Pittsburgh Compound B Research Articles

Rates of β-amyloid deposition indicate widespread simultaneous accumulation throughout the brain

Amyloid plaque aggregation is a pathologic hallmark of Alzheimer's disease (AD) that occurs early in the disease. However, little is known about its progression throughout the brain. Using Pittsburgh Compound B (PIB)-PET imaging, we investigated the progression of regional amyloid accumulation in cognitively normal older adults. We found that all examined regions reached their peak accumulation rates 24–28 years after an estimated initiation corresponding to the mean baseline PIB-PET signal in amyloid-negative older adults. We also investigated the effect of increased genetic risk conferred by the apolipoprotein-E ɛ4 allele on rates of amyloid accumulation, as well as the relationship between regional amyloid accumulation and regional tau pathology, another hallmark of AD, measured with Flortaucipir-PET. Carriers of the ɛ4 allele had faster amyloid accumulation in all brain regions. Furthermore, in all regions excluding the temporal lobe, faster amyloid accumulation was associated with greater tau burden. These results indicate that amyloid accumulates near-simultaneously throughout the brain and is associated with higher AD pathology, and that genetic risk of AD is associated with faster amyloid accumulation.

Support vector machine learning and diffusion-derived structural networks predict amyloid quantity and cognition in adults with Down's syndrome

Down's syndrome results from trisomy of chromosome 21, a genetic change which also confers a probable 100% risk for the development of Alzheimer's disease neuropathology (amyloid plaque and neurofibrillary tangle formation) in later life. We aimed to assess the effectiveness of diffusion-weighted imaging and connectomic modelling for predicting brain amyloid plaque burden, baseline cognition and longitudinal cognitive change using support vector regression. Ninety-five participants with Down's syndrome successfully completed a full Pittsburgh Compound B (PiB) PET-MR protocol and memory assessment at two timepoints. Our findings indicate that graph theory metrics of node degree and strength based on the structural connectome are effective predictors of global amyloid deposition. We also show that connection density of the structural network at baseline is a promising predictor of current cognitive performance. Directionality of effects were mainly significant reductions in the white matter connectivity in relation to both PiB+ status and greater rate of cognitive decline. Taken together, these results demonstrate the integral role of the white matter during neuropathological progression and the utility of machine learning methodology for non-invasively evaluating Alzheimer's disease prognosis.

Deep residual inception encoder-decoder network for amyloid PET harmonization.

Multiple positron emission tomography (PET) tracers are available for amyloid imaging, posing a significant challenge to consensus interpretation and quantitative analysis. We accordingly developed and validated a deep learning model as a harmonization strategy. AResidual Inception Encoder-Decoder Neural Network was developed to harmonize images between amyloid PET image pairs made with Pittsburgh Compound-B and florbetapir tracers. The model was trained using a dataset with 92 subjects with 10-fold cross validation and its generalizability was further examined using an independent external dataset of 46 subjects. Significantly stronger between-tracer correlations (P<.001) were observed after harmonization for both global amyloid burden indices and voxel-wise measurements in the training cohort and the external testing cohort. We proposed and validated a novel encoder-decoder based deep model to harmonize amyloid PET imaging data from different tracers. Further investigation is ongoing to improve the model and apply to additional tracers.

Effect of vascular amyloid on white matter disease is mediated by vascular dysfunction in cerebral amyloid angiopathy

We postulated that vascular dysfunction mediates the relationship between amyloid load and white matter hyperintensities (WMH) in cerebral amyloid angiopathy (CAA). Thirty-eight cognitively healthy patients with CAA (mean age 70 ± 7.1) were evaluated. WMH was quantified and expressed as percent of total intracranial volume (pWMH) using structural MRI. Mean global cortical Distribution Volume Ratio representing Pittsburgh Compound B (PiB) uptake (PiB-DVR) was calculated from PET scans. Time-to-peak [TTP] of blood oxygen level-dependent response to visual stimulation was used as an fMRI measure of vascular dysfunction. Higher PiB-DVR correlated with prolonged TTP (r = 0.373, p = 0.021) and higher pWMH (r = 0.337, p = 0.039). Prolonged TTP also correlated with higher pWMH (r = 0.485, p = 0.002). In a multivariate linear regression model, TTP remained independently associated with pWMH (p = 0.006) while PiB-DVR did not (p = 0.225). In a bootstrapping model, TTP had a significant indirect effect (ab = 0.97, 95% CI: 0.137–2.461), supporting that the association between PiB-DVR and pWMH is mediated by TTP response. There was no longer a direct effect independent of the hypothesized pathway. Our study suggests that the effect of vascular amyloid load on white matter disease is mediated by vascular dysfunction in CAA. Amyloid lowering strategies might prevent pathophysiological processes leading to vascular dysfunction, therefore limiting ischemic brain injury.

