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Daphne L Mourits,1 Dyonne T Hartong,1 Andries E Budding,2 Machteld I Bosscha,1 H Stevie Tan,1 Annette C Moll1 1Department of Ophthalmology, VU University Medical Center, 2Department of Microbiology, Academic Medical Center, Amsterdam, the Netherlands Purpose: To investigate the causes and treatment options for socket discharge and infection in patients enucleated for retinoblastoma (Rb). Methods: A questionnaire was filled out by (parents of) ocular prosthesis-wearing patients with a history of enucleation as treatment for Rb. We collected data on patients’ characteristics, cleaning habits of the prosthesis, frequency of socket irritation, discharge, and infection, and use of antibiotics. With ordinal logistic regression analysis, factors related to the outcome parameters (frequency of irritation, mucoid and purulent discharge) were identified. In a subset of young asymptomatic and symptomatic patients, a swab culture of the socket was performed to determine the presence of microorganisms. Results: A total of 186 patients or their parents (mean age of the patients: 17.3 years, ranging from 0.8 to 88.3 years) filled out the questionnaire. Irritation, mucoid discharge, and purulent discharge were frequently (once a month or more often) experienced in 75 (39.5%), 127 (66.8%), and 15 (13.2%) sockets, respectively. Younger age was associated with a higher frequency of mucoid and purulent discharge. Radiation therapy, chemotherapy, gender, age at surgery, cleaning frequency, and nocturnal wear were not associated with the outcome parameters. In a subgroup of 26 patients, the sockets were swabbed and cultured. All symptomatic patients had a positive bacterial culture versus 15% (2/13) of the asymptomatic patients (P

Cognitive functioning depends on intact brain networks that can be assessed with functional magnetic resonance imaging (fMRI) techniques. We hypothesized that cognitive decrements in type 1 diabetes mellitus (T1DM) are associated with alterations in resting-state neural connectivity and that these changes vary according to the degree of microangiopathy. T1DM patients with (MA(+): n = 49) and without (MA(-): n = 52) microangiopathy were compared with 48 healthy control subjects. All completed a neuropsychological assessment and resting-state fMRI. Networks were identified using multisubject independent component analysis; specific group differences within each network were analyzed using the dual-regression method, corrected for confounding factors and multiple comparisons. Relative to control subjects, MA(-) patients showed increased connectivity in networks involved in motor and visual processes, whereas MA(+) patients showed decreased connectivity in networks involving attention, working memory, auditory and language processing, and motor and visual processes. Better information-processing speed and general cognitive ability were related to increased degree of connectivity. T1DM is associated with a functional reorganization of neural networks that varies, dependent on the presence or absence of microangiopathy. [ABSTRACT FROM AUTHOR]

Dommering CJ, Garvelink MM, Moll AC, van Dijk J, Imhof SM, Meijers-Heijboer H, Henneman L. Reproductive behavior of individuals with increased risk of having a child with retinoblastoma. To investigate reproductive behavior of individuals at increased risk of having a child with retinoblastoma (Rb), we conducted a cross-sectional questionnaire survey among 118 counselees visiting the Clinical Genetics Department of the National Rb Center in the Netherlands. The recurrence risk for counselees ranged from <1% to 50%. The response rate was 69%. Of 43 respondents considering having children after becoming aware of their increased risk, Rb influenced reproductive behavior for 25 (58%), of whom 14 had a recurrence risk <3%. Twenty of these 25 decided against having more children and 5 used prenatal diagnosis. Eighteen of the 43 respondents did not use any of the alternative reproductive options and had children (or more children), although half indicated having had doubts about their decisions. Multiple logistic regression showed that only perceived risk (p = 0.003) was significantly associated with Rb influencing reproductive behavior. Of 17 respondents planning children (or more children), 11 (65%) considered using one of the alternative reproductive options. We conclude that reproductive behavior is greatly influenced by Rb and that perceived risk, not objective risk, is the most important factor of influence. It is important to offer individuals at increased risk continued access to genetic counseling, even when this risk is small. [ABSTRACT FROM AUTHOR]

