Citations

Objective Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f‐FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f‐FTLD. We used a Bayesian linear mixed‐effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. Methods Participants included 234 asymptomatic or prodromal carriers of C9orf72 , GRN , or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1‐weighted scans. The BLME models established individual voxel‐wise gray matter trajectories using the first 2 scans. Person‐specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time‐varying Cox proportional hazard models covarying for age. Receiver‐operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. Results The BLME cluster volume predicted conversion to dementia in f‐FTLD mutation carriers overall and separately in C9orf72 , GRN , and MAPT , with comparable hazard ratios observed for atrophy W‐maps and regional volumes. Within a 24‐month timeframe, BLME cluster volume discriminated dementia converters from non‐converters with larger areas under the curve (AUCs) than other approaches. Interpretation Bayesian‐modeled individualized atrophy scores predict dementia progression among asymptomatic f‐FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a–n/a

Background: There is much interest in drug development to prevent rebleeding after symptomatic hemorrhage (SH) in cerebral cavernous malformations (CCM) and its neurologic sequelae. A recent randomized prospective controlled trial (AT CASH EPOC clinicaltrials.gov NCT02603328) demonstrated that atorvastatin for up to 2 years was safe but did not significantly alter CCM iron deposition or SH rates. However, the consequences of discontinuing atorvastatin in CCM patients remain unknown. Given reports of rebound effects with discontinuation of statins, we here hypothesize that SH recurs more frequently in hemorrhagic CCMs after discontinuation of atorvastatin than placebo. Methods: We conducted 12-month (±1 month) post-treatment follow-up of all 80 patients randomized in the AT CASH EPOC trial (41 atorvastatin, 39 placebo) to identify potential recurrent SH from the date of trial drug discontinuation. Every SH was adjudicated by review of imaging and corresponding symptoms. Patients were excluded for < 90% compliance with study drug or its discontinuation <3 months during the trial, and for lack of follow-up. Cases were censored during follow-up upon CCM resection/radiation or atorvastatin initiation/re-initiation. Results: Follow-up included 33 patients who had been randomized to placebo and 32 who had taken atorvastatin.During follow-up, 4 SH events occurred at 3, 49, 84, and 225 days after atorvastatin discontinuation, and only 1 SH 395 days after discontinuing placebo. Kaplan–Meier curves demonstrated significantly lower symptomatic hemorrhage-free survival in the atorvastatin-discontinuation group (log-rank chi=4.136, p=0.042). The Gehan–Breslow–Wilcoxon test (chi=4.080, p=0.043) highlighted early divergence in recurrent SH risk. The hazard ratio was 0.162 (95% CI 0.027–0.977) for placebo vs. atorvastatin discontinuation. Conclusion: While there was no difference in SH rates during 2 years of treatment with atorvastatin versus placebo in randomized clinical trial, discontinuation of atorvastatin was associated with a significantly higher and earlier risk of recurrent SH compared with placebo discontinuation. This raises concern for a rebound effect during the year after statin withdrawal in hemorrhagic CCM patients, potentially mediated by reactivation of Rho-associated kinase. Additional studies are warranted to confirm these observations and to assess whether statin tapering or maintenance therapy can mitigate the risk of discontinuation in hemorrhagic CCM.

Introduction: Functional outcome scales are commonly used in neurological clinical trials. Prior studies suggested that these scales may reflect symptomatic hemorrhage (SH), but their performance in detecting treatment effects has not been assessed in clinical trials of cerebral cavernous malformations (CCM). And they have not been correlated with CCM bleeding as reflected by lesional iron content assessed by quantitative susceptibility mapping (QSM) MRI. Hypothesis: We hypothesized that functional outcome measures would detect differences between treatment arms in a randomized clinical trial of hemorrhagic CCM, and reflect new SH or a ≥6% increase in mean lesional QSM reflective of CCM bleeding. Methods: Eighty adults with CCM-related SH in the prior 12 months of enrollment were randomized 1:1 to atorvastatin 80 mg/day or placebo for 2 years. Functional outcomes, including mRS, EQ-5D index, EQ-VAS, and PROMIS-29 domains, were collected at baseline, Year 1, and Year 2. Analyses were conducted in 63 participants (32 atorvastatin, 31 placebo) in the modified intention-to-treat trial cohort who had contributed at least one paired annual clinical and imaging assessment. Results: No significant differences were found between atorvastatin and placebo groups in any functional outcome measure across timepoints. Rates of functional decline and improvement were comparable, except for PROMIS Fatigue which improved more in the atorvastatin than placebo patients from baseline to Year 1 (p=0.019). Pooled analyses showed that several functional domains had strong specificity for identifying SH. PROMIS Sleep Disturbance decline from baseline to Year 2 was associated with SH (p=0.0045; specificity 92.3%, sensitivity 57.1%). A ≥10-point drop in EQ-VAS from baseline to Year 1 identified all SH cases during that interval (p=0.007; sensitivity 100%, specificity 83.6%). Functional decline had low sensitivity in detecting CCM bleeding on QSM, though specificity was high (>75%) across domains. Conclusions: Atorvastatin did not influence functional change over 2 years by any measure. PROMIS Sleep Disturbance and EQ-VAS demonstrated high specificity, and in the case of EQ-VAS also a high sensitivity for identifying SH. Functional outcomes across domains also had high specificity for occult bleeding in CCMs as measured by QSM. Poor sensitivity and consistent improvements over time demonstrate the limitations of functional outcome measures as endpoints of drug effects on CCM bleeding.