Mitochondrial complex I abnormalities underlie neurodegeneration and cognitive decline in Alzheimer's disease.

Abnormal mitochondrial metabolism has been described in the Alzheimer's disease (AD) brain. However, the relationship between AD pathophysiology and key mitochondrial processes remains elusive. The purpose of this study was to investigate whether mitochondrial complex I dysfunction is associated with amyloid aggregation or glucose metabolism and brain atrophy in patients with mild AD using positron emission tomography (PET). Amyloid- and tau-positive symptomatic AD patients with clinical dementia rating 0.5 or 1 (N=30; mean age±standard deviation: 71.8±7.6years) underwent magnetic resonance imaging and PET scans with [18 F]2-tert-butyl-4-chloro-5-2H-pyridazin-3-one (BCPP-EF), [11 C]Pittsburgh Compound-B (PiB) and [18 F]fluorodeoxyglucose (FDG) to assess brain atrophy, mitochondrial complex I dysfunction, amyloid deposition, and glucose metabolism, respectively. Local cortical associations among these biomarkers and gray matter volume were evaluated with voxel-based regressions models. [18 F]BCPP-EF standardized uptake value ratio (SUVR) was positively correlated with [18 F]FDG SUVR in the widespread brain area, while its associations with gray matter volume were restricted to the parahippocampal gyrus. Reductions in [18 F]BCPP-EF SUVR were associated with domain-specific cognitive performance. We did not observe regional associations between mitochondrial dysfunction and amyloid burden. In symptomatic cases, although mitochondrial complex I reduction is linked to a wide range of downstream neurodegenerative processes such as hypometabolism, atrophy, and cognitive decline, a link to amyloid was not observable. The data presented here support [18 F]BCPP-EF as an excellent imaging tool to investigate mitochondrial dysfunction in AD.

1H MR spectroscopy biomarkers of neuronal and synaptic function are associated with tau deposition in cognitively unimpaired older adults

Proton magnetic resonance spectroscopy (1H MRS) may provide information on pathophysiological changes associated with tau deposition in cognitively unimpaired older adults. In this study, the associations of posterior cingulate gyrus tau and amyloid beta (Aβ) deposition on PET with 1H MRS metabolite ratios acquired from bilateral posterior cingulate gyri were investigated in cognitively unimpaired older adults. Participants (n = 40) from the Mayo Clinic Study of Aging underwent single-voxel sLASER 1H MRS from the posterior cingulate gyrus at 3 Tesla, 18F-flortaucipir, and 11C- Pittsburgh Compound B (PiB) PET. An increase in posterior cingulate gyrus tau deposition, but not elevated Aβ, was associated with lower N-acetylaspartate/total creatine (tCr) and glutamate (Glu)/tCr ratios, and sex by tau interaction was observed in association with Glu/tCr. Higher tau levels in cognitively unimpaired older adults are associated with biomarkers of neural and synaptic injury even in the absence of cognitive impairment and these relationships appear to be stronger in women than in men.

Serum Adiponectin and In Vivo Brain Amyloid Deposition in Cognitively Normal Older Adults: A Cohort Study.

High blood adiponectin has been associated with Alzheimer's disease (AD) dementia and related cognitive decline. We aimed to investigate the association between serum adiponectin level and in vivo AD pathologies. Cross-sectional and longitudinal study designs for the data of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease, an ongoing prospective cohort study that began in 2014. A total of 283 cognitively normal older adults between 55 and 90 years of age were included in community and memory clinic setting. Participants underwent comprehensive clinical assessments, measurement of serum adiponectin level, and multimodal brain imaging, including Pittsburgh compound-B positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and MRI at baseline and 2-year follow-up. Serum adiponectin level was positively associated with global beta-amyloid protein (Aβ) retention and change therein over 2 years, but not with other AD neuroimaging markers including tau deposition, AD-related neurodegeneration, and white matter hyperintensities. Blood adiponectin level is associated with increased brain amyloid deposition, which suggests that adiponectin may be a potential target for therapeutic and preventive strategies against AD.