Objective: Hyperglycemia-associated microvascular disease may underlie changes in cerebral functioning and cognitive performance in patients with type 1 diabetes. Functional connectivity, an indicator of functional interactions and information exchange between brain regions, provides a measure of cerebral functioning. This study addresses functional connectivity and cognition in type 1 diabetic patients with and without proliferative retinopathy, relative to healthy control subjects, using magnetoencephalography.Research Design and Methods: Fluctuations in magnetic field at scalp for Delta, theta, lower and upper alpha, beta, and lower and upper gamma frequency bands were measured using magnetoencephalography. Synchronization likelihood, a measure of functional connectivity, was computed. Using neuropsychological tests, cognitive functioning was assessed and its associations with functional connectivity were determined.Results: Compared with control subjects, type 1 diabetic patients performed poorer on general cognitive ability, information processing speed, and motor speed, irrespective of their microvascular complication status. Functional connectivity, however, was lowest for type 1 diabetic patients with retinopathy, compared with type 1 diabetic patients without microvascular complications and control subjects, whereas type 1 diabetic patients without microvascular complications showed an increase relative to control subjects. Positive associations were found between functional connectivity and executive functioning, memory, information processing speed, motor speed, and attention.Conclusions: Compared with healthy control subjects, functional connectivity and cognition differed in type 1 diabetic patients irrespective of microvascular complication status, indicating that chronic hyperglycemia, among other factors, may negatively affect brain functioning even before microvascular damage becomes manifest. The association found between synchronization likelihood and cognition suggests functional connectivity plays a significant role in cognitive functioning. [ABSTRACT FROM AUTHOR]

Objective: To study potential risk factors for retinopathy in diabetic and nondiabetic individuals.Research Design and Methods: The Hoorn Study is a population-based study including 2,484 50- to 74-year-old Caucasians. A subsample of 626 individuals stratified by age, sex, and glucose tolerance underwent extensive measurements during 1989-1992, including ophthalmologic examination and two-field 45-degree fundus photography. The prevalence of (diabetic) retinopathy was assessed among individuals with normal glucose metabolism (NGM) and impaired glucose metabolism (IGM) and individuals with newly diagnosed diabetes mellitus (NDM) and known diabetes mellitus (KDM) (new World Health Organization 1999 criteria).Results: The prevalence of retinopathy was 9% in NGM, 11% in IGM, 13% in NDM, and 34% in KDM. Retinopathy worse than minimal nonproliferative diabetic retinopathy was present in 8% in KDM and 0-2% in other glucose categories. The prevalence of retinopathy was positively associated with elevated blood pressure, BMI, cholesterol, and triglyceride serum levels in all glucose categories. The age-, sex-, and glucose metabolism category-adjusted odds ratios were 1.5 (95% CI 1.2-1.9), 1.3 (1.0-1.7), and 1.3 (1.0-1.6) per SD increase of systolic blood pressure, BMI, and total cholesterol concentration, respectively, and 1.2 (1.0-1.5) per 50% increase of triglyceride level. Elevated blood pressure and plasma total and LDL cholesterol levels showed associations with retinal hard exudates.Conclusions: Retinopathy is a multifactorial microvascular complication, which, apart from hyperglycemia, is associated with blood pressure, lipid concentrations, and BMI. [ABSTRACT FROM AUTHOR]

Retinoblastoma patients have a strongly increased risk of second malignancies, and survivors with a third or subsequent malignancy are increasingly observed. However, it has not been examined whether survivors who developed a second malignancy have a greater risk of a subsequent malignancy. On the basis of the Dutch retinoblastoma registry, the risk of a third malignancy was compared with cancer risk in the Dutch population. Cox model analysis with a time-dependent covariate was used to compare the subsequent malignancy risk and survival among patients with and without a second malignancy. Risk of a third malignancy was increased 8-fold compared with the general population. The hazard ratio (HR) of a third malignancy after a second malignancy was more than 7-fold increased compared to the risk of a second malignancy after retinoblastoma. Radiotherapy increased the risk 3-fold. A third malignancy was associated with worse survival compared with survival of patients only diagnosed with a second malignancy (HR=5.0). Survivors of retinoblastoma who already developed a second primary malignancy have an even higher risk of subsequent primary malignancies than retinoblastoma survivors without a second malignancy. Treating physicians and patients should be aware of this higher risk. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the suggested association between IVF, retinoblastoma, and tumor methylation characteristics. Design: Laboratory analysis. Setting: National Retinoblastoma Center in the Netherlands. Patient(s): Retinoblastoma tumors from seven children conceived by IVF or intracytoplasmic sperm injection (ICSI). Intervention(s) and Main Outcome Measure(s): DNA from frozen retinoblastoma tumors was tested for mutations in the RB1 gene and for methylation status of the RB1 promoter. Result(s): For all tumors two causative RB1 mutations were found. None of the tumors showed hypermethylation of the RB1 promoter. Conclusion(s): Examination of retinoblastoma tumors of seven children conceived by IVF or ICSI did not show hypermethylation of the RB1 promoter. This demonstrates that an association between IVF or ICSI and retinoblastoma through this epigenetic mechanism is unlikely. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate axial length (AL), orbital width (OW) and height (OH) development in congenital microphthalmia and anophthalmia (MICA) using serial ultrasonography measurements., Methods: A longitudinal prospective cohort (n = 74) of unilaterally and bilaterally affected MICA patients was followed from 2013 to 2022 at the university hospital in Amsterdam, the Netherlands. Clinical entity, age, severity category based on axial length, conformer treatment and intra-orbital cysts were registered. The main outcome measures were the absolute and relative growth of AL, OW and OH. Surgical and intra-orbital cyst cases were described separately., Results: Absolute microphthalmic eye size increased in 27/49 (55%) unilateral MICA eyes, but growth arrest/decrease in the remaining could shift the case to a more severe category over time. A final affected/unaffected orbital symmetry ≥80% was seen in the large majority of unilateral cases (45/46 for OW, 43/46 for OH). Cases with AL < 10.5 mm had orbital symmetry <80% more often. Most orbital symmetry changes were seen in moderate and severe unilateral cases treated with 3D-printed conformer therapy starting at age <1 year, with 6/10 (60%) symmetry increase, 30% unchanged symmetry and 10% symmetry decrease. All cases older than 6.5 years (n = 6) did not show any change anymore, regardless of treatment. For bilateral and unilateral mild cases, orbital dimensions kept the same proportions during follow-up, with or without conformer treatment., Conclusions: Using severity categories in MICA based on relative AL may aid the decision to start conformer treatment, as most orbital symmetry changes were seen in moderate and severe unilateral cases receiving 3D-printed conformer therapy that started under age 1., (© 2024 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: Choroidal vascular hyperpermeability (CVH) on indocyanine green angiography (ICGA) is a hallmark feature of central serous chorioretinopathy (CSC). We identified three distinct CVH phenotypes in CSC: uni-focal indistinct signs of choroidal hyperpermeability (uni-FISH) with one focal area of CVH, multiple areas of focal CVH (multi-FISH), and diffuse hyperpermeability covering most of the posterior pole (DISH). This report investigates the distribution of these phenotypes and their association with signs of disease chronicity., Methods: The CERTAIN study is a monocentric, retrospective study on consecutive CSC patients referred to a large tertiary referral centre that underwent ultra-widefield (UWF) and 55° ICGA. Two independent graders assessed CVH patterns based on mid- to late-phase UWF and 55° ICGA with a third grader acting as referee., Results: Of the 167 eyes of 91 patients included in this study, 43 (26%) showed uni-FISH, 87 (52%) multi-FISH, and 34 (20%) showed DISH based on UWF ICGA. Median age (40 vs. 45 vs. 57; p < 0.001) and logMAR visual acuity (0 vs. 0 vs. 0.1, p < 0.001) differed significantly in-between groups, as did the occurrence of cystoid retinal degeneration (PCRD; 0% vs. 1% vs. 18%, p < 0.001) or diffuse atrophic RPE alterations (DARA; 0% vs. 17% vs. 29%, p < 0.001). The same was true when grading was based on 55° ICGA., Conclusions: The CVH patterns of uni-FISH, multi-FISH, and DISH are typical of CSC. These patterns correlate with established signs of CSC chronicity. Their predictive role in treatment response and prognosis remains to be evaluated., (© 2024 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Introduction/aims: Corneal confocal microscopy (CCM) detects small nerve fiber loss and correlates with skin biopsy findings in diabetic neuropathy. In chronic idiopathic axonal polyneuropathy (CIAP) this correlation is unknown. Therefore, we compared CCM and skin biopsy in patients with CIAP to healthy controls, patients with painful diabetic neuropathy (PDN) and diabetics without overt neuropathy (DM)., Methods: Participants with CIAP and suspected small fiber neuropathy (n = 15), PDN (n = 16), DM (n = 15), and healthy controls (n = 16) underwent skin biopsy and CCM testing. Inter-center intraclass correlation coefficients (ICC) were calculated for CCM parameters., Results: Compared with healthy controls, patients with CIAP and PDN had significantly fewer nerve fibers in the skin (IENFD: 5.7 ± 2.3, 3.0 ± 1.8, 3.9 ± 1.5 fibers/mm, all p < .05). Corneal nerve parameters in CIAP (fiber density 23.8 ± 4.9 no./mm 2 , branch density 16.0 ± 8.8 no./mm 2 , fiber length 13.1 ± 2.6 mm/mm 2 ) were not different from healthy controls (24.0 ± 6.8 no./mm 2 , 22.1 ± 9.7 no./mm 2 , 13.5 ± 3.5 mm/mm 2 , all p > .05). In patients with PDN, corneal nerve fiber density (17.8 ± 5.7 no./mm 2 ) and fiber length (10.5 ± 2.7 mm/mm 2 ) were reduced compared with healthy controls (p < .05). CCM results did not correlate with IENFD in CIAP patients. Inter-center ICC was 0.77 for fiber density and 0.87 for fiber length., Discussion: In contrast to patients with PDN, corneal nerve parameters were not decreased in patients with CIAP and small nerve fiber damage. Therefore, CCM is not a good biomarker for small nerve fiber loss in CIAP patients., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Purpose: To evaluate the effectiveness of baseline screening and follow-up with magnetic resonance imaging (MRI) for detecting trilateral retinoblastoma (TRb) and assessing the risk of TRb development., Design: Prospective multicenter cohort study., Methods: A total of 607 retinoblastoma patients from 2012 through 2022 were included and followed up until September 1, 2023. At each center, a neuroradiologist categorized pineal glands on baseline and follow-up scans into 4 groups: (A) normal, (B) cystic gland, (C) suspicious gland, or (D) TRb. Different follow-up schedules were assigned to each category. Categories B and C were followed up with MRI after approximately 3 months and repeated 3 months later if suspicion remained. On each MRI, they measured the height and width, evaluated the aspect (solid, partly cystic, and completely cystic) of the pineal gland, and evaluated radiologic features suspicious of pineal TRb. The effectiveness of the current TRb screening method was assessed by evaluating its sensitivity and specificity to detect TRb. Determining the TRb incidence was a secondary outcome measure., Results: Heritable retinoblastoma patients had a risk of 3.78% to develop TRb. One of 4 pineal TRbs was detected during a follow-up scan and 4 of 5 nonpineal TRbs were detected on the baseline MRI. Screening for pineal TRb had a sensitivity of 25% and specificity of 100%; for nonpineal TRb, the sensitivity was 80%. It required 494 follow-up scans to detect 1 pineal TRb. However, when restricting the follow-up to solely suspicious glands, only 22 scans were required to detect 1 pineal TRb., Conclusion: During extended follow-up after baseline MRI, only 1 pineal trilateral retinoblastoma was detected in our study. Follow-up after 3 months should be restricted to patients with a suspicious pineal gland defined as irregular thickening of the cyst wall (>2 mm), fine nodular aspect of the cyst wall, or when a solid or cystic gland exceeds the upper 99% prediction interval for size; patients with an unsuspicious cystic gland should not be followed up. Baseline MRI screening was able to detect most nonpineal trilateral retinoblastomas., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To assess the diagnostic accuracy of nerve thickening on MRI to predict early-stage postlaminar optic nerve invasion (PLONI) in retinoblastoma. Furthermore, this study aimed to incorporate measurements into a multiparametric model for radiological determination of PLONI., Methods: In this retrospective multicenter case-control study, high-spatial-resolution 3D T2-weighted MR images were used to measure the distal optic nerve. Histopathology was the reference standard for PLONI. Two neuroradiologists independently measured the optic nerve width, height, and surface at 0, 3, and 5 mm from the most distal part of the optic nerve. Subsequently, PLONI was scored on contrast-enhanced T1-weighted and 3D T2-weighted images, blinded for clinical data. Optic nerve measurements with the highest diagnostic accuracy for PLONI were incorporated into a prediction model for radiological determination of PLONI., Results: One hundred twenty-four retinoblastoma patients (median age, 22 months [range, 0-113], 58 female) were included, resulting in 25 retinoblastoma eyes with histopathologically proven PLONI and 206 without PLONI. ROC analysis of axial optic nerve width measured at 0 mm yielded the best area under the curve of 0.88 (95% confidence interval: 0.79, 0.96; p < 0.001). The optimal width cutoff was ≥ 2.215 mm, with a sensitivity of 84% (95% CI: 64, 95%) and specificity of 83% (95% CI: 75, 89%) for detecting PLONI. Combining width measurements with the suspicion of PLONI on MRI sequences resulted in a prediction model with an improved sensitivity and specificity of respectively up to 88% and 92%., Conclusion: Postlaminar optic nerve thickening can predict early-stage postlaminar optic nerve invasion in retinoblastoma., Clinical Relevance Statement: This study provides an additional tool for clinicians to help determine postlaminar optic nerve invasion, which is a risk factor for developing metastatic disease in retinoblastoma patients., Key Points: • The diagnostic accuracy of contrast-enhanced MRI for detecting postlaminar optic nerve invasion is limited in retinoblastoma patients. • Optic nerve thickening can predict postlaminar optic nerve invasion. • A prediction model combining MRI features has a high sensitivity and specificity for detecting postlaminar optic nerve invasion., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Purpose: Congenital microphthalmia and anophthalmia are rare development disorders with underdevelopment of the orbital region, resulting in asymmetry of the face. No clear guidelines exist to determine when these deviations are acceptable., Methods: The face of a healthy 6-year-old child was three-dimensionally scanned. On this scan, we modeled various incremental degrees of facial asymmetries using three-dimensional modeling software. We modeled for smaller palpebral fissures, sunken eyes, and downward displacement of the eye. We also tested whether adjusting the vertical palpebral fissure height in relation to the horizontal palpebral fissure width affected perception. A total of