Background Cerebral amyloid angiopathy (CAA), a cerebral small vessel disease characterized by vascular amyloid deposition, presents with heterogeneous imaging features, but the biological mechanisms underlying hemorrhagic markers remain unclear. We assessed hemorrhage patterns in CAA to determine their associations with amyloid burden and related imaging markers. Methods Sixty‐two patients with probable CAA underwent Pittsburgh compound B‐positron emission tomography and structural magnetic resonance imaging. Participants were classified by dominant hemorrhagic pattern: lobar cerebral microbleed‐dominant (n=31), cortical superficial siderosis‐dominant (n=17), and nondominant (n=14). Global cortical amyloid burden was quantified as Pittsburgh compound B distribution volume ratio. White matter hyperintensity volume and high‐degree centrum semiovale‐enlarged perivascular spaces were assessed. Associations were tested using age‐ and sex‐adjusted regression models. Results Global Pittsburgh compound B distribution volume ratio was significantly higher in the cerebral microbleed‐dominant (1.40±0.23) and cortical superficial siderosis‐dominant (1.45±0.27) groups than nondominant group (1.20±0.17; P=0.007 and P=0.006, respectively), and these associations remained independent after adjustment (odds ratio [OR], 1.8 [95% CI, 1.1–2.8]; P=0.009 and OR, 1.6 [95% CI, 1.1–2.5]; P=0.020). Compared with the nondominant group, high‐degree centrum semiovale‐enlarged perivascular spaces were independently associated with both cerebral microbleed‐dominant (OR, 9.3 [95% CI, 1.6–52]; P=0.011) and cortical superficial siderosis‐dominant (OR, 10 [95% CI, 1.6–62]; P=0.013). In the full cohort, Pittsburgh compound B distribution volume ratio was independently associated with high‐degree centrum semiovale‐enlarged perivascular spaces (P=0.016) and white matter hyperintensity volume (P=0.049). Findings were unchanged in sensitivity analyses, adjusting for intracerebral hemorrhage. Conclusions Amyloid burden in CAA is associated with hemorrhage‐dominant patterns, high‐degree centrum semiovale‐enlarged perivascular spaces, and greater WMH volume. These findings support a close link between vascular amyloid deposition and downstream vascular brain injury, underscoring its relevance as a therapeutic target in CAA.

Background Prevention of Alzheimer’s disease (AD) requires biomarkers sensitive to the earliest amyloid-β (Aβ) deposits. Objectives To characterize performance of a recently-developed Aβ-PET spatial extent metric (EXT) for early Aβ detection using 18[F]-florbetapir (FBP)-PET, evaluating its sensitivity, reliability, and associations with plasma pTau217, tau-PET, and cognition. Design Longitudinal study with up to 5.5 years of PET, plasma and cognitive measures. Setting The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) Study and its companion screen-fail study Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) conducted across 67 international sites. Participants 1118 cognitively unimpaired older adults from the A4 placebo arm and LEARN. Measurements EXT (% of neocortex above region-specific thresholds), global Aβ SUVR, plasma pTau217, medial temporal (MTL) and temporal neocortical (nTEMP) tau-PET SUVR, and Preclinical Alzheimer Cognitive Composite (PACC). Results EXT showed high cross-sectional reliability and longitudinal stability. Using EXT reclassified 21.4% of SUVR-participants from Aβ− to Aβ+ and predicted who would progress to SUVR+ 5.5 years later with 83% sensitivity and 94% specificity. In SUVR− individuals, higher pTau217 associated with greater SUVR only within EXT+ individuals. Baseline EXT outperformed SUVR in predicting MTL tau proliferation. For neocortical tau SUVR and PACC change, EXT was the better predictor in earlier Aβ stages (while Aβ spread) while SUVR was superior later (after Aβ was widespread). Conclusions EXT is a robust, generalizable PET metric that detects Aβ before global positivity and early Aβ-related changes in tau and cognition, supporting its relevance for trial enrichment and early therapeutic monitoring in AD prevention trials.