Limited Longitudinal Change in Self-reported Spatial Navigation Ability in Preclinical Alzheimer Disease.

Subtle changes in objective spatial navigation ability have been observed in the preclinical stage of Alzheimer disease (AD) cross-sectionally and have been found to predict clinical progression. However, longitudinal change in self-reported spatial navigation ability in preclinical AD has yet to be examined. The current study examined whether AD biomarkers suggestive of preclinical AD at baseline spatial navigation assessment and APOE genotype predicted decline in self-reported spatial navigation ability and whether APOE genotype moderated the association of AD biomarkers with change in self-reported spatial navigation. Clinically normal (Clinical Dementia Rating Scale=0) adults aged 56 to 90 completed the Santa Barbara Sense of Direction Scale (SBSOD) annually for an average of 2.73 years. Biomarker data was collected within +/-2 years of baseline (ie, cerebrospinal fluid Aβ42, p-tau181, p-tau181/Aβ42 ratio, positron emission tomography imaging with Florbetapir or Pittsburgh Compound-B, and hippocampal volume). APOE genotyping was obtained for all participants. SBSOD demonstrated a nonsignificant trend toward a decline over time (P=0.082). AD biomarkers did not predict change in self-reported spatial navigation (all Ps>0.163). APOE genotype did not moderate the relationship between AD biomarkers and self-reported spatial navigation in planned analyses (all Ps>0.222). Results suggest that self-reported spatial navigation ability, as estimated with the SBSOD, may be limited as a measure of subtle cognitive change in the preclinical stage of AD.

Distinctive Mediating Effects of Subcortical Structure Changes on the Relationships Between Amyloid or Vascular Changes and Cognitive Decline.

Objective: We investigated the mediation effects of subcortical volume change in the relationship of amyloid beta (Aβ) and lacune with cognitive function in patients with mild cognitive impairment (MCI).Methods: We prospectively recruited 101 patients with MCI who were followed up with neuropsychological tests, MRI, or Pittsburgh compound B (PiB) PET for 3 years. The mediation effect of subcortical structure on the association of PiB or lacunes with cognitive function was analyzed using mixed effects models.Results: Volume changes in the amygdala and hippocampus partially mediated the effect of PiB changes on memory function (direct effect = −0.168/−0.175, indirect effect = −0.081/−0.077 for amygdala/hippocampus) and completely mediated the effect of PiB changes on clinical dementia rating scale sum of the box (CDR-SOB) (indirect effect = 0.082/0.116 for amygdala/hippocampus). Volume changes in the thalamus completely mediated the effect of lacune on memory, frontal executive functions, and CDR-SOB (indirect effect = −0.037, −0.056, and 0.047, respectively).Conclusions: Our findings provide a better understanding of the distinct role of subcortical structures in the mediation of the relationships of amyloid or vascular changes with a decline in specific cognitive domains.

Regional beta‐amyloid and tau deposition: Results from the Framingham Heart Study

