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AbstractBackgroundQuantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating the local tissue magnetic susceptibility of every voxel. Dysregulation of neuronal iron has been correlated with typical Alzheimer’s disease (tAD), but little is known about iron distribution in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA).MethodEleven PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five‐echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions‐of‐interest across the brain using the Mayo Clinic Adult Lifespan Template. Hierarchical models were fit per‐region and per‐hemisphere to compare PCA and LPA to each other, to 20 healthy controls, and to 20 patients with tAD recruited by the Alzheimer’s Disease Research Center.ResultStrong evidence (posterior probability>0.99) was observed for greater susceptibility in the left middle occipital gyrus and amygdala in both LPA and PCA, and in the right precuneus and inferior temporal gyrus in PCA compared to controls. Moderate evidence for greater susceptibility (posterior probability>0.90) was also observed in the left insula, inferior occipital gyrus, entorhinal cortex, and right inferior parietal gyrus and amygdala in both LPA and PCA, along with right angular gyrus and middle occipital gyrus in PCA and right insula and caudate in LPA, when compared to controls. Comparing between phenotypes, LPA showed moderate evidence for greater susceptibility in the caudate, hippocampus, substantia nigra, left supramarginal gyrus and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right precuneus compared to LPA. Both LPA and PCA showed moderate‐strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions.ConclusionUnique iron profiles were identified in LPA and PCA within cortical and subcortical structures. These changes are in line with disease‐related neurodegenerative changes in the clinical phenotypes, suggesting that QSM could be an informative marker to study iron deposition in these patients.

ImportanceLate-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm.ObjectiveTo report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months’ corrected age.Design, Setting, and ParticipantsThis cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks’ gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers.ExposuresCulture-confirmed LOM.Main Outcomes and MeasuresIncidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021).ResultsAmong 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P < .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P < .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P < .001) and among those with culture-confirmed LOS (23%-79%, P < .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection.Conclusions and RelevanceIn this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.

AbstractIntroductionAlzheimer's disease (AD) patients ≥70 years show smaller medial temporal volumes despite less 18F‐flortaucipir‐positron emission tomography (PET) uptake than younger counterparts. We investigated whether TAR DNA‐binding protein 43 (TDP‐43) was contributing to this volume‐uptake mismatch.MethodsSeventy‐seven participants with flortaucipir‐PET and volumetric magnetic resonance imaging underwent postmortem AD and TDP‐43 pathology assessments. Bivariate‐response linear regression estimated the effect of age and TDP‐43 pathology on volume and/or flortaucipir standardized uptake volume ratios of the hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices.ResultsOlder participants had lower hippocampal volumes and overall flortaucipir uptake. TDP‐43‐immunoreactivity correlated with reduced medial temporal volumes but was unrelated to flortaucipir uptake. TDP‐43 effect size was consistent across the age spectrum. However, at older ages, the cohort mean volumes moved toward those of TDP‐43‐positives, reflecting the increasing TDP‐43 pathology frequency with age.DiscussionTDP‐43 pathology is a relevant contributor driving the volume‐uptake mismatch in older AD participants.Highlights TDP‐43 pathology affects medial temporal volume loss but not tau radiotracer uptake. Greater TDP‐43 pathology effect is seen in old age due to its increasing frequency. TDP‐43 pathology is a relevant driver of the volume‐uptake mismatch in old AD patients.

