Citations

AbstractBackgroundThe prognosis in patients with advanced cardiac amyloidosis (CA) remains poor.ObjectivesWe sought to describe survival post heart transplantation (HT) in amyloid compared with non‐amyloid recipients, highlight waitlist times within the new allocation system across three Organ Procurement and Transplantation Network (OPTN) regions, and describe multiorgan transplantation (MOT) in hereditary amyloidosis.MethodsThis is a retrospective review of end‐stage CA patients who underwent HT at Mayo Clinic from January 2007 to December 2020. Wait time was compared in the new versus old OPTN allocation era starting December 18, 2018 by Wilcoxon rank sum test. All‐cause mortality for those with and without CA was compared using Kaplan–Meier estimates with log rank analysis, censoring December 16, 2022.ResultsFifty‐five patients with CA underwent HT between 2007 and 2020, 8 light chain amyloidosis (AL) (14.5%), 28 hereditary transthyretin (ATTRv) (50.9%), 17 wildtype transthyretin (ATTRwt) (30.9%), and 2 hereditary apolipoprotein A1 (AApoA1) amyloidosis patients (3.6%). No significant difference in overall survival post‐transplant was seen in amyloid compared with non‐amyloid (p = 0.816). Median time to HT was shorter in the new system, 45 days (IQR 24, 78) versus 174 days (IQR 76.5, 483.5), p = 0.006. There was a decline in MOT in hereditary amyloidosis over time with the concomitant rise in disease‐targeted therapies.ConclusionsHT survival in CA patients was similar to non‐amyloid patients. The new allocation system benefits this cohort with shorter wait times. There is less MOT in hereditary amyloidosis with increased utilization of disease‐targeted therapy.

Background: Mismatch between osteochondral allograft (OCA) donor and recipient sex has been shown to negatively affect outcomes. This study accounts for additional donor variables and clinically relevant outcomes. Purpose: To evaluate whether donor sex, age, donor-recipient sex mismatch, and duration of graft storage affect clinical outcomes and failure rates after knee OCA transplantation. Study Design: Cohort study; Level of evidence, 3. Methods: Patients undergoing knee OCA transplantation between 2003 and 2018 were prospectively followed. Inclusion criteria consisted of primary OCA transplantation and minimum 2-year follow-up. Patient descriptive data and allograft donor sex, age, and graft storage time before implantation were collected. Patients were evaluated for reoperation, failure, and achievement of clinically significant outcomes for International Knee Documentation Committee scores. Reoperation was defined as subsequent surgical intervention of the transplanted allograft, including second-look arthroscopy for graft evaluation, debridement, and loose body removal. Failure was defined as revision of the primary OCA transplantation or conversion to arthroplasty. A Kaplan-Meier curve determined cumulative survivability of OCA transplantations, and log-rank testing was used to compare survivorship between groups. Stepwise regression analysis was utilized to evaluate associations between donor variables and achievement of clinically significant outcomes, reoperation, and failure. Results: A total of 372 patients undergoing OCA transplantation were included and followed for a mean 5.4 years (SD, 2.7; range, 2.0-16.3). Isolated OCA transplantation was performed in 45% of cases (169/372). A mismatch in donor and recipient sex was present for more female patients (90%) than male patients (10%; P < .001). Those who had a sex-mismatched graft more frequently underwent concomitant tibial tubercle osteotomy ( P = .034). When controlling for patient sex, no other differences were seen between groups matched and mismatched by sex. Univariable and multivariable analysis found no significant difference in survival free from reoperation or failure on the basis of donor-recipient sex mismatch, donor age, or graft storage time before implantation. Conclusion: In contrast to previous historical data, no donor variables were associated with inferior clinical outcomes in patients who underwent OCA transplantation. These data can help inform graft selection, expedient recipient selection, and outcome optimization after OCA transplantation.

AbstractBackgroundGenome‐wide association studies (GWAS) in Alzheimer’s disease (AD) leveraging endophenotypes beyond case/control diagnosis, such as brain amyloid β pathology, have shown promise in identifying novel variants and understanding their potential functional impact. In this study, we leverage two brain amyloid β pathology measurement modalities, PET imaging and neuropathology, to address sample size limitations and to discover novel genetic drivers of disease.MethodWe conducted a meta‐analysis on an amyloid PET imaging GWAS (N = 7,036, 35% amyloid positive, 53.67% female, age = 71) and an autopsy GWAS of brain amyloidosis (N = 6,519, 63.08% amyloid positive, 51.34% female, age at death = 83), both adjusted for covariates including age, sex and principal components of genetic ancestry. All participants in both GWAS were unrelated individuals of European descent. We defined amyloid positivity as moderate or frequent neuritic plaques using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) staging scores within each autopsy cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET imaging cohort to identify the cohort and tracer‐specific cut‐offs that differentiate amyloid positive and negative populations.ResultThe genome‐wide significant results from the meta‐analysis identified three known AD loci (APOE, CR1, and BIN1) and a novel chromosome 17 locus (rs35635959, intergenic, MAF = 0.27, OR = 1.18, p = 1.47 × 10‐8). The MAGMA gene‐level analysis excluding the APOE region suggests significant associations between rs35635959 and COASY, PLEKHH3, and TUBG2 on chromosome 17, implying the potential roles of these genes on amyloidosis. Functional annotations of rs35635959 leveraging brain eQTL databases indicate its association with differential gene expression of COASY and TUBG2 in AD brains. ROSMAP bulk and single‐nucleus RNAseq analyses link TUBG2 downregulation to the higher amyloid burden and AD diagnosis while suggesting such observations are enriched in excitatory and inhibitory neurons, reaching FDR significance.ConclusionThis study is the most extensive European GWAS of brain amyloidosis, and our findings replicate known AD loci and identify a possible novel locus (index SNP rs35635959) on chromosome 17. Functional annotations of the novel variant indicate TUBG2, implicating in microtubule organization, warrants further assessment. Ongoing efforts aim to validate these novel effects using independent datasets.