Higher cerebrospinal fluid noradrenergic metabolic turnover has been associated with higher levels of Alzheimer’s disease pathology in cognitively impaired individuals. It remains unclear whether there is a specific anatomic vulnerability to metabolic alterations within the locus coeruleus (LC) and whether this hypermetabolism relates to steeper rates of pathology accumulation. Here, we overcome a spatial limitation of Positron Emission Tomography (PET) imaging in small nuclei with a dedicated Magnetic Resonance Imaging (MRI)-guided framework to recover PET resolution. This method allowed us to investigate the [ 18 F]Fluorodeoxyglucose (FDG)-PET signal, reflecting energetic metabolic demand of the LC and its association with serial beta-amyloid and tau-PET. We included 78 amyloid-positive, cognitively impaired participants from the ADNI-3 cohort (Table 1). The LC was identified using a dilated Keren template registered to each T1 (Figure 1A). The LC mask was subdivided into a rostral, middle, and caudal part to investigate region-specific associations (Figure 1B). We used an MR joint-entropy-penalty algorithm to quantify PET signal via deconvolution based on spatially-variant blur kernels. The deconvolution step was stabilized using an anatomical-based joint-entropy prior (Figure 1C). The FDG-PET signal was referenced to the pons, excluding the LC (Figure 1D). Amyloid positivity was determined as a centiloid score ≥ 21, reflecting moderate neuritic plaques, on florbetaben and florbetapir scans. Linear mixed effects models investigated relationships between LC-FDG, global beta-amyloid and meta-temporal tau burden (flortaucipir) over time. Age and sex were included as covariates. Higher LC FDG-PET signal was associated with higher meta-temporal tau-PET at baseline (T=2.87, p=0.00463) and accumulation over time (T=2.257, p=0.0273; Figure 2A&C). Higher LC FDG-PET signal was associated with higher global amyloid at baseline (T=2.066, p=0.041) and faster amyloid accumulation over time in the dementia group (T=-2.74, p=0.00904; Figure 2B&D), following a rostro-caudal gradient. In a cohort with cognitive impairment, we observed steeper accumulation of Alzheimer’s disease pathology in individuals with higher LC FDG-PET signal, with a specific amyloid-related vulnerability for the rostral parts of the LC. Future steps will be to include cognitively unimpaired individuals to investigate the relationship between LC FDG-PET signal and pathology accumulation in early stages of the disease process.

Estimating the time course of locus coeruleus integrity changes is important for a better understanding of the pathophysiological cascade and for identifying the optimal window of opportunity for prevention trials. We used samples iterative local approximation (SILA) to determine the individual estimated time of onset of low LC integrity and related this to early cortical tau deposition and cognitive decline. 101 individuals from the Harvard Aging Brain Study+ with longitudinal 3T MRI-LC imaging, 18F-Flortaucipir (FTP)-PET imaging (n=92 with longitudinal data), longitudinal cognitive assessments and baseline PiB-PET imaging were included (mean age: 69.97 years (SD: 12.46); 62 females; Table 1). LC intensity was derived by normalizing the LC to the pontine reference and averaging 5-voxel-clusters with the highest intensities (GMM-based cut-off: <1.34 = LC+). FTP-burden was quantified in the entorhinal cortex (cerebellar grey reference region, partial volume corrected, GMM-based cut-off: >1.41 SUVr = EC+). SILA was used to model trajectories of LC intensity and EC FTP separately. Time to onset of LC+ was correlated with baseline entorhinal tau and neocortical amyloid. Repeated measures correlations related the time to onset to LC+ to longitudinal entorhinal FTP and longitudinal PACC scores. Time to onset to LC+ and elevated EC+ were correlated to each other. 75.25% (n=76) of the individuals were considered LC+ (Figure 1A) and 40.22% (n=37) was EC+ (Figure 2A). Being closer to the LC+ time to onset was correlated with higher entorhinal FTP (r=0.34, p<0.001), but not with neocortical PiB (r=0.09, p=0.42; Figure 1B-C). Moving closer to the time to onset to LC+ was associated with faster accumulation of entorhinal FTP (r=0.40, p<0.001), and faster cognitive decline (r=-0.39, p<0.001; Figure 1D-E). The LC+/EC+ onset trajectories were positively correlated (r=0.23, p=0.025; Figure 2B), and 36% of the individuals was LC-EC-, 3% LC-EC+, 50% LC+EC- and 36% LC+EC+, and the time between LC+EC- to LC+EC+ was 6.06 years (SD:3.15; Figure 2C). LC integrity imaging allows for temporal modeling and our data suggests that LC integrity precedes accumulation of entorhinal tau by on average 6 years. Future work will evaluate the impact of risk and protective factors on these trajectories.