AbstractBackgroundThe Framingham Heart Study (FHS), a three‐generation community‐based cohort studying cardiovascular disease across the adult lifespan, has expanded to include positron emission tomography (PET) of beta‐amyloid (Aβ) and tau. Our aim is to characterize these pathologies in this unique sample and utilize the wide age range to assess the spatiotemporal ordering of emerging Aβ and tau.Method211 clinically‐normal adults aged 33‐74 from FHS underwent Pittsburgh Compound B (PIB) and Flortaucipir (FTP) PET. PIB and FTP were regionally quantified in Desikan regions using distribution volume ratio (DVR) for PIB and standardized uptake volume ratio (SUVR) for FTP. Three approaches were used to identify early accumulating regions: 1. A series of Age*APOE linear models to identify regions accumulating earlier in the lifespan in ε4 carriers. 2. Identification of early regions as those more frequently elevated as previously used in older adults, with Gaussian mixture models (GMM) conducted to evaluate bimodality and set biomarker positivity thresholds for each region. 3. Applied the same frequency approach using well‐validated PIB GMM thresholds based on older adults from the Harvard Aging Brain Study (HABS).ResultFor PIB, significant Age*APOE interactions (Fig. 1) were seen across multiple regions previously implicated as early‐accumulating based on elevation frequencies from older adult samples, as well as the pars opercularis (p=0.005) and lateral parietal cortices (p&lt;0.04). PIB was significantly bimodal across all ROIs (LRT&gt;36.1, p&lt;0.001; Fig. 1). Application of GMM‐based regional positivity frequencies derived within FHS versus from HABS thresholds led to substantial discrepancies in the spatiotemporal ordering of PIB (rs=0.30, p=0.17).Age*APOE effects were not detected for any tau regions, but inferior temporal (IT), middle temporal (MT), and amygdala (AM) increased with age (Fig. 2). Higher global Aβ was also associated with higher FTP SUVR in IT, MT, and a trend for AM, as well as inferior parietal and precuneus (Fig. 2).ConclusionAβ and tau mainly follow spatiotemporal patterns consistent with prior evidence in older adult samples. GMM‐based methods used in older adult samples to dichotomize biomarker positivity may be suboptimal in younger samples. Continuous approaches may better capture early Aβ and tau in younger populations.

Longitudinal cascades of Alzheimer disease biomarkers across the entire adult lifespan among cognitively normal adults

AbstractBackgroundThe temporal cascade of Alzheimer disease (AD) biomarkers among cognitively normal individuals, including cerebral spinal fluid (CSF) Aβ42, Aβ40, total tau (Tau) and phosphorylated tau (pTau), standardized uptake value ratio (SUVR) from the molecular imaging of cerebral fibrillar β‐amyloid with positron emission tomography (PET) using the [11C] benzothiazole tracer, Pittsburgh Compound‐B (PiB), magnetic resonance imaging (MRI)‐based hippocampal volume and cortical thickness, and cognition has been hypothesized, but not yet fully tested with longitudinal data.MethodLeveraging a large harmonized database of 2703 cognitively normal individuals 18 to 103 years of age from 8 longitudinal studies with a median follow up of 5∼6 years, we estimated the longitudinal trajectories of all major AD biomarkers as functions of baseline age, located the age window at which the longitudinal change accelerated by comparing it across adjacent age bins, and examined possible modifying effects of apolipoprotein E (APOE) genotypes.ResultParticipants 18 to 45 years of age at baseline exhibited ‘learning effects’ on both cognition and all but the MRI‐based biomarkers. The earliest acceleration of longitudinal change occurred for CSF Aβ42 and Aβ42/Aβ40 ratio at the baseline age of 45 to 50 years, followed by hippocampal volume at the baseline age of 55 to 60 years, further by CSF Tau, PET PiB mean cortical SUVR, cortical thickness, and cognition at the baseline age of 65 to 70 years. The accelerated longitudinal changes remained in the covariate‐adjusted analyses. APOE ε4 modified the observed ‘learning effects’ from 18 to 45 years. Further, there was preliminary evidence that APOE ε4 carriers may have experienced the first significant acceleration of the longitudinal change in almost all major AD markers within the baseline age window of 45 to 55 years, whereas among APOE ε4 non‐carriers, only PiB PET SUVRs and cortical thickness and the cognitive composite showed the earliest longitudinal acceleration of change at the same baseline age interval.ConclusionOur results characterize the temporal cascades of longitudinal changes for all major AD biomarkers across entire adult lifespan, and address the modifying effect of APOE ε4. These findings may better inform the design of prevention trials on AD.

Tau pathology mediates the effects of amyloid on cerebral blood flow and propagation of tau