Background: It is not clear if changes in lesion volume might represent a clinically relevant and statistically advantageous outcome parameter in early phase trials of novel drugs aimed at preventing bleeding in cerebral cavernous malformations (CCM). Methods: We analyzed the modified intention to treat cohort (33 patients receiving atorvastatin and 31 placebo) who contributed at least one paired imaging biomarker in the recently completed double-blinded randomized controlled AT CASH EPOC trial (clinicaltrials.gov NCT02603328). We examined prospective changes in CCM lesion volume and correlated these with symptomatic hemorrhage (SH) events. We contemporaneously assessed changes in lesional iron content by quantitative susceptibility mapping (QSM) on MRI, and objective (mRS) and subjective (EQ-VAS) functional status. We also simulated sample sizes needed to detect potential effects of a drug on lesion volume. Results: There was excellent correlation between independently assessed maximum lesion diameter and CCM lesion volume (R 2 = 0.68, P<0.0001). The mean (SD) percentage change in lesion volume per year was +6 (65) and +18 (94) in atorvastatin and placebo patients, respectively (P= 0.43). All cases with SH had increases in lesion volume as well as increases in mean lesional iron content by QSM, and most had declines in functional status on mRS and EQ-VAS. But there were many cases with increases in lesion volume with improved functional status or decreased mean lesional QSM, and other cases with worsening in function or increased lesional QSM and decreased lesion volume. There were no significant correlations of changes in lesion volume with concomitant changes in mean lesional QSM, mRS or EQ-VAS (all R/R 2 <0.5 and Bonferroni corrected P>0.05), including in brainstem lesions analyzed separately. Sample size simulations indicate larger numbers of cases needed to demonstrate a drug effect on changes in lesion volume than those needed to detect an effect on QSM change with a=0.05 and b=0.8, and even larger samples to detect effects on the proportion of cases with increased or decreased lesion volume. Conclusion: Changes in lesion volume occur frequently in CCM lesions after recent SH, but do not correlate with measures of bleeding in the lesions, nor appear to reflect functional changes. And they are not statistically advantageous in comparison to QSM measures for detecting potential drug effects.

Background While SARS-CoV-2 vaccines are highly effective in healthy individuals, the magnitude and durability of humoral and cellular responses in patients with solid malignancies receiving chemotherapy remain understudied. Previous reports suggest that patients with cancer may not mount adequate immune response after SARS-CoV-2 vaccination. Additionally, most studies focused on humoral responses, while data regarding cellular immune responses are scarce. In this study, we evaluated humoral and cellular responses in patients with solid tumors receiving chemotherapy compared to healthy individuals up to one year after vaccinations. Methods Patients aged ≥18 who were willing to receive the SARS-CoV-2 vaccine were enrolled. Anti-SARS-CoV-2 immunoassays were used to detect antibodies against nucleocapsid and spike proteins. Human IFN-γ Fluorospot assay was used to determine antigen−specific T-cell responses. Data were compared between groups using Mann−Whitney test for continuous variables and Fisher’s exact test for categorical variables. Results A total of 67 subjects (47 patients with cancer and 20 healthy individuals) were included. 1–3 months following the second vaccine doses, 96% of patients with cancer and 100% of healthy individuals demonstrated a positive humoral response. While the positivity rate was not significantly different, patients with cancer had significantly lower spike IgG antibodies than healthy individuals. However, this difference diminished at 6 months when patients with cancer had increased antibodies compared to decreased antibodies in the healthy cohort and no difference was noticed at 12-month. Patients with cancer developed a similar antigen-specific T-cell response as healthy individuals at 1–3 months, 6 months and 12 months. There were no significant differences when comparing patients aged ≤ 55 years vs. &gt;55 years, stages I-III vs. IV, single vs. multiple chemotherapy, and BNT162b2 vs. mRNA-1273 vaccines. There was a significant moderate correlation between neutralization and antibody levels at 12 months. However, despite patients with cancer having a significantly higher COVID risk score, there were no significant differences in COVID-19 infection and hospitalization between patients with cancer and healthy individuals. Conclusion Despite initial impaired antibody responses to SARS-CoV-2 vaccinations, patients with solid malignancies receiving chemotherapy effectively generated long-term cellular and humoral responses by 6 and 12 months, leading to similar infection and hospitalization rates compared to healthy individuals.