Higher cerebrospinal fluid noradrenergic metabolic turnover has been associated with higher levels of Alzheimer’s disease pathology in cognitively impaired individuals. It remains unclear whether there is a specific anatomic vulnerability to metabolic alterations within the locus coeruleus (LC) and whether this hypermetabolism relates to steeper rates of pathology accumulation. Here, we overcome a spatial limitation of Positron Emission Tomography (PET) imaging in small nuclei with a dedicated Magnetic Resonance Imaging (MRI)-guided framework to recover PET resolution. This method allowed us to investigate the [18F]Fluorodeoxyglucose (FDG)-PET signal, reflecting energetic metabolic demand of the LC and its association with serial beta-amyloid and tau-PET. We included 78 amyloid-positive, cognitively impaired participants from the ADNI-3 cohort (Table 1). The LC was identified using a dilated Keren template registered to each T1 (Fig 1A). The LC mask was subdivided into a rostral, middle, and caudal part to investigate region-specific associations (Fig 1B). We used an MR joint-entropy-penalty algorithm to quantify PET signal via deconvolution based on spatially-variant blur kernels. The deconvolution step was stabilized using an anatomical-based joint-entropy prior (Fig 1C). The FDG-PET signal was referenced to the pons, excluding the LC (Fig 1D). Amyloid positivity was determined as a centiloid score = 21, reflecting moderate neuritic plaques, on florbetaben and florbetapir scans. Linear mixed effects models investigated relationships between LC-FDG, global beta-amyloid and meta-temporal tau burden (flortaucipir) over time. Age and sex were included as covariates. Higher LC FDG-PET signal was associated with higher meta-temporal tau-PET at baseline (T = 2.87, p = 0.00463) and accumulation over time (T = 2.257, p = 0.0273; Fig 2A&C). Higher LC FDG-PET signal was associated with higher global amyloid at baseline (T = 2.066, p = 0.041) and faster amyloid accumulation over time in the dementia group (T = -2.74, p = 0.00904; Fig 2B&D), following a rostro-caudal gradient. In a cohort with cognitive impairment, we observed steeper accumulation of Alzheimer’s disease pathology in individuals with higher LC FDG-PET signal, with a specific amyloid-related vulnerability for the rostral parts of the LC. Future steps will be to include cognitively unimpaired individuals to investigate the relationship between LC FDG-PET signal and pathology accumulation in early stages of the disease process.

Background: Previous case reports suggested co-localization of tau but not β-Amyloid with cortical superficial siderosis (cSS) in cerebral amyloid angiopathy (CAA). We thus hypothesized that the tau load represents a continuum with amyloid accumulation in the disease cascade and that the tau load would be higher in lobes with cSS and intracerebral hemorrhages (ICH) when compared to the contralateral lobes without hemorrhages in CAA patients. Methods: The study included 26 cognitively healthy probable CAA patients (mean age 71±7.5, 53.8% male) who underwent multimodal MRI, Pittsburgh compound B (PiB, for amyloid), and 18 F-flortaucipir (FTP, for tau) PET imaging. Mean global cortical PiB uptake and FTP uptake were calculated in each lobar region. The presence of ICH and cSS were identified in each lobar region independent of molecular imaging. A pairwise comparison of PiB and FTP uptake was done between lobes with any hemorrhagic lesion (ICH/cSS) and their corresponding lobes without hemorrhages. Results: The FTP uptake was significantly higher in 8 frontal, 16 temporal, and 11 occipital lobes with hemorrhages compared to their corresponding contralateral lobes without hemorrhages (1.18±0.1 vs. 1.13±0.1; p=0.002, 1.28±0.1 vs. 1.20±0.1; p=0.004, 1.29±0.1 vs. 1.10±0.1; p=0.002, respectively) but not in parietal lobes (p=0.107). The PiB uptake was significantly higher in occipital lobes with hemorrhages compared to their contralateral lobes without hemorrhages (1.41±0.3 vs. 1.35±0.3, p=0.004) but there was no difference in the comparison of amyloid burden for the remaining lobar regions with or without hemorrhage (p>0.2 for all comparisons). Conclusions: Reduced PiB uptake at sites of larger hemorrhagic lesions (cSS/ICH) has been observed in the past so the lack of differences in amyloid between most lobes with and without hemorrhage was not surprising in our study. Our results otherwise show significantly increased tau load at most brain lobes with hemorrhagic lesions among CAA patients. Potential clinical effects of the tau burden related to cSS/ICH should be studied in larger CAA cohorts using appropriate clinical testing.

