectivity to PCC/IP were defined based on task‐free fMRI data from cognitively normal participants from neurosynth.org (Figure 2). Imaging variables were transformed into age‐adjusted z‐scores using demographic‐matched modality‐specific control groups (Table 1). Multiple regression analyses were run to identify variables associated with FDG‐SUVR, using a composite disease severity score combining Mini‐Mental State Examination and Clinical Dementia Rating scores as a covariate. Result: Local gray matter volume (GMV) and FTP‐SUVR, but not PIB‐SUVR, were independently associated with FDG‐SUVR in PCC (R2=.603, βGMV=0.353, βFTP=‐0.374) and IP (R2=.702, βGMV=0.419, βFTP=‐0.361) in a model that included disease severity (Table 2). Models including PIB/FTP in connected regions did not outperform models with disease severity and local GMV/FTP alone. Results were similar when including measures of pathology in non‐connected regions. Similarly, models including MTL volume did not outperform models with disease severity and local GMV/FTP alone. Volume of WMH was weakly associated with FDG‐SUVR in PCC but not IP. Conclusion: Hypometabolism reflected local atrophy and tau pathology. A weak association between WMH volume and PCC hypometabolism was seen, suggesting that white matter damage may also be a driver of hypometabolism. Our data did not support hypotheses of a detrimental effect of pathology in connected regions or MTL volume in the symptomatic stage of AD. [ABSTRACT FROM AUTHOR]

Background: The 2018 NIA‐AA Alzheimer's disease (AD) Research Framework states that subtle cognitive decline in cognitively unimpaired individuals can be measured by subjective report or evidence of objective decline on neuropsychological measures. Both subjective memory complaint (SMC) and objective subtle cognitive decline (Obj‐SCD) have been shown to be associated with future cognitive decline and AD biomarkers. We examined whether there are tau PET differences in a) SMC‐ vs. SMC+ participants, b) Obj‐SCD‐ vs. Obj‐SCD+ participants, and c) participants with overlapping/discrepant SMC and Obj‐SCD classifications. Method: Participants without MCI or dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 236) were classified at baseline as positive or negative for SMC (SMC‐ n = 77; SMC+ n = 159) based on the first 12 items of the Cognitive Change Index and/or classified as positive or negative for Obj‐SCD (Obj‐SCD‐ n = 173; Obj‐SCD+ n = 63) based on previously defined neuropsychological criteria. Analyses of covariance, adjusting for age, sex, APOE ε4 status, and pulse pressure, examined group differences in tau PET (AV‐1451) using a composite SUVR for regions consistent with Braak stage III/IV. Chi‐squared tests examined tau positivity rates across groups. Result: Obj‐SCD+ participants had higher tau levels (p =.035, ηp2 =.019) and higher rates of tau positivity (15.8% Obj‐SCD‐ vs. 30.2% Obj‐SCD+) than Obj‐SCD‐ participants. Neither tau levels (p =.381, ηp2 =.003) nor tau positivity rates (18.2% SMC‐ and 20.1% SMC+) differed for SMC groups. There was little agreement between SMC and Obj‐SCD (42%; κ = 0.01, p =.811). Participants with only Obj‐SCD had the highest tau PET levels and differed from participants with only SMC (p =.022). Tau levels in SMC+/Obj‐SCD+ participants did not differ from those with only Obj‐SCD (p =.216). Tau positivity rates across SMC‐/Obj‐SCD‐, SMC+/Obj‐SCD‐, SMC‐/Obj‐SCD+, and SMC+/Obj‐SCD+ groups were 10.5%, 18.1%, 40.0%, and 25.6%, respectively. Conclusion: Participants with Obj‐SCD had greater tau burden than those without Obj‐SCD, but SMC was not associated with higher tau levels. The combination of SMC and Obj‐SCD did not have higher tau levels than Obj‐SCD alone. Findings add to the evidence that the Obj‐SCD classification is associated with AD biomarkers and faster cognitive decline in ADNI participants, but further work is needed to validate this approach in more representative/diverse cohorts. [ABSTRACT FROM AUTHOR]