Abstract Background Current literature suggestsisocitrate dehydrogenase (IDH)-mutant astrocytoma contains several molecular subgroups. In this study, we are interested in determining the connection between different molecular subgroups with grade and/or survival. Methods A cohort of 470 Mayo Clinic adult patients (≥18 years, 56.2% male) with primary IDH-mutant astrocytoma diagnosed by World Health Organization (WHO) 2021 criteria were examined. Results were validated in an independent cohort of 614 Mayo Clinic Neuropathology consult patients and 235 The Cancer Genome Atlas (TCGA) patients. Results The Mayo Clinic Practice cohort confirmed the association of CDKN2A/B deletion with overall survival (OS, homozygous vs hemizygous vs intact, 2.7 vs 9.6 vs 17.2 years, P &lt; .001). Phosphatase and tensin homolog (PTEN) deletion was also associated with poor OS (7.3 vs 17.4 years, P &lt; .001). Increased number of copy number alterations was associated with OS (continuous variable, HR = 1.027, P &lt; .001). Carrying one or more copies of the germline risk allele at rs55705857 was associated with earlier age of onset (median age 33 vs 35 years, P = .01), and a shorter OS after adjusting for age, grade, sex and treatment (HR = 1.81, P = .007). The Mayo Clinic Neuropathology Consult cohort and TCGA were utilized to validate age of onset and survival, respectively. Unsupervised clustering of the copy number alterations identified several clinically significant groups that may define pathways to disease progression. Losses of chromosomes 11p, 13q, 1p, and 10q were all associated with reduced overall survival in the Mayo Clinic cohort. Conclusions Patients with hemizygous loss of CDKN2A/B, loss of PTEN, increased number of copy number alterations, specific chromosomal arm losses or rs55705857 germline risk allele have reduced overall survival.

In 1995, Medicare reduced payments by 50% for anesthesiologists teaching two residents concurrently. By 2004, anesthesiology residency programs were losing, on average, $400,000 per year, causing many institutions to close their anesthesiology training programs. American Society of Anesthesiologists leaders tried unsuccessfully for several years to address this situation through appeals to Medicare. They then organized an advocacy effort to pass the Medicare Anesthesiology Teaching Funding Restoration Act of 2007, which in 2010 restored full payments for teaching anesthetics. From 2010 through 2024, anesthesiologists received $1.262 billion from Medicare for 2.8 million cases involving residents, which is between $442 million and $568 million more than if the legislation had not been enacted. Anesthesiology residency programs increased from 131 to 167 after the enactment. This historic legislation taught anesthesiologists that changing Medicare policies may require congressional action and that persistent and broad-based advocacy can make a legislative campaign successful.

Cellular senescence is a heterogeneous phenotype characterized primarily in mesenchymal cells, but the extent to which immune cells differ in their senescence phenotype, or “senotype,” is unclear. Here, we applied single-cell approaches alongside both global and cell-specific genetic senolytic mouse models to evaluate the senotype of immune cells in the bone marrow of aging mice. We found that myeloid-lineage cells exhibited the highest expression of p16 and senescence-associated secretory phenotype markers among all immune cell types. In contrast with clearance of p16 + senescent mesenchymal cells, targeted clearance of p16 + myeloid cells in aged mice had only minor effects on age-related bone loss in male mice, with no effects in females. In more detailed analyses, p16 + myeloid cells were only acutely cleared, being repopulated back to basal levels within a short time. This led to a lack of long-lasting reduction in senescent cell burden, unlike when targeting bone mesenchymal cells. In vitro, myeloid-lineage cells differed markedly from mesenchymal cells in the development of a senescent phenotype. Collectively, our findings indicate that aged bone marrow myeloid cells do not achieve the fully developed senescent phenotype originally described in mesenchymal cells, justifying further characterization of senotypes of immune cells across tissues.