AbstractBackgroundAmyloid is associated with greater tau pathology and is thought to facilitate the spread of tau from the medial temporal lobe (MTL) to the neocortex. The extent to which amyloid versus MTL tau is involved in propagating tau remains unclear. Given the potential role of cortical tau in early neurodegeneration, understanding the contributors to its spread might inform preventative strategies.MethodWe acquired 18F‐flortaucipir (FTP) PET scans to measure tau pathology in 113 non‐demented Baltimore Longitudinal Study of Aging participants. To assess if amyloid facilitates the spread of tau from the MTL to the neocortex, we investigated whether amyloid moderates the association between tau in the entorhinal cortex (EC) and the inferior temporal gyrus (ITG). To quantify the involvement of amyloid versus MTL tau in propagating tau, we investigated whether EC tau mediates the association between amyloid and ITG tau. Finally, we investigated the local relationship between ITG tau and cerebral blood flow (CBF), an indicator of neurodegeneration, quantified as the relative radiotracer delivery parameter R1 computed from dynamic Pittsburgh compound B (PiB) PET scans. We used robust linear regression for all statistical models to mitigate the influence of the few outlying tau data points on the estimates, and included age, sex, race, and education as covariates.ResultAmyloid positive (A+) participants had higher FTP‐SUVR in the EC and ITG. Higher FTP‐SUVR in the EC was associated with higher FTP‐SUVR in the ITG. This association was steeper among A+ individuals (amyloid and EC FTP‐SUVR interaction β=0.269, p=0.023). EC FTP‐SUVR mediated the association between amyloid and ITG FTP‐SUVR (indirect effect=0.136, p=0.043).Higher ITG FTP‐SUVR was associated with lower PiB‐R1 (β=‐0.277, p=0.039). The direct association between amyloid and PiB‐R1 was not statistically significant (direct effect=‐0.366, p=0.192), but there was an indirect effect via ITG FTP‐SUVR (indirect effect=‐0.14, p=0.015).ConclusionOur findings suggest that both amyloid and MTL tau pathology are involved in the spread of tau into the neocortex. Tau accounted for 28% of the amyloid‐CBF relationship, indicating its role in early neuronal hypoactivity. Therapeutics may need to target both amyloid and tau early to prevent neocortical involvement.

Association between the Harvard automated phone task and Alzheimer’s disease pathology in clinically normal older adults

AbstractBackgroundWith the advent of prevention trials in preclinical Alzheimer’s disease (AD), evaluating novel and sensitive methods to measure instrumental activities of daily living (IADL) is becoming increasingly important in order to detect these clinically meaningful changes at the earliest stages of disease. The objective of the current exploratory study was to examine the cross‐sectional relationship between a phone performance‐based IADL test, the Harvard Automated Phone Task (APT), and regional cerebral tau and cortical amyloid burden in clinically normal (CN) older adults.MethodThirty‐one CN participants (mean age 70.0 (SD 4.8), 70% female) underwent flortaucipir (FTP) tau and Pittsburgh Compound B (PiB) amyloid positron emission tomography (PET). IADL were assessed using the 3 Harvard APT tasks: refilling a prescription (APT‐Script), calling the health insurance company to select a new primary care physician (APT‐PCP), and making a bank account transfer and payment (APT‐Bank). Linear regression models were used in the primary analyses to determine the associations between each APT task rate (correct responses/time) as the dependent variable and cortical amyloid aggregate, entorhinal cortex, inferior temporal, or precuneus tau as predictors of interest in separate analyses. In secondary analyses, models were repeated with an interaction between cortical amyloid and regional tau. Analyses included age, sex, and education as covariates.ResultA significant association was found between the APT‐Script rate and entorhinal cortex tau (β=‐0.08, 95% CI=‐0.14, ‐0.21, t value=‐2.78, p=0.01). No significant associations were found between other APT tasks and amyloid and tau regions. Additionally, no significant associations were found with the interaction between amyloid and tau regions.ConclusionOur preliminary findings suggest an association between a region of early tau accumulation in CN adults, the entorhinal cortex, and a real‐life IADL test. Moreover, APT‐Script task was more normally distributed, and had overall larger variability compared to the other two tasks, suggesting that it may be a more sensitive IADL measurement in CN individuals. Further analyses should explore this relationship in larger samples 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.