INTRODUCTION:Alterations in locus coeruleus' (LC) metabolic turnover are associated with Alzheimer's disease (AD)-pathology and cognitive impairment. However, the evolution of these changes across disease stages and their functional relevance remains unknown. METHODS:We examined associations of [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) -derived LC metabolism with clinical diagnostic status, cerebrospinal fluid (CSF) -based AD biomarkers of AD pathology, and cognitive decline in Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n = 604). RESULTS:FDG-PET-derived LC metabolism was elevated in the earliest preclinical stages and lower in later disease stages. Higher LC metabolism was associated with attenuated memory decline in preclinical stages, particularly in those with low CSF Aβ42, but not in AD patients with cognitive impairment. DISCUSSION:Higher locus coeruleus [18F]-FDG-PET-derived signal in the early preclinical stages of AD can confer cognitive resilience and may reflect increased metabolic activity, whereas later stages are characterized by lower LC FDG-PET-derived signal, possibly due to neurodegeneration. HIGHLIGHTS:LC FDG-PET signal is lower in Alzheimer's disease (AD) patients. LC FDG-PET signal is higher in the preclinical stage of AD. We observed less memory decline in those with higher LC FDG-PET signal. Higher LC FDG-PET signal conferred cognitive resilience in preclinical AD.

OBJECTIVE:Elevated entorhinal cortex (EC) tau in low beta-amyloid individuals can predict accumulation of pathology and cognitive decline. We compared the accuracy of magnetic resonance imaging (MRI)-derived locus coeruleus integrity, neocortical beta-amyloid burden by positron emission tomography (PET), and hippocampal volume in identifying elevated entorhinal tau signal in asymptomatic individuals who are considered beta-amyloid PET-negative. METHODS:We included 188 asymptomatic individuals (70.78 ± 11.51 years, 58% female) who underwent 3T-MRI of the locus coeruleus, Pittsburgh compound-B (PiB), and Flortaucipir (FTP) PET. Associations between elevated EC tau and neocortical PiB, hippocampal volume, or locus coeruleus integrity were evaluated and compared using logistic regression and receiver operating characteristic analyses in the PiB- sample with a clinical dementia rating (CDR) of 0. Associations with clinical progression (CDR-sum-of-boxes) over a time span of 6 years were evaluated with Cox proportional hazard models. RESULTS:We identified 26 (21%) individuals with high EC FTP in the CDR = 0/PiB- sample. Locus coeruleus integrity was a significantly more sensitive and specific predictor of elevated EC FTP (area under the curve [AUC] = 85%) compared with PiB (AUC = 77%) or hippocampal volume (AUC = 76%). Based on the Youden-index, locus coeruleus integrity obtained a sensitivity of 77% and 85% specificity. Using the resulting locus coeruleus Youden cut-off, lower locus coeruleus integrity was associated with a two-fold increase in clinical progression, including mild cognitive impairment. INTERPRETATION:Locus coeruleus integrity has promise as a low-cost, non-invasive screening instrument to detect early cortical tau deposition and associated clinical progression in asymptomatic, low beta-amyloid individuals. ANN NEUROL 2024;96:650-661.

INTRODUCTION:Spatial extent-based measures of how far amyloid beta (Aβ) has spread throughout the neocortex may be more sensitive than traditional Aβ-positron emission tomography (PET) measures of Aβ level for detecting early Aβ deposits in preclinical Alzheimer's disease (AD) and improve understanding of Aβ's association with tau proliferation and cognitive decline. METHODS:Pittsburgh Compound-B (PIB)-PET scans from 261 cognitively unimpaired older adults from the Harvard Aging Brain Study were used to measure Aβ level (LVL; neocortical PIB DVR) and spatial extent (EXT), calculated as the proportion of the neocortex that is PIB+. RESULTS:EXT enabled earlier detection of Aβ deposits longitudinally confirmed to reach a traditional LVL-based threshold for Aβ+ within 5 years. EXT improved prediction of cognitive decline (Preclinical Alzheimer Cognitive Composite) and tau proliferation (flortaucipir-PET) over LVL. DISCUSSION:These findings indicate EXT may be more sensitive to Aβ's role in preclinical AD than level and improve targeting of individuals for AD prevention trials. HIGHLIGHTS:Aβ spatial extent (EXT) was measured as the percentage of the neocortex with elevated Pittsburgh Compound-B. Aβ EXT improved detection of Aβ below traditional PET thresholds. Early regional Aβ deposits were spatially heterogeneous. Cognition and tau were more closely tied to Aβ EXT than Aβ level. Neocortical tau onset aligned with reaching widespread neocortical Aβ.