Abstract Background Computed tomography (CT) is an essential imaging modality for disease diagnosis, treatment efficacy, and image‐based guidance of various medical procedures. The locally deposited radiation dose in tissues, as estimated by the computed tomography dose index (CTDI), can vary considerably across exposures delivered by CT scanners from different vendors, even if the scans are performed using similar technique factors, such as tube potential and tube current. The volumetric CTDI (CTDI vol ) is a common dose metric that reports an average radiation dose (in mGy) delivered to a specific volume within a test phantom. The CTDI vol is important in dosimetry applications as the organ absorbed dose within the patient has been shown to scale in near‐linear proportion, creating a basis for comparing organ doses across different scan protocols and scanner models. Purpose To develop a database of tube current‐time product (mAs) normalized CTDI vol values for currently utilized CT scanner models for each of the four primary CT vendors for use in the MIRDct organ dosimetry software available at MIRDsoft.org. This data forms the basis of the MIRDct code, which reports organ doses across a range of computational phantoms based upon axial organ dose coefficient libraries generated through Monte Carlo radiation transport for a reference CT scanner. Organ doses delivered by alternate CT scanner vendors and models may then be reported using ratios of normalized CTDI vol values under similar technique factors. Methods Scanners were selected from four major CT manufacturers: Philips Healthcare, GE Healthcare, Canon Medical Systems, and Siemens Healthineers. Technique parameters were also selected for each scanner that closely matched values used in the generation of an equivalent CT source term (small to large bowtie filters; 80–140‐kVp tube voltage; and 10‐mm to 40‐mm beam collimation). For each scanner chosen, the appropriate technique factors and protocols were selected, and the console‐reported CTDI vol values were recorded and normalized to a set value of 100 mAs. The normalized CTDI vol data collected for use within the MIRDct code were analyzed for noticeable patterns, features, and trends, and were compared to similar normalized CTDI vol datasets used within the National Cancer Institute NCICT software and the Virtual Phantoms, Inc. VirtualDose software. Results For all given CT scanner and technique factor combinations, there was strong agreement in normalized CTDI vol values across all three codes: between 0% and 12% difference for the compared scanners. Ratios of CTDI vol values for various CT scanner vendors and models to the corresponding CTDI vol values for the MIRDct reference scanner (Cannon Aquilion One Genesis) were also compared on the basis of either the 16‐cm head PMMA phantom or the 32‐cm body PMMA phantom. The mean quotient of these normalized CTDI vol ratios (head ratios to body ratios) was found to be approximately 1.06, and thus either ratio may be applied in reporting patient organ dose by MIRDct. Conclusions A database of normalized CTDI vol (mGy/100 mAs) was created for 17 models of CT scanners from four manufacturers at varying tube potentials, collimations, x‐ray bowtie filters, and phantom sizes for use in the MIRDct software.

Abstract Early-onset Alzheimer’s disease (EOAD) and Late-onset AD (LOAD) differ in clinical presentations and rates of progression. We aimed to compare baseline and longitudinal tau PET burden, and their relationship with clinical variables in amyloid-PET positive, cognitively impaired participants from the Longitudinal Early-Onset Alzheimer’s Disease Study (EOAD; n=390) and Alzheimer’s Disease Neuroimaging Initiative (LOAD; n=211). Patients with EOAD showed higher baseline tau PET retention, broader neuroanatomical involvement and faster accumulation rates over time compared to LOAD, after adjusting for amyloid load and clinical stage. Tau PET showed stronger correlations with baseline amyloid burden and clinical measures of global cognition and function in EOAD than LOAD. We conclude that earlier age of onset in AD is linked to a more aggressive tauopathy, which in turn is a primary driver of clinical decline. These findings suggest that optimal therapeutic targets and strategies may differ between EOAD and LOAD. One Sentence Summary Younger patients with Alzheimer’s disease show more aggressive tau spread, suggesting age of onset defines distinct disease pathways with key clinical implications.