Correspondence of CSF biomarkers measured by Lumipulse assays with amyloid PET

AbstractBackgroundTraditional plate‐based assays for cerebrospinal fluid (CSF) biomarkers have been limited by relatively high assay variance that reduces the accuracy of individual measurements. Next generation automated assay platforms for CSF biomarkers reduce the variability of measurements, including across sample runs. In the current study, we utilized the Lumipulse G1200 (Fujirebio; Malvern, PA), a fully‐automated assay platform to compare CSF biomarkers to brain amyloid burden as determined by positron emission tomography (PET) imaging.MethodParticipants (n=758) were enrolled in studies of memory and aging at the Knight ADRC in St. Louis, Missouri. Concentrations of CSF amyloid‐beta 40 (Aβ40), amyloid‐beta 42 (Aβ42), total tau (tTau) and phosphorylated tau‐181 (pTau) were measured using the Lumipulse G1200 automated assay system. Brain amyloid burden was measured via amyloid PET imaging using Florbetapir or Pittsburgh compound B (PIB). The correspondence of CSF biomarkers with amyloid PET status based on established cut‐offs for each radiotracer was evaluated.ResultFor pooled CSF controls representing a range of three values (low, medium, high), coefficients for inter‐day variability ranged from 2‐4%. CSF collected within two years of an amyloid PET scan was evaluated from 521 amyloid PET‐negative and 237 amyloid PET‐positive individuals. Correspondence with amyloid PET by receiver operating characteristic (ROC) area under the curve (AUC) was highest for ratios including Aβ42: pTau/Aβ42 (0.97, 95% confidence intervals 0.96‐0.99), Aβ42/Aβ40 (0.97, 0.95‐0.98), and tTau/Aβ42 (0.96, 0.94‐0.97). A CSF pTau/Aβ42 value of &gt;0.0649 had the highest combined positive and negative percent agreement (PPA of 0.91, 0.86‐0.94; NPA of 0.96, 0.93‐0.97) with amyloid PET status. The CSF value for Aβ42/Aβ40 with highest combined PPA and NPA was slightly more sensitive but less specific: &lt;0.0673 had a PPA of 0.97 (0.94‐0.99) and NPA of 0.91 (0.88‐0.93) with amyloid PET status.ConclusionMeasurement of CSF biomarkers with the Lumipulse G1200 automated assay system was highly precise, with low variability over multiple runs. Values for pTau/Aβ42, Aβ42/Aβ40, and tTau/Aβ42 were highly concordant with amyloid PET status.

Steeper basal cortisol slopes are associated with elevated risk of pathological amyloid‐beta accumulation

AbstractBackgroundThe accumulation of amyloid‐beta (Aβ) plaques, the hallmark neuropathology of Alzheimer’s disease (AD), begins several decades prior to the onset of cognitive symptoms. The progression of the disease is believed to be driven by this accumulation; therefore, there is interest in identifying factors which trigger or accelerate the aggregation of Aβ. We examined whether changes or elevations in basal cortisol levels predicted the transition to a state of Aβ‐positivity, as determined by Pittsburgh Compound B (PIB) thresholds.MethodData were utilized from the neuroimaging subset of the Baltimore Longitudinal Study of Aging. One‐hundred and fifteen middle‐aged to older adults (mean age 58.39 at baseline) with at least two 24‐hour urinary free cortisol measures collected prior to reaching the threshold for Aβ‐positivity were included.ResultA Cox regression model showed that after controlling for age, the slope of basal cortisol levels over time was significantly associated with the risk of becoming Aβ‐positive, such that each standard deviation unit increase in slope was associated with a 38% increase in Aβ‐positivity risk. Conversely, the average cortisol level during this same period was not significantly associated with Aβ‐positivity risk (HR = 1.03, p = 0.14).ConclusionThese results suggest that increases in basal cortisol levels, regardless of the average level, are associated with increased likelihood of pathological Aβ accumulation. Further investigation is warranted to determine whether basal cortisol increases directly contribute to increased Aβ accumulation and whether this mechanism can be targeted by therapeutic intervention.

Self‐reported history of estrogen hormone therapy differentiates rates of amyloid accumulation (PiB‐PET) relative to males: Findings from the Harvard Aging Brain Study

