Citations

BACKGROUND: Cerebral microbleeds (CMBs) are associated with dementia, but the impact of specific microbleed patterns (with distinct pathophysiologies) is unclear. Lobar CMBs commonly result from cerebral amyloid angiopathy (sometimes with cortical superficial siderosis [cSS]), while subcortical microbleeds indicate a hypertensive cause. This study investigates the association of CMB presence, patterns, and frequency with dementia risk. METHODS: Participants from the ARIC-NCS (Atherosclerosis Risk in Communities-Neurocognitive Study), a community-based longitudinal cohort, with a 3T research magnetic resonance imaging scan at visit 5 (2011–2013) and without prior intracerebral hemorrhage or dementia were included. CMB and cSS presence and location were evaluated using a T2* gradient-recalled echo sequence. Each individual’s pattern of CMBs was classified as no CMBs, subcortical only, mixed (subcortical and lobar±cSS), lobar±cSS only, or cSS. Dementia adjudication was determined by blinded review of cognitive testing, informant interviews, and hospital discharge codes or death certificates (from follow-up visits and ongoing surveillance). Cox proportional hazards models assessed associations between CMBs and incident dementia through 2020, adjusted for demographics, vascular risk factors, and white matter hyperintensities. RESULTS: Among 1583 participants (mean age, 76 years; 24.7% cumulative dementia incidence over a median of 23.6 follow-up years), 361 had CMBs. Compared with individuals without CMBs, those with mixed (hazard ratio, 1.99 [95% CI, 1.40–2.83]) or lobar±cSS (hazard ratio, 1.96 [95% CI, 1.30–2.97]) CMB patterns had increased dementia risk, whereas individuals with a subcortical-only pattern did not (hazard ratio, 1.04 [95% CI, 0.78–1.39]). cSS presence (n=21; versus absence) showed an increased risk of dementia (hazard ratio, 2.57 [95% CI, 1.36–4.89]). Greater numbers of microbleeds across all CMB subtypes exhibited an increased risk of dementia. CONCLUSIONS: Lobar and mixed CMB patterns and increasing numbers of CMBs are associated with incident dementia. Certain CMB patterns have differential associations with dementia, but severe enough disease burden, regardless of CMB distribution, is associated with increased dementia risk.

Abstract Associations of Alzheimer’s disease biomarker progression with cognitive decline are important to inform patient prognosis. Of particular interest is how newly available plasma biomarkers evolve relative to cognitive decline. The goals of this work are to measure how much earlier versus later an individual’s progression on plasma and PET Alzheimer’s disease biomarkers is associated with earlier versus later cognitive progression and to estimate the average timeline of progression of these processes in the population. In this cohort study of 2369 Mayo Clinic Study of Aging (MCSA) and 1591 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants, we fit non-linear mixed-effects models to estimate how much earlier versus later each individual progresses on plasma phosphorylated tau (p-tau)217, amyloid PET, tau PET and auditory verbal learning test (AVLT) sum of trials relative to the population mean (individual adjustment), the associations of these individual adjustments among biomarker pairs and how covariates affect the timing of biomarker progression. The association of individual adjustments implies mechanistic associations and the amount of variability in cognitive decline accounted for by each biomarker. By applying cut-off points, we also estimated the relative timing that these biomarkers become abnormal in the population. Associations of individual adjustments were moderate between all biomarkers and AVLT (R = 0.38–0.47) in the MCSA and stronger (R = 0.74–0.81) in ADNI; plasma p-tau217 accounted for 16% of the variability in timing of AVLT decline in the MCSA and 64% in ADNI. APOE ɛ4 carriership was associated with earlier biomarker progression. AVLT became abnormal after the biomarkers up to age 90, after which AVLT was estimated to become abnormal prior to tau biomarkers. The association of the timing of plasma and PET Alzheimer’s disease biomarker progression with cognitive decline was modest in the MCSA population-based sample and stronger in the Alzheimer’s disease-enriched ADNI cohort. The timing of plasma p-tau217 progression explained a similar degree of variability in AVLT progression as amyloid PET, supporting its utility as a marker of disease progression. The estimated temporal ordering of biomarkers and cognitive abnormality was as anticipated (amyloid, tau, cognition) up to the age of 90, beyond which AVLT was estimated to become abnormal prior to tau biomarkers, likely related to the effects of non-Alzheimer’s disease co-pathologies.

Sickle cell disease (SCD) is the most common genetic haemoglobinopathy worldwide. Due to advancements in care, SCD patients are living longer. Consequently, there is increased interest in long term sequalae of chronic micro-vascular sickling and resultant end organ damage. Sickle cell cardiomyopathy is an emerging clinical entity characterised by a unique combination of ventricular dilatation, ventricular hypertrophy, diastolic dysfunction and pulmonary hypertension. Additionally, SCD patients have impaired autonomic function which is thought to pre-dispose to vaso-occlusive crises through sympathetic activation and parasympathetic withdrawal during times of physiologic stress. Furthermore, sudden death is a major cause of mortality among patients with SCD, however the mechanism has not been elucidated. This review summarizes the sickle cell cardiomyopathy literature, its relationship with autonomic dysfunction and its association with sudden death.