BackgroundChanges in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer's disease. Performance-based assessments of everyday functioning might help uncover these early changes. We aimed to investigate how changes over time in everyday functioning relate to tau and amyloid in cognitively unimpaired older adults.MethodsSeventy-six cognitively unimpaired participants (72 ± 6 years old, 61% female) completed multiple Harvard Automated Phone Task (APT) assessments over 2.0 ± 0.9 years. The Harvard APT consists of three tasks, performed through an automated phone system, in which participants refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and transfer money to pay a bill (APT-Bank). Participants underwent Pittsburgh compound-B and flortaucipir positron emission tomography scans at baseline. We computed distribution volume ratios for a cortical amyloid aggregate and standardized uptake volume ratios for medial temporal and neocortical tau regions. In separate linear mixed models, baseline amyloid by time and tau by time interactions were used to predict longitudinal changes in performance on the Harvard APT tasks. Three-way amyloid by tau by time interactions were also investigated. Lastly, we examined associations between tau and change in Harvard APT scores in exploratory voxel-wise whole-brain analyses. All models were adjusted for age, sex, and education.ResultsAmyloid [unstandardized partial regression coefficient estimate (β) = −0.007, 95% confidence interval (95% CI) = (−0.013, −0.001)], and medial temporal tau [β = −0.013, 95% CI = (−0.022, −0.004)] were associated with change over time in years on APT-PCP only, i.e., higher baseline amyloid and higher baseline tau were associated with steeper rate of decline of APT-PCP. Voxel-wise analyses showed widespread associations between tau and change in APT-PCP scores over time.ConclusionEven among cognitively unimpaired older adults, changes over time in the performance of cognitively complex everyday activities relate to cortical amyloid and widespread cerebral tau burden at baseline. These findings support the link between Alzheimer's disease pathology and function and highlight the importance of measuring everyday functioning in preclinical disease stages.

BACKGROUND AND OBJECTIVES:Hippocampal volume (HV) atrophy is a well-known biomarker of memory impairment. However, compared with β-amyloid (Aβ) and tau imaging, it is less specific for Alzheimer disease (AD) pathology. This lack of specificity could provide indirect information about potential copathologies that cannot be observed in vivo. In this prospective cohort study, we aimed to assess the associations among Aβ, tau, HV, and cognition, measured over a 10-year follow-up period with a special focus on the contributions of HV atrophy to cognition after adjusting for Aβ and tau. METHODS:We enrolled 283 older adults without dementia or overt cognitive impairment in the Harvard Aging Brain Study. In this report, we only analyzed data from individuals with available longitudinal imaging and cognition data. Serial MRI (follow-up duration 1.3-7.0 years), neocortical Aβ imaging on Pittsburgh Compound B PET scans (1.9-8.5 years), entorhinal and inferior temporal tau on flortaucipir PET scans (0.8-6.0 years), and the Preclinical Alzheimer Cognitive Composite (3.0-9.8 years) were prospectively collected. We evaluated the longitudinal associations between Aβ, tau, volume, and cognition data and investigated sequential models to test the contribution of each biomarker to cognitive decline. RESULTS:We analyzed data from 128 clinically normal older adults, including 72 (56%) women and 56 (44%) men; median age at inclusion was 73 years (range 63-87). Thirty-four participants (27%) exhibited an initial high-Aβ burden on PET imaging. Faster HV atrophy was correlated with faster cognitive decline (R2 = 0.28, p < 0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of Aβ and tau measures, uniquely accounting for 10% of the variance. Altogether, 45% of the variance in cognitive decline was explained by combining the change measures in the different imaging biomarkers. DISCUSSION:In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of Aβ or tau, suggesting that non-AD pathologies (e.g., TDP-43, vascular) may contribute to hippocampal-mediated cognitive decline. Serial HV measures, in addition to AD-specific biomarkers, may help evaluate the contribution of non-AD pathologies that cannot be measured otherwise in vivo.