Abstract BACKGROUND Interpretation of serial magnetic resonance imaging (MRI) for glioblastoma following radiation therapy (RT) is complicated by difficulty differentiating tumor from treatment-related changes, even using updated RANO criteria. The incorporation of novel imaging such as 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) PET/CT to post-treatment serial imaging may improve prognostication and better facilitate future treatment decisions. METHODS The secondary analysis of a recent phase II prospective clinical trial of 18F-DOPA PET/CT-directed dose-escalated RT included patients with IDH-wildtype, MGMT-unmethylated glioblastoma who underwent post-treatment serial 18F-DOPA PET/CT surveillance. Quantitative features were extracted from pre-RT and post-RT serial PET/CT images, and robust prognostic features were selected using an in-house workflow. Both an automated machine learning (ML) algorithm and an interpretable ML algorithm were utilized to correlate surveillance PET image features with subsequent survival of greater than 12 months versus less than 12 months from the surveillance timepoint. Changes from pre-RT to post-RT PET/CT (delta model) were also assessed for association with post-RT survival and validated with a separate cohort. RESULTS Thirty-five patients with IDH-wildtype, MGMT-unmethylated glioblastoma who had at least one available (range: 1-14) post-treatment 18F-DOPA PET/CT were included. Twenty-four were used for model training, while 11 were used for validation. Ultimately, a five-feature post-RT model utilizing two shape, two texture, and one first-order radiomic feature was selected. For the delta model, five texture, two shape, and one first order radiomic feature were selected. The models show 90% accuracy in predicting survival < 12 months post-surveillance on the training set, and 68%-73% accuracy (AUC 0.64-0.73) for the validation cohort. Delta features were significantly associated with overall survival (p < 0.05). CONCLUSIONS Post-RT serial 18F-DOPA PET/CT imaging can help distinguish true tumor progression in patients with glioblastoma using a radiomics model. Tumor response evaluated for changes from pre-RT to post-RT 18F-DOPA PET/CT also predicted subsequent overall survival.

AbstractGlycogen synthase kinase‐3 α/β is involved in dysregulation of neuronal tau protein in Alzheimer's disease (AD). There is an unmet clinical need for a blood‐brain barrier (BBB) permeable positron emission tomography (PET) probe for imaging of GSK‐3α/β in the brain to understand the pathogenesis of AD. Herein, we synthesized two PET probes, [18F]F‐CNBI and [18F]F‐CNPIFE, and evaluated their BBB permeability and affinity towards GSK‐3α/β. [19F]F‐CNPIFE showed higher in‐vitro binding towards GSK‐3α/β (IC50=19.4±2.5 nM; n=3, for GSK‐3α, IC50=19.4±3.8 nM; n=3, for GSK‐3β) compared to [19F]F‐CNBI (IC50=107.6±26.0 nM; n=4, for GSK‐3α, IC50=105.3±18.2 nM; n=3, for GSK‐3β). [18F]F‐CNPIFE showed 9.5‐fold higher brain uptake than [18F]F‐CNBI, in normal FVB/NJ mice, which was increased by additional 1.5‐fold on co‐administration of [19F]F‐CNPIFE with respect to [18F]F‐CNBI. Overall, [18F]F‐CNPIFE is a promising PET probe for GSK‐3α/β imaging and warrants further evaluation in an AD mouse model.

AbstractBackgroundGlobular glial tauopathy (GGT) has been associated with frontotemporal dementia syndromes; little is known about the clinical and imaging characteristics of GGT and how they differ from other non‐globular glial 4‐repeat tauopathies (N4GT) such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD).MethodsFor this case–control study the Mayo Clinic brain banks were queried for all cases with an autopsy‐confirmed diagnosis of GGT between 1 January 2011 and 31 October 2021. Fifty patients with N4GT (30 PSP, 20 CBD) were prospectively recruited and followed by the Neurodegenerative Research Group at Mayo Clinic, Minnesota. Magnetic resonance imaging was used to characterize patterns of gray/white matter atrophy, MR‐parkinsonism index, midbrain volume, and white matter hyperintensities.18F‐Fluorodeoxyglucose‐, 11C Pittsburg compound‐, and 18F‐flortaucipir‐positron emission tomography scans were reviewed.ResultsTwelve patients with GGT were identified: 83% were women compared to 42% in NG4T (p = 0.02) with median age at death 76.5 years (range: 55–87). The most frequent clinical features were eye movement abnormalities, parkinsonism, behavioral changes followed by pyramidal tract signs and motor speech abnormalities. Lower motor neuron involvement was present in 17% and distinguished GGT from NG4T (p = 0.035). Primary progressive apraxia of speech was the most frequent initial diagnosis (25%); 50% had a Parkinson‐plus syndrome before death. Most GGT patients had asymmetric frontotemporal atrophy with matching hypometabolism. GGT patients had more gray matter atrophy in temporal lobes, normal MR‐parkinsonism index, and larger midbrain volumes.ConclusionsFemale sex, lower motor neuron involvement in the context of a frontotemporal dementia syndrome, and asymmetric brain atrophy with preserved midbrain might be suggestive of underlying GGT.