Objective: To explore the existing evidence on novel imaging modalities that may aid in prognostication of vestibular schwannoma (VS) clinical outcomes across various management approaches. Study design: Scoping review. Setting: Not applicable. Patients: Individuals diagnosed with VS. Interventions: Novel imaging techniques. Main outcome measures: Tumor growth and response to medical therapy. Results: A total of 18 articles were included in this review. Of these, 7 focused on pretreatment prognosis, 6 evaluated radiosurgery outcomes, 4 examined microsurgery outcomes, and 1 assessed response to bevacizumab. The imaging modalities investigated included radiomics (n = 10), positron emission tomography (PET; n = 2), dynamic contrast-enhanced MRI (DCE-MRI; n = 2), both PET and DCE-MRI (n = 1), magnetic resonance elastography (MRE; n = 1), contrast-enhanced CT (CE-CT; n = 1), and slip interface imaging (SII; n = 1). Radiomic studies yielded encouraging results in predicting tumor growth after wait-and-scan and radiosurgery, with reported accuracies ranging from 52% to 88%, sensitivities from 13% to 95%, specificities from 50% to 94%, and area under the curves from 0.65 to 0.99. PET studies identified several promising ligands associated with tumor growth during wait-and-scan, suggesting a potential role in prognostication. DCE-MRI also demonstrated associations with tumor growth and treatment response to bevacizumab. Studies on MRE, CE-CT, and SII identified novel imaging parameters associated with tumor stiffness and adhesion. Conclusions: Several emerging imaging modalities hold potential for improving clinical outcome prognostication in VS. Techniques such as radiomics, PET, and DCE-MRI have shown promising results; however, the supporting evidence is still limited and heterogeneous. Further research is necessary to validate and refine these approaches to enhance their clinical utility.

Abstract INTRODUCTION The Centiloid scale is the standard for amyloid (Aβ) PET quantification in research and clinical settings. However, variability between tracers and scanners remains a challenge. METHODS This study introduces DeepSUVR, a deep learning method to correct Centiloid quantification, by penalizing implausible longitudinal trajectories during training. The model was trained using data from 2,129 participants (7,149 Aβ positron emission tomography [PET] scans) in the Australian Imaging, Biomarkers and Lifestyle Study of ageing (AIBL)/Alzheimer's Disease Neuroimaging Initiative (ADNI) and validated using 15,807 Aβ PET scans from 10,543 participants across 10 external datasets. RESULTS DeepSUVR increased correlation between tracers, and reduced variability in the Aß‐negatives. It showed significantly stronger association with cognition, visual reads, neuropathology, and increased longitudinal consistency between studies. DeepSUVR also increased the effect size for detecting small treatment related slowing of amyloid accumulation in the A4 study. DISCUSSION DeepSUVR substantially advances Aβ PET quantification, outperforming all standard approaches, which is particularly important for clinical decision making and to detect subtle or early changes in Aβ. Highlights Novel artificial intelligence (AI)‐method that penalizes biologically implausible longitudinal trajectories, enabling the model to learn standardized uptake value ratios (SUVR) correction factors without requiring longitudinal data at inference time. Improves Centiloid consistency across tracers and studies, significantly enhancing cross‐sectional and longitudinal amyloid positron emission tomography (PET) quantification. DeepSUVR‐derived Centiloids show stronger associations with cognition, visual reads, and neuropathology. Longitudinal variability is reduced three‐ to five‐fold, enabling more reliable tracking of amyloid accumulation and better detection of treatment effects. Novel reference and target masks derived from DeepSUVR replicate most of the model's performance, offering a practical alternative for integration into existing pipelines.

Abstract Repetitive injury is hypothesized to lead to progressive tissue fibrosis and end-stage organ failure. Whether tissue-resident mesenchymal cell populations retain epigenetic memory of prior injuries that contribute to this pathological process is unknown. Here we used a genetic lineage labeling approach to mark the lung mesenchyme prior to injury, then performed multimodal analyses on isolated lung mesenchyme during the initiation, progression, and resolution of the fibrotic response. Our results demonstrate the remarkable epigenetic and transcriptional plasticity of the lung mesenchyme during fibrotic activation and de-activation. Despite this plasticity, we also find that the lung mesenchyme exhibits an enhanced fibrotic program upon reinjury. We identify RUNX1 as a critical driver of both fibrotic activation and fibrotic memory. Comparison of fresh isolated and cultured lung mesenchyme demonstrates that RUNX1 is spontaneously activated in standard culture conditions, previously masking these roles of RUNX1. Targeted knockdown of RUNX1 dampens fibrotic mesenchymal cell activation immediately after cell isolation, but with reduced efficacy after only days of culture, confirming its functional importance to both early activation and long-term memory. Collectively, our findings implicate RUNX1 in the initiation and memory of fibrotic mesenchymal cell activation that together prime enhanced mesenchymal cell responses upon repeated injury.