The locus coeruleus (LC), the primary noradrenergic nucleus in the brainstem, is among the earliest brain structures to accumulate tau pathology, one of the neuropathologic hallmarks of Alzheimer’s disease (AD). Tau pathology in the earlier stages and significant cell loss in the disease’s later stages can affect the metabolic turnover of the LC. In addition, alterations in the LC’s metabolic turnover have been associated with tau formation and propagation. We investigated differences in LC glucose metabolism across AD clinical diagnostic and biomarker groups and its association with longitudinal tau, beta-amyloid, and cognitive measurements. We investigated LC FDG-PET signal of 295 participants from the ADNI-1 and ADNI-2/GO cohorts, who were equally distributed across the CSF beta-amyloid (A) and phosphorylated-tau (T) biomarker groups (Table 1). An in-house developed joint-entropy-penalized image deblurring algorithm was used to quantify Positron Emission Tomography (PET) signal within small brain regions (Figure 2A). ANCOVA was used to investigate diagnostic and biomarker-based group differences in LC metabolism. Post-hoc Tukey contrasts corrected for multiple comparisons in subsequent pairwise analyses. Linear mixed-effects models investigated the predictive value of LC metabolism on the rate of change in CSF-based p-tau, beta-amyloid and cognitive scores. Low LC FDG-PET signal was observed in the amyloid and tau-positive group compared to the other groups (p<0.0001). Pair-wise differences between the diagnostic groups did not survive correction for multiple comparisons. Combining biomarker and diagnostic status, we observed lower LC metabolism in A+T+ MCI and AD groups compared to CN and MCI A+T- and A-T- groups ( p <0.001; Figure 1B). Lower LC metabolism predicted accumulation of p-tau ( t (127) = -2.65, p = 0.009) and PACC decline ( t (128) = 2.2, p = 0.029; Figure 2). LC metabolism did not significantly predict changes in beta-amyloid levels or MMSE scores. This is the first study relating in-vivo spatially specific measures of LC metabolism to AD-related biomarker status. Low LC metabolism was most pronounced in those with evidence of underlying AD pathologic change and cognitive impairment. Furthermore, lower LC metabolism predicted greater CSF-based p-tau accumulation and declining cognition over time, providing an early marker of AD progression.

Background and Purpose: We aimed to compare the amyloid load and degree of microstructural injury among Cerebral Amyloid Angiopathy (CAA) patients with either higher lobar cerebral microbleed (CMB) counts or higher cortical superficial siderosis (cSS) extent against CAA patients with lower hemorrhagic load. Methods: The study included 38 cognitively healthy probable CAA patients with lobar intracerebral hemorrhage (ICH) and 38 age, sex-matched healthy controls (HC) who underwent advanced MRI, and Pittsburgh Compound B (PiB) PET scans. Patients were categorized into CMB-Dominant (CMB-D) and cSS-Dominant (cSS-D) based on the number and extent of CMB and cSS using previously identified cutoffs (Figure). The mean global cortical amyloid load was calculated from PiB-PET scans and represented by PiB-DVR. Within the CAA cohort, the Peak Width of Skeletonized Mean Diffusivity (PSMD) was calculated from diffusion MRIs and used as a marker of microstructural integrity. Results: Patients with CAA had significantly higher PiB-DVR than HCs (1.40±0.24 vs. 1.19±0.22, p<0.001). Both CMB-D and cSS-D CAA patients had significantly higher amyloid and increased (worse) PSMD compared to CAA patients with a non-dominant low hemorrhagic load (Figure). These results did not change in separate regression models corrected for age and sex. PiB-DVR significantly correlated with increased PSMD (r=0.346, p=0.033). Conclusions: Our findings support the view that vascular amyloid load drives higher CMB counts, more extensive cSS, and microstructural injury in patients with CAA. Furthermore, the correlations among these markers suggest that these MRI-based categorizations (CMB-D and cSS-D patients) can be used for disease staging and further research.

Background: Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer’s disease (AD) is critical. Objective: The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults. Methods: Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid. Results: Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone. Conclusion: Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.

BackgroundCerebral Amyloid Angiopathy (CAA) is a cerebral small vessel disease that can lead to microstructural disruption of white matter (WM), which can be measured by the Peak Width of Skeletonized Mean Diffusivity (PSMD). We hypothesized that PSMD measures would be increased in patients with CAA compared to healthy controls (HC), and increased PSMD is associated with lower cognitive scores in patients with CAA.MethodsEighty-one probable CAA patients without cognitive impairment who were diagnosed with Boston criteria and 23 HCs were included. All subjects underwent an advanced brain MRI with high-resolution diffusion-weighted imaging (DWI). PSMD scores were quantified from a probabilistic skeleton of the WM tracts in the mean diffusivity (MD) image using a combination of fractional anisotropy (FA) and the FSL Tract-Based Spatial Statistics (TBSS) algorithm (www.psmd-marker.com). Within CAA cohort, standardized z-scores of processing speed, executive functioning and memory were obtained.ResultsThe mean of age and sex were similar between CAA patients (69.6 ± 7.3, 59.3% male) and HCs (70.6 ± 8.5, 56.5% male) (p = 0.581 and p = 0.814). PSMD was higher in the CAA group [(4.13 ± 0.94) × 10–4 mm2/s] compared to HCs [(3.28 ± 0.51) × 10–4 mm2/s] (p < 0.001). In a linear regression model corrected for relevant variables, diagnosis of CAA was independently associated with increased PSMD compared to HCs (ß = 0.45, 95% CI 0.13–0.76, p = 0.006). Within CAA cohort, higher PSMD was associated with lower scores in processing speed (p < 0.001), executive functioning (p = 0.004), and memory (0.047). Finally, PSMD outperformed all other MRI markers of CAA by explaining most of the variance in models predicting lower scores in each cognitive domain.DiscussionPeak Width of Skeletonized Mean Diffusivity is increased in CAA, and it is associated with worse cognitive scores supporting the view that disruption of white matter has a significant role in cognitive impairment in CAA. As a robust marker, PSMD can be used in clinical trials or practice.