AbstractBackgroundWomen’s Health Initiative Memory Study (WHIMS) findings suggest that hormone therapy increases risk of dementia. Conversely, evidence from the Kronos Early Estrogen Prevention Study (KEEPS) implicates estrogen hormone therapy (HT) as protective against ß‐amyloid (Aß) burden. We sought to explore if self‐reported HT use is associated with rates of Aß accumulation in an observational sample of clinically‐unimpaired older adults.Method134 participants (Age=73yrs±5.8) underwent at least three timepoints of Pittsburgh compound‐B (PiB)‐PET scans over an average of 9.7 years. Longitudinal PiB‐PET was examined as aggregate neocortical DVR (composite reference region: whole cerebellum + eroded white matter). Concurrent with baseline PiB‐PET, female participants self‐reported if they ever took HT. Participants were thus identified as: females who never used HT (HT‐:n=36), females who have ever taken HT to any extent (HT+:n=42), and males (M:n=56). We examined the relationship between these three groups and longitudinal PiB‐PET using linear mixed models, adjusting for baseline age, and with random slopes and intercepts. Post‐hoc analyses adjusted for APOEε4 status and examined interactions between HT and baseline PiB‐PET on change in PiB‐PET from baseline.ResultWhile we found no significant sex (male/female) difference in PiB‐PET accumulation (t=1.5,p&gt;0.05,Fig 1A), we observed significant HT group differences with HT‐ exhibiting approximately half the PiB‐PET rate of change than M (t=2.3,p=0.02) and HT+ (t=1.8,p=0.07; Fig 1B). There was no significant slope difference between M and HT+ (t=0.32,p=0.75). These differences survived after covarying for APOEε4. A three‐way interaction with baseline PiB‐PET revealed a greater slope difference between HT‐ and M (t=2.1,p=0.04) in those with higher baseline PiB‐PET relative to lower baseline PiB‐PET (Fig 2).ConclusionHT‐ showed significantly slower rates of Aß accumulation than males and a trend‐level slower rate compared to HT+; these differences appear heightened with greater baseline Aß burden. With similar ages across HT groups (p=0.20), these differences did not appear to be a function of chronological age. It remains unclear whether the introduction of estrogen, a mediating commonality, or collider bias is driving these results. Our findings, in conjunction with other studies, suggest the relationship between HT and Aß is complicated and necessitates examination of HT type and duration.

Abstract 14336: Association of Mid-Life Cardiovascular Disease and Late-Life Alzheimer's Disease Pathology: Insights From Heart Score Study

Introduction: Data show an association of CVD risk factors in mid-life with older age dementia. Atherosclerosis (ATH) and arteriosclerosis (ART) are both implicated in incident dementia however their relationship with incident Alzheimer’s disease (AD) remains elusive. We investigated the association of mid-life cardiovascular risk factors and mid-life subclinical CVD (ATH and ART) with late-life AD pathology. Methods: Non-demented participants over the age of 65 from the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study underwent brain PET acquisition (2018-2020) for AD specific amyloid deposition [by Pittsburgh Compound B (PiB)]. Pearson’s correlation and OR (95% CI) using Cox regression for association of cortical PiB retention with mid-life (2003-2005) markers of ATH (coronary artery calcium [CAC] score and carotid intima thickness [CIMT]) and ART (vascular stiffness) were calculated. Results: Among 121 participants in late-life (mean age ~79y), age was significantly correlated to lower cognition ( r =0.19, p=0.03) but gender, race and diabetes were not. Late-life AD pathology was not significantly associated with mid-life CAC (&gt;150) [OR=0.12 (0.01, 2.36); p=0.16] or CIMT [OR=1.80 (0.84, 3.86); p=0.40]. Presence of increased vascular stiffness in mid-life showed a significant association with late-life PiB retention (Table ). Conclusions: In a small number of biracial middle-aged adults, subclinical markers of atherosclerosis did not independently predict increased biomarkers of AD pathology. However, vascular stiffness in mid-life was significantly associated with late-life brain biomarkers of Alzheimer’s disease pathology. Further research can elucidate the role of mid-life athero- and arteriosclerosis in Alzheimer's disease dementia.

Global cognitive dysfunction and β-amyloid neuropathology in late-life and treatment-resistant major depression