AbstractBackgroundAlzheimer disease (AD) involves neurodegenerative disorders with progressive cognitive decline. Atypical presentations like Posterior Cortical Atrophy (PCA) and Logopenic Variant Primary Progressive Aphasia (lvPPA) exhibit distinct clinical profiles. PCA affects the posterior parietal and occipital lobes, causing visuospatial deficits, while lvPPA manifests as language impairment in the temporoparietal region. Understanding the biological underpinnings of these variants is crucial for deciphering AD’s heterogeneity.MethodParticipants diagnosed with AD dementia (n = 54, female = 25, Age: 75.23±6.52), PCA (n = 9, female = 8, Age: 62.78±7.21), and lvPPA (n = 6, female = 2, Age: 66.33±6.38) from the Knight Alzheimer Disease Research Center (Knight ADRC) underwent 18F‐AV‐1451 tau‐PET imaging. Tau deposition, along with nine biological properties, was mapped to the cortical surface (Figure 1A): gene expression, myelin, cortical thickness, sensorimotor association axis, evolutionary expansion, cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of glucose (CMRglu) (Figure 1B). Correlation matrices and generalized linear models (GLMs) assessed relationships between tau accumulation and biological properties.ResultA correlation matrix (Figure 2A) shows significant positive associations (p<0.05) between evolutionary expansion patterns and tau accumulation in AD (r = 0.53), PCA (r = 0.29), and lvPPA (r = 0.56); and gene expression in PCA (r = 0.51). Conversely, strongest negative associations were observed in AD (r = ‐0.38, r = ‐0.15) and lvPPA (r = ‐0.18, r = ‐0.28) for CBF and myelin mapping, respectively, and in PCA (r = ‐0.25, ‐0.23) for cortical thickness and sensorimotor association axis. GLMs demonstrated significant relationships between cerebrovascular health and evolutionary expansion with tau measures across all groups. AD (r = ‐0.52) and PCA (r = ‐0.19) exhibited negative associations with gene expression and myelin mapping, respectively. Additionally, lvPPA (r = 0.39) displayed positive association with the sensorimotor association cortex.ConclusionResults elucidate distinct tau deposition patterns in AD, PCA, and lvPPA, providing insights into subtype‐specific pathophysiology. The correlation matrix and GLMs highlight the significance of evolutionary expansion and cerebrovascular health in tau accumulation. Associations underscore the complex interplay of gene expression, myelin mapping, and cortical thickness with tau pathology. Findings contribute to understanding heterogeneity within AD spectrum disorders, emphasizing the multifaceted nature of neurodegenerative processes. Further research promises refined diagnostic and therapeutic strategies tailored to distinct neurobiological profiles in AD, PCA, and lvPPA.

AbstractBackgroundAutosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset. However, whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear.MethodUtilizing T1 and task‐free functional magnetic resonance imaging (tf‐fMRI) from 49 presymptomatic and 26 symptomatic GRN mutation carriers, we determined the relationships between functional connectivity as measured by voxel‐wise whole brain degree and GRN‐relevant markers of disease progression, which included plasma neurofilament light chain (NfL) concentrations, CSF complement C1q and C3b protein levels, grey matter atrophy, and OCD symptom severity.ResultNfL concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in presymptomatic GRN carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter, in symptomatic carriers. Presymptomatic carriers with thalamic hyperconnectivity tended to have lower grey matter volume in bilateral insula and left lateral parietal cortex, which are among regions that deteriorate in GRN‐FTD. OCD symptom severity was associated with hypoconnectivity across all GRN carriers.ConclusionIn presymptomatic carriers, the co‐occurrence of hyperconnectivity, high NfL, and low gray matter suggests that tf‐fMRI hyperconnectivity may portend the onset of the neurodegenerative phase. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