In this work, we developed a novel text-guided image synthesis technique which could generate realistic tau PET images from textual descriptions and the subject's MR image. The generated tau PET images have the potential to be used in examining relations between different measures and also increasing the public availability of tau PET datasets. The method was based on latent diffusion models. Both textual descriptions and the subject's MR prior image were utilized as conditions during image generation. The subject's MR image can provide anatomical details, while the text descriptions, such as gender, scan time, cognitive test scores, and amyloid status, can provide further guidance regarding where the tau neurofibrillary tangles might be deposited. Preliminary experimental results based on clinical [18F]MK-6240 datasets demonstrate the feasibility of the proposed method in generating realistic tau PET images at different clinical stages.

Despite considerable advances in beta amyloid (Aβ)-PET imaging over the last decade, the standard approach of estimating the average neocortical Aβ burden remains largely unchanged. However, as research and clinical trials increasingly shift earlier in the disease process, measures of how far Aβ has spread throughout the cortex (spatial extent) may prove more sensitive than average neocortical magnitude for detecting and quantifying early Aβ deposits and their association with future tau proliferation and cognitive decline. Clinically-normal individuals (n = 214) were included from the Harvard Aging Brain Study with longitudinal PIB-PET (2-4 scans, median = 4.7±2.7 years) and annual cognitive data (median = 5.2±2 years), as well as a subset (n = 181) with flortaucipir (FTP)-PET. Spatial extent (EXT) was computed as the number of cortical ROIs (n = 62, Desikan atlas) above their ROI-specific threshold for Aβ positivity. EXT was compared to a traditional mean neocortical DVR using logistic growth modeling. Receiver Operator Characteristic (ROC) curve analyses evaluated EXT’s ability to identify baseline PIB- individuals (<1.19DVR/24CL) who progressed to PIB+ at 3-year follow-up. Linear Mixed Effects (LME) modeling assessed baseline EXT (or DVR) as a predictor of increasing inferior temporal tau (IT FTP SUVR) and cognitive decline on the Preclinical Alzheimer’s Cognitive Composite (PACC). EXT begins rising below the neocortical DVR threshold (Figure1A), reaching a maximal growth rate of 14 ROIs per 0.1 DVR increase (∼10CL) and plateauing as full cortical EXT is achieved starting at ∼1.5DVR/68CL. A 3-ROI EXT threshold predicts progression from PIB- to PIB+ in 3 years (AUC = .97, SE = .82,SP = .97), outperforming neocortical DVR (AUC = .92, SE = .65,SP = .94, Figure1B). EXT provides a stronger biomarker of Aβ change than DVR (lower coefficient of variation, Figure2) across the Aβ continuum due to its low variance, even after EXT has plateaued. Baseline EXT is also a stronger predictor of increases in IT FTP SUVR (Figure 3A, η 2 EXT = .25, η 2 DVR = .20) and PACC decline (Figure3B, η 2 EXT = .28, η 2 DVR = .22). By describing the spread of Aβ throughout the cortex rather than average neocortical Aβ burden, spatial extent provides a more sensitive measure of Aβ at early, preclinical stages of AD that may improve design of AD prevention trials and open new avenues for research into AD pathogenesis.