Background: It has consistently been demonstrated that individuals with higher cognitive reserve (CR) exhibit decreased risk for dementia, and differences in cerebral blood flow (CBF) among those with higher CR may offer a protective mechanism against the cognitive changes associated with dementia. We sought to investigate CR as a moderator of the effect of CBF on memory and language performance in patients with mild cognitive impairment (MCI) and those who are cognitively unimpaired (CU). Method: Older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 46 MCI, 101 CU) underwent neuropsychological evaluation and arterial spin labeling MRI, which was used to quantify CBF in a priori regions. Estimated VIQ from the American National Adult Reading Test was used as a CR proxy. Multiple linear regressions assessed for (1) effect of CR on cognition, (2) effect of CR on CBF, and (3) interaction between CR and CBF on cognition. Cognitive outcomes included memory (word list) and language (category fluency, naming). All models adjusted for age, gender, APOE e4 allele frequency, and education, and interactions additionally adjusted for baseline FDG and pulse pressure. Result: VIQ was not associated with memory but was positively associated with fluency and naming in both groups (ps<0.005). VIQ was not associated with CBF in either group. Individuals with MCI showed a significant interaction between VIQ and CBF on fluency across several regions, including the bilateral hippocampus (p = 0.003), bilateral inferior temporal gyrus (p = 0.008), superior frontal gyrus (p = 0.005), and inferior frontal gyrus (p<0.001). For all models, as CR increased, the magnitude of the association between CBF and performance increased. These interactions were not significant in the CU group. Models with naming or memory as the outcome variable were not significant in either group. Results remained similar when education was not adjusted for. Conclusion: These results suggest that among individuals with MCI, the association between CBF and category fluency is dependent on CR, even after adjusting for several factors. Specifically, higher CR may serve as a protective factor against the negative effect of CBF reductions on fluency. Further research is needed to clarify the role that CR plays as a moderator of CBF and cognition. [ABSTRACT FROM AUTHOR]

Background: White matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, increase risk of developing mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, less is known about the extent and pattern of WMH in pre‐MCI stages, such as among those with objectively‐defined subtle cognitive decline (Obj‐SCD). Therefore, we aimed to examine regional WMH volume in Obj‐SCD versus those who were cognitively normal (CN) and MCI. Method: Six hundred twenty‐one Alzheimer's Disease Neuroimaging Initiative participants (182 CN; 96 Obj‐SCD; 343 MCI) underwent neuropsychological testing and MRI exams. Cerebrospinal fluid (CSF) data were available for ∼50% of the sample. MCI was classified using Jak/Bondi criteria and Obj‐SCD was classified using criteria proposed by Thomas et al. (2018, 2020). ANCOVA models were used to compare cognitive groups on regional WMHs adjusting for age, sex, and apolipoprotein E (APOE) ɛ4 status. We also ran analyses stratified by CSF phosphorylated tau (p‐tau)/amyloid‐β (Aβ) ratio positivity versus negativity. Result: Compared to the CN group, those with Obj‐SCD had greater frontal (p=.036) and temporal WMH (p=.034) with a trend toward greater occipital WMH (p=.052). Those with MCI had greater frontal, temporal, parietal, and occipital WMH (p's <.01). No significant differences in WMH volume were observed between Obj‐SCD and MCI (p's >.05). Among p‐tau/Aβ negative individuals, those with Obj‐SCD showed a trend toward greater temporal WMH (p=.053) compared to CN individuals. In addition, the p‐tau/Aβ negative MCI participants showed significantly higher frontal (p=.001), temporal (p=.004), and parietal (p=.027) WMH relative to the CN group. Among p‐tau/Aβ positive individuals, there were no significant group differences in WMH volume. Conclusion: Regional WMH vary across cognitive groups. Compared to the CN group, the Obj‐SCD group showed higher temporal and frontal WMH whereas the MCI group showed more widespread WMH increases affecting all lobes, which is in line with their greater cognitive impairment. Notably, these findings do not appear to be driven by p‐tau/Aβ positive individuals. Findings add to growing evidence of associations between Obj‐SCD and imaging biomarkers, providing support for utility of our criteria to capture very subtle cognitive changes. [ABSTRACT FROM AUTHOR]

Background: Approximately 5% of Alzheimer disease (AD) occurs before the age of 65, known as early onset AD (EOAD); 5‐10% of the patients with EOAD are caused by dominantly inherited mutations (DIAD) and the remainder appear to be sporadic EOAD (sEOAD). The extent to which clinical presentations, cognitive and biomarker profiles in DIAD and sEOAD overlap remains unknown. Methods: We compared the clinical presentation, cognitive performance and cerebrospinal fluid (CSF) AD biomarker concentrations in DIAD and sEOAD. We included all DIAD symptomatic (CDR>0) participants (n=92) from the Dominantly Inherited Alzheimer Network (DIAN) cohort and 120 sEAOD symptomatic participants from the UCSF Alzheimer's Disease Research Center. All EOAD cases were amyloid‐positive via PIB‐PET. All participants completed clinical measures, a battery of cognitive tests and CSF biomarker studies (Aβ‐42, p‐tau‐181, t‐tau). Baseline differences in clinical and biomarkers variables between sEOAD and DIAD were compared using t‐tests, and differences in the rates of decline on clinical and cognitive measures were compared using linear mixed effects models. Results: DIAD participants had an earlier age at symptom onset compared to the sEOAD group (42.9y (±8.1) and 54.8y (±5.1) respectively, p<0.001). The sEOAD group showed a lower performance on executive measures, including verbal fluency (p=0.001), Trail making test (p=0.001) and digit span (p<0.001). CSF Aβ‐42 levels were significantly lower in DIAD compared to sEOAD participants (242.0 pg/ml [IQR=164.5, 318.8] vs 295.0 pg/ml [IQR=243.9, 364.1] respectively, p=0.014). Ptau‐181 levels were higher in the DIAD cohort (p=0.003), but no significant differences were found for t‐tau levels (p=0.11). Longitudinal analyses did not reveal significant differences in the rates of functional (CDRTM‐SB) and cognitive (MMSE) decline between two groups. Conclusions: Although sporadic and inherited EOAD differed in AD core pathological CSF biomarkers concentrations and baseline cognitive profiles, the rates of functional and cognitive changes were similar across these groups. These findings provide unique insights into the similarities and differences between DIAD and sEOAD and may inform the design of future clinical trials. [ABSTRACT FROM AUTHOR]