AbstractBackgroundCognitive impairment is common in late-life depression, which may increase Alzheimer disease (AD) risk. Therefore, we aimed to investigate whether late-life major depressive disorder (MDD) has worse cognition and increases the characteristic AD neuropathology. Furthermore, we carried out a comparison between treatment-resistant depression (TRD) and non-TRD. We hypothesized that patients with late-life depression and TRD may have increased β-amyloid (Aβ) deposits in brain regions responsible for global cognition.MethodsWe recruited 81 subjects, including 54 MDD patients (27 TRD and 27 non-TRD) and 27 matched healthy controls (HCs). Neurocognitive tasks were examined, including Mini-Mental State Examination and Montreal Cognitive Assessment to detect global cognitive functions. PET with Pittsburgh compound-B and fluorodeoxyglucose were used to capture brain Aβ pathology and glucose use, respectively, in some patients.ResultsMDD patients performed worse in Montreal Cognitive Assessment (p = 0.003) and had more Aβ deposits than HCs across the brain (family-wise error-corrected p &lt; 0.001), with the most significant finding in the left middle frontal gyrus. Significant negative correlations between global cognition and prefrontal Aβ deposits existed in MDD patients, whereas positive correlations were noted in HCs. TRD patients had significantly more deposits in the left-sided brain regions (corrected p &lt; 0.001). The findings were not explained by APOE genotypes. No between-group fluorodeoxyglucose difference was detected.ConclusionsLate-life depression, particularly TRD, had increased brain Aβ deposits and showed vulnerability to Aβ deposits. A detrimental role of Aβ deposits in global cognition in patients with late-onset or non-late-onset MDD supported the theory that late-life MDD could be a risk factor for AD.

Prominent Striatum Amyloid Retention in Early-Onset Familial Alzheimer's Disease With PSEN1 Mutations: A Pilot PET/MR Study.

Background: With the advancements of amyloid imaging in recent years, this new imaging diagnostic method has aroused great interest from researchers. Till now, little is known regarding amyloid deposition specialty in patients with early-onset familial Alzheimer's disease (EOFAD), and even less is known about its role in cognitive impairments.Objectives: Our study aimed to evaluate the amyloid deposition in five patients with EOFAD, 15 patients with late-onset sporadic AD, and 12 healthy subjects utilizing 11C-labeled Pittsburgh compound-B (11C-PiB) amyloid PET imaging. Moreover, we figured out the correlation between striatal and cortical standardized uptake value ratios (SUVRs). We also investigated the correlation between 11C-PiB retention and cognitive presentation.Results: All patients with EOFAD showed high amyloid deposition in the striatum, a pattern that is not usually seen in patients with late-onset sporadic AD. The SUVR in the striatum, especially in the amygdala, showed significant correlations with cortex SUVR in EOFAD. However, neither striatal nor cortical 11C-PiB retention was related to cognitive decline.Conclusions: The amyloid distribution in patients with EOFAD differs from late-onset sporadic AD, with higher amyloid deposits in the striatum. Our study also demonstrated positive correlations in 11C-PiB retention between the striatum and other cortical areas. We revealed that the distribution of amyloid in the brain is not random but diffuses following the functional and anatomical connections. However, the degree and pattern of amyloid deposition were not correlated with cognitive deficits.

Cerebral Amyloid Angiopathy Pathology and Its Association With Amyloid-β PET Signal.

To determine the contribution of cerebral amyloid angiopathy (CAA) to Pittsburgh compound B (PiB)-PET tracer retention. Participants from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center with antemortem PiB-PET imaging for β-amyloid (Aβ) who later underwent autopsy were included in this study. Pathologic regional leptomeningeal, parenchymal, capillary CAA, and Aβ plaque burden were calculated from one hemisphere. Regional lobar amyloid standardized uptake value ratio (SUVR) on PET was calculated from the same hemisphere sampled at autopsy. Single- and multiple-predictor linear regression models were used to evaluate the relative contributions of pathologically determined regional CAA and Aβ plaques to antemortem PiB-PET SUVR. Forty-one participants (30 male, 11 female) with a mean (SD) age at death of 75.7 (10.6) years were included. Twenty-seven (66%) had high PiB signal with a mean (SD) of 2.3 (1.2) years from time of PET scan to death; 24 (59%) had a pathologic diagnosis of Alzheimer disease. On multivariate analysis, CAA was not associated with PiB-PET SUVR, while plaques remained associated with PiB-PET SUVR in all regions (all p < 0.05). In patients without frequent amyloid plaques, CAA was not associated with PiB-PET in any region. We did not find evidence that pathologically confirmed regional CAA burden contributes significantly to proximal antemortem regional PiB-PET signal, suggesting that amyloid PET imaging for measurement of cortical amyloid burden is unconfounded by CAA on a lobar level. Whether CAA burden contributes to PiB-PET signal in patients with severe CAA phenotypes, such as lobar hemorrhage, requires further investigation.