Objective . Positron emission tomography (PET) imaging of tau deposition using [ 18 F]-MK6240 often involves long acquisitions in older subjects, many of whom exhibit dementia symptoms. The resulting unavoidable head motion can greatly degrade image quality. Motion increases the variability of PET quantitation for longitudinal studies across subjects, resulting in larger sample sizes in clinical trials of Alzheimer’s disease (AD) treatment. Approach . After using an ultra-short frame-by-frame motion detection method based on the list-mode data, we applied an event-by-event list-mode reconstruction to generate the motion-corrected images from 139 scans acquired in 65 subjects. This approach was initially validated in two phantoms experiments against optical tracking data. We developed a motion metric based on the average voxel displacement in the brain to quantify the level of motion in each scan and consequently evaluate the effect of motion correction on images from studies with substantial motion. We estimated the rate of tau accumulation in longitudinal studies (51 subjects) by calculating the difference in the ratio of standard uptake values in key brain regions for AD. We compared the regions’ standard deviations across subjects from motion and non-motion-corrected images. Main results . Individually, 14% of the scans exhibited notable motion quantified by the proposed motion metric, affecting 48% of the longitudinal datasets with three time points and 25% of all subjects. Motion correction decreased the blurring in images from scans with notable motion and improved the accuracy in quantitative measures. Motion correction reduced the standard deviation of the rate of tau accumulation by −49%, −24%, −18%, and −16% in the entorhinal, inferior temporal, precuneus, and amygdala regions, respectively. Significance . The list-mode-based motion correction method is capable of correcting both fast and slow motion during brain PET scans. It leads to improved brain PET quantitation, which is crucial for imaging AD.

[18F]MK-6240 meningeal/extracerebral off-target binding may impact tau quantification. We examined the kinetics and longitudinal changes of extracerebral and reference regions. [18F]MK-6240 PET was performed in 24 cognitively-normal and eight cognitively-impaired subjects, with arterial samples in 13 subjects. Follow-up scans at 6.1 ± 0.5 (n = 25) and 13.3 ± 0.9 (n = 16) months were acquired. Extracerebral and reference region (cerebellar gray matter (CerGM)-based, cerebral white matter (WM), pons) uptake were evaluated using standardized uptake values (SUV90-110), spectral analysis, and distribution volume. Longitudinal changes in SUV90-110 were examined. The impact of reference region on target region outcomes, partial volume correction (PVC) and regional erosion were evaluated. Eroded WM and pons showed lower variability, lower extracerebral contamination, and lower longitudinal changes than CerGM-based regions. CerGM-based regions resulted larger cross-sectional effect sizes for group differentiation. Extracerebral signal was high in 50% of subjects and exhibited irreversible kinetics and nonsignificant longitudinal changes over one-year but was highly variable at subject-level. PVC resulted in higher variability in reference region uptake and longitudinal changes. Our results suggest that eroded CerGM may be preferred for cross-sectional, whilst eroded WM or pons may be preferred for longitudinal [18F]MK-6240 studies. For CerGM, erosion was necessary (preferred over PVC) to address the heterogenous nature of extracerebral signal.

The locus coeruleus (LC) is one of the first regions to accumulate tau in Alzheimer’s disease (AD). As the disease progresses, tau in the LC has been related to increasing allocortical tau. Recent autopsy work reported that LC neurodegeneration correlated with parietal amyloid, suggesting that the LC may impact both Ab and tau, but with regionally varying contributions. We investigated whether cross-sectional and longitudinal relationships between in vivo LC integrity and regional tau or Ab are uniquely determined by one pathology or exhibit shared vulnerabilities. 213 individuals from the Harvard Aging Brain Study (mean age:71.6 years, 58% female; 11% cognitively impaired; Figure 1) who underwent 3T LC-MRI, Ab- and tau-PET imaging were included. Of these, 62 individuals received a second MRI and PET session. For the LC, we extracted the 5 highest normalized intensity voxels. PET-data was referenced to cerebellar gray and partial volume corrected. Linear regressions associated LC integrity to tau or Ab and variance contributions were quantified. Mixed effects models examined LC changes to changes in tau or Ab. Mediation analyses examined whether local Ab mediated relationships between LC integrity and local tau. Analyses were adjusted for age, sex and multiple comparisons using FDR-correction. LC integrity was negatively associated with medial-lateral temporal tau, and widespread Ab. Multivariable analyses demonstrated that LC integrity associated uniquely with tau in medial temporal lobe (MTL) regions and with Ab in frontoparietal regions. LC integrity was associated with both tau and Ab in inferior temporal (IT) and posterior cingulate cortices, and mediation analyses showed that LC integrity – tau associations in these regions were Ab-mediated (Figure 2). Longitudinal analyses revealed stronger local associations between LC integrity and tau changes, compared to Ab. LC integrity changes were uniquely associated with tau changes in MTL, but longitudinal LC integrity-IT tau correlations were mediated by local Ab (Figure 3). The LC may have anatomically distinct cortical tau and Ab-pathways in AD, with MTL correlations being almost uniquely tau-related, frontoparietal associations uniquely Ab-related and lateral temporal regions showing Ab-mediated tau accumulation. Potential underlying mechanisms can include synaptic plasticity alterations, glial activation or neuronal hyperactivation.