AbstractBackgroundThe newly proposed criteria by the AA working group incorporates both biological and clinical stages to characterize the progression of AD. In this study, we aim to evaluate the agreement between these two complementary systems.MethodsUsing 188 participants from McGill TRIAD and 139 from the HEAD cohorts, we categorized participants into biological (0‐4) and clinical (0‐4) stages using amyloid PET, tau PET(MK‐6240), and clinical measures as described by the working group. Participants were then stratified into three categories: congruent (clinical = biological), higher in the biological stage (clinical < biological), and higher in the clinical stage (clinical > biological). In the TRIAD cohort, we further compared these groups for age, sex, years of education, vascular burden (WMH), microglial activation (PBR scan), Astrocyte reactivity (GFAP), amyloid load, tau load, and NPI‐Q scores using Welch two‐sided t‐test with FDR multiple comparison correction.ResultsIn the TRIAD cohort, 34% of participants were congruent, 24.5% had a higher clinical stage, and 41.5% had a higher biological stage. Meanwhile in the HEAD cohort 68.2% were congruent, 20.7% had a higher clinical stage, and 17% had a higher biological stage. TRIAD participants with a higher clinical stage had lower education (P = 0.02), more neuropsychiatric symptoms (P = 0.03), and a higher vascular burden (P = 0.03) (Table 1). As expected, people with higher biological stage had more amyloid(P<0.001), tau(P<0.001), and astrocyte reactivity(P<0.001) (Table 1, Figure 2).ConclusionsOur findings highlight important discordance between clinical and biological stages, which could be partially explained by cognitive reserve. This was supported by the protective effects of educational attainment in participants with a higher biological stage. Vascular burden played a major role in the cognitive impairment of individuals with higher clinical stages. Future studies should replicate these findings in larger more representative population‐based cohorts.

AbstractBackgroundRecent studies showed that neuroinflammation plays a key role in triggering specific neuropsychiatric symptoms (NPS), such as irritability and agitation, in individuals with Alzheimer’s disease (AD). While prior studies showed an association between tau pathology and all NPS domains, the extent to which tau influences each specific NPS domain remains unclear. Here, we aim to investigate the association of tau and NPS domains in the AD continuum. We hypothesize that tau plays a comparatively greater effect on the emergence of psychotic symptoms compared to other NPS domains.MethodWe assessed 56 individuals (21 cognitively unimpaired (CU), 23 MCI, and 12 AD dementia) from the HEAD study who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q) and had positron emission tomography (PET) for amyloid‐β (Aβ) ([18F]AZD4694 or [11C]PiB), and tau tangles ([18F]MK6240) at the same visit. We selected individuals with an NPI‐Q total score ≥1. Tau SUVR values were tailored with a mask from Braak stages I‐VI, using the inferior cerebellar gray matter as reference region. Leave‐one‐out voxel wise and linear regression tested the association between each NPI‐Q domain and biomarkers accounting for age, sex, cognitive status, and study site.ResultCI individuals had significantly higher NPI‐Q score and Braak VI PET SUVR than CU individuals (Table 1). NPI‐Q score was significantly associated with tau‐PET in the periRolandic and supplementary motor cortex (Figures 1A). Linear regression showed that NPI‐Q associates with tau‐PET in the Braak stage VI (Figure 1B). Leave‐one‐out regression analysis revealed that delusions, motor disturbances, and anxiety contributed most to the association between tau‐PET and NPS (Figure 2A, C). These domains presented a higher magnitude of association compared to each other NPI‐Q domain (Figure 2B). Notably, irritability, agitation, and disinhibition exerted a negative effect to the association, emphasizing that tau may not play a role in the development of these symptoms (Figure 2A, D)ConclusionOur study supports previous evidence suggesting that irritability and agitation may not be triggered by tau, but rather by other pathological process such as neuroinflammation. These findings provide additional rationale for the therapeutics aiming to mitigate irritability and agitation in AD patients.

Abstract Dementia caregivers are at heightened risk for developing mental and physical health problems. Interventions designed to protect caregiver health often create additional demands on time and energy (e.g., exercise programs). Technology-based interventions (e.g., remote monitoring) can be effective, scalable, and do not add greatly to caregiver burden. Through a collaboration with a local technology company, Care Daily, we conducted two randomized controlled trials to evaluate People Power Caregiver (PPCg), a system of sensors in the home connected to cloud-based AI that alerts caregivers about worrisome deviations from normal patterns (e.g., care-recipient’s falls, wandering). Across two studies (study 1: 9-month duration with professional installation of PPCg; study 2: 6-month duration with caregiver self-installing the PPCg using remote tech support), 284 caregivers were recruited; 261 completed initial study deployment (e.g., system installation); and 235 completed the entire study protocol. Use of PPCg was associated with (a) reduced caregiver anxiety in study 1; (b) greater protection from declines in sleep efficiency in studies 1 and 2. These findings underscore the promise of technology-based intervention to mitigate health problems in dementia caregivers. However, challenges and complexities in recruitment (e.g., remote consenting both caregivers and care recipients), retention (e.g., due to changes in home environment or caregiving status), system installation (e.g., working with caregivers with less experience using technology), data quality assurance (e.g., invalid sensor data) as well as our efforts to overcome these challenges have been instructive. Lessons learned from these studies can provide useful guidance for future large-scale, technology-based interventions for dementia caregivers.