Abstract INTRODUCTION Associations of short‐term use of menopausal hormone therapy (mHT) with Alzheimer's disease (AD) and structural magnetic resonance imaging (MRI) biomarkers were investigated 10 years after an mHT trial. METHODS Recently menopausal women with good cardiovascular health were randomized to oral conjugated equine estrogens (oCEE) or transdermal 17β‐estradiol (tE2) and micronized progesterone, or placebo for 4 years. Amyloid beta (Aβ) on positron emission tomography, hippocampal atrophy, and dorsolateral prefrontal cortex thickness on MRI were assessed 10 years after completion of the mHT trial ( n = 266). RESULTS Aβ and structural MRI biomarkers were not different in the oCEE and tE2 groups compared to placebo. Apolipoprotein E ε4 status did not modify the findings. DISCUSSION There was no evidence of adverse effects or benefits associated with 4 years of use of oral or transdermal mHT on Aβ and structural MRI biomarkers in relatively healthy women, 10 years after mHT. Findings support the long‐term safety of short‐term use of mHT on brain health. CLINICAL TRIALS REGISTRATION NCT00154180 Kronos Early Estrogen Prevention Study (KEEPS) Highlights There were no menopausal hormone therapy–related adverse effects or benefits on amyloid beta and magnetic resonance imaging biomarkers in the long term. Apolipoprotein E ε4 carrier status did not modify these findings. Findings align with neutral cognitive and cerebrovascular outcomes in this cohort.

Objective: Epidemiological data have suggested that late-life depression (LLD) occurs as a consequence of cerebrovascular and neurodegenerative disorders, but there is also some evidence suggesting that the relationship may occur in the other direction, namely that LLD may be a risk factor for cerebrovascular and neurodegenerative disorders. However, the neurobiological basis of these associations remain unclear. This study investigated the associations of LLD with markers of cerebrovascular pathology, brain volumes, and cortical thickness from 3-Tesla brain magnetic resonance imaging (MRI). Methods: Participants from the Atherosclerosis Risk in Communities Study received brain MRI scans in late-life (ages 67-90). The following neuroimaging outcomes were assessed: cortical infarcts, lacunar infarcts, any microhemorrhages, lobar microhemorrhages, subcortical microhemorrhages, white matter hyperintensity volume, total and regional brain volumes (z-scores), and total average and regional cortical thickness (z-scores). At the same visit, LLD was evaluated with the 11-item Center for Epidemiological Studies Depression Scale (CES-D) and defined as CES-D score≥9. Associations between LLD and neuroimaging outcomes were examined using logistic and linear regression models, and were adjusted for age, race-center, sex, education level, vascular risk factors, stroke, cognitive status, APOE e4 carrier status, and total intracranial volume when assessing volumes. Results: Among 1,857 participants, the median age was 76 years, 59.5% were female, 28.3% were Black, and 6.8% had LLD. LLD was not associated with infarcts or microhemorrhages. There was no evidence of an association between LLD and total white matter hyperintensity volume or total average cortical thickness. However, LLD was independently associated with smaller volume (SD) of the rostral anterior cingulate (b 1 : -0.18; 95% CI: -0.33, -0.04) and greater cortical thickness (SD) in the medial orbitofrontal cortex (b 1 : 0.19; 95% CI: 0.01, 0.38), though effect sizes were small and did not survive correction for multiple comparisons. Conclusion: Findings from this study suggest LLD is not cross-sectionally associated with neuroimaging markers of cerebrovascular disease. While LLD may be linked to subtle volume and cortical thickness changes in specific regions of interest, future longitudinal research is warranted to validate and clarify these associations and explore their potentially bidirectional relationship.

Abstract Systemic amyloidosis is a rare, multisystem disorder that is often challenging to diagnose due to vague and nonspecific symptoms that frequently overlap with other disorders. By the time patients are diagnosed, irreversible organ impairment from amyloid deposition occurrs, contributing to substantial morbidity and mortality. Although developing the American Society of Hematology (ASH) guidelines on systemic amyloidosis, we identified a critical knowledge gap in the recognition of the clinical presentation of its most common subtypes. Therefore, we conducted a scoping review of 117 studies following PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) guidelines to identify clinical “red flags” for light chain (AL) and transthyretin (ATTR; wild-type [ATTRwt] and hereditary [ATTRv]) amyloidosis. Studies were identified from the comprehensive systematic review through the ASH amyloidosis diagnosis guideline panel, data mining, and gray literature review. Data were extracted and synthesized by systems to characterize the earliest and most frequently overlooked clinical red flags for the different types of amyloidosis. Shortness of breath and fatigue, the earliest symptoms of AL amyloidosis, contrast with the carpal tunnel syndrome occurring years before ATTRwt cardiac amyloidosis is diagnosed. Weight loss, unexplained abdominal pain, and early satiety were overlooked red flags for AL amyloidosis, compared to the preceding arrhythmias often missed in evaluation for ATTRwt amyloidosis. Sensory loss was the predominant neuropathic presentation for AL amyloidosis compared to the painful length-dependent neuropathy of ATTRv amyloidosis. Awareness of the early symptoms and distinct patterns across subtypes can enhance cross-specialty awareness and support earlier diagnosis and intervention of AL and ATTR amyloidosis.