Background: Intraindividual variability (IIV) across neuropsychological measures within a single testing session has become a promising sensitive marker predictive of cognitive decline and development of Alzheimer's disease (AD). We have previously shown that higher IIV is associated with medial temporal lobe atrophy. However, to our knowledge, IIV has yet to be examined in relation to cerebral blood flow (CBF). Therefore, we examined associations between IIV and regional CBF among older adults free of dementia. Method: 141 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants underwent neuropsychological testing, magnetic resonance imaging (MRI), and florbetapir positron emission tomography (PET) imaging. The IIV index was calculated as the intraindividual standard deviation across 6 demographically‐corrected neuropsychological measures. Mean neuropsychological performance was computed as the mean of the 6 z‐scores. Pulsed arterial spin labeling MRI was used to quantify CBF. Six free‐surfer derived a priori CBF regions of interest were examined: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. PET amyloid‐β (Aβ) positivity was determined using the recommended threshold for cross‐sectional florbetapir of 1.11 using whole cerebellum as the reference region. Result: In the entire sample, linear regression models showed that after adjusting for age, sex, mean neuropsychological performance, and regional cortical thickness, greater IIV was significantly associated with lower inferior parietal CBF (β=‐2.712, p=.004), inferior temporal CBF (β=‐3.259, p=.001), and reduced entorhinal CBF at trend level (β=‐.407, p=.073). Sensitivity analyses showed that among Aβ+ individuals, greater IIV was significantly associated with lower CBF in inferior parietal (β=‐2.729, p=.018) and inferior temporal regions (β=‐2.704, p=.043). In Aβ‐ individuals, there were no significant associations between IIV and CBF (all ps>.05). Conclusion: IIV may be sensitive to early cerebrovascular changes in AD‐vulnerable regions above and beyond demographics, mean neuropsychological performance, and cortical thickness. These relationships were seen among Aβ+ individuals, suggesting that IIV may be a marker of early brain changes among those individuals on the AD continuum. Future studies should examine how IIV may predict future brain and cognitive changes in more diverse samples and among those with greater vascular risk burden. [ABSTRACT FROM AUTHOR]

Background: Approximately 5% of patients with Alzheimer’s Disease (AD) develop symptoms before age 65, with this early‐onset presentation attributed to either sporadic (sEOAD) or dominantly‐inherited (DIAD) etiology. Both sEOAD and DIAD are characterized by brain amyloid‐beta (Aβ) accumulation and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. Method: We included 108 sEOAD Aβ‐PET positive cases from the UCSF Alzheimer’s Disease Research Center (mean±standard deviation age 59.7±5.4 years) and 86 DIAD cases from the Dominantly Inherited Alzheimer Network (DIAN) study (age 45.5±9.5 years) with symptom onset before 65 years (see Table 1). All cases were symptomatic (clinical dementia rating [CDR] global ≥0.5) and underwent standard clinical and cognitive measures, 11C‐PiB‐PET (Aβ), 18F‐FDG‐PET (glucose metabolism) and structural MRI. PET scans were processed to obtain Standardized Uptake Value Ratio (SUVR, PIB50‐70, FDG30‐60) images. Warped PET SUVR and modulated, warped gray matter images were compared across the two cohorts with SPM12 after smoothing to ∼8mm3, covarying for age, CDR sum of boxes, years of education, APOE e4 status, and respective global biomarker score. A‐priori statistical threshold was set at p<0.001 uncorrected, with a Family Wise Error p<0.05 correction at the cluster‐level. Result: sEOAD participants were older, more educated, had greater cognitive impairment, had higher Aβ burden and were more likely to be APOE ε4 carriers (see Table 1). sEOAD participants exhibited higher relative PIB‐PET binding in anterior temporal and frontal (mostly white matter) regions, as well as lower relative FDG‐PET binding and sMRI‐based volumes in temporoparietal regions. DIAD participants showed higher relative PIB‐PET binding in the medial occipital, thalami, basal ganglia (caudate nuclei and putamen) and medial/dorsal frontal regions. DIAD participants showed lower relative FDG‐PET binding mostly in the frontal and parietal white matter (see Figure 1). Conclusion: Aβ pathology in DIAD was more likely to affect subcortical systems, whereas both Aβ pathology and neurodegeneration tended to be relatively more cortical and extensive in sEOAD. These results highlight EOAD heterogeneity and show that sporadic and inherited AD exhibit distinct regional vulnerabilities in neurodegeneration as well as differing topography and magnitude of biomarker abnormalities. [ABSTRACT FROM AUTHOR]