Abstract Background. Dementia with Lewy bodies (DLB) is a neurodegenerative disorder with a wide heterogeneity of symptoms, which suggests the existence of different subtypes. Objectives. We used data-driven analysis of MRI data to investigate DLB subtypes. Methods. We included 165 probable DLB from the Mayo Clinic and 3 centers from the European DLB consortium and performed a hierarchical cluster analysis to identify subtypes based on gray matter (GM) volumes. To characterize the subtypes, we used demographic and clinical data, as well as β-amyloid and cerebrovascular biomarkers at baseline, and cognitive decline over three years. Results. We identified 3 subtypes: an older subtype with reduced cortical GM volumes, worse cognition, and faster cognitive decline (n=49, 30%); a subtype with low GM volumes in fronto-occipital regions (n=76, 46%); and a subtype of younger patients with the highest cortical GM volumes, proportionally lower GM volumes in basal ganglia and the highest frequency of cognitive fluctuations (n=40, 24%). Conclusions. This study shows the existence of MRI subtypes in DLB, which may have implications for clinical workout, research, and therapeutic decisions.

AbstractBackgroundProstatic specific antigen (PSA) has well‐recognized limitations as a marker for treatment response and disease progression. Post hoc analysis of the PREVAIL trial reported 24.5% of chemotherapy naïve metastatic castration‐resistant prostate cancer (mCRPC) patients on enzalutamide had radiographic progression on conventional imaging with nonrising PSA. In this study, we sought to study the discordance of imaging with PSA kinetics in mCRPC patients on second generation anti‐androgens (SGA) post‐chemotherapy using combined conventional imaging, and new generation imaging in the form of C‐11 choline positron emission tomography/computed tomography (C[11] choline PET/CT) scan.MethodsWe retrospectively reviewed the medical records of 123 patients with mCRPC treated with SGA (Abiraterone or Enzalutamide) after docetaxel between 2016 and 2019. Patients underwent PSA testing, and C[11] choline PET/CT scan at baseline level before starting treatment with SGA, then every 3–6 months as part of their follow up evaluation. Loss of response to SGA was defined by increase in corrected maximum standardized uptake value (SUVmax) of pretreatment lesions on C‐11 Choline PET/CT, and/or development of new lesions. Suspicious new lesions were confirmed by biopsy and/or conventional imaging.ResultsWe identified 123 mCRPC patients who received SGA (Abiraterone, n = 106; Enzalutamide, n = 17) after docetaxel. Median duration of therapy was 13.9 months (interquartile range: 8.75–21.14). Approximately 43% (n = 53) of subjects in this study exhibited an increase in choline avidity while on SGA. Of this group, 60.4% of patients experienced a parallel rise in PSA (Group‐A), whereas 39.6% displayed a paradoxical response (PR) (Group‐B), defined as increased choline avidity combined with stable or down‐trending PSA. Median PSA at time of increase in choline avidity was 3.1 ng/ml for Group‐A, and 1.3 ng/ml for Group‐B (p = 0.0176). Median SUVmax was similar in both groups (4.9 for Group‐A, 4.6 for Group‐B; p = 0.6072). The median time for increase in choline avidity was 9.5 versus 3.9 months for Group‐A versus Group‐B, respectively (Log‐Rank = 0.0063).ConclusionNearly 40% of mCRPC patients placed on SGA post docetaxel chemotherapy will exhibit paradoxical responses to therapy, therefore, warranting close follow up with imaging. C‐11 choline PET/CT imaging is a useful tool that can help in early predication of disease progression or treatment failure.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co‐primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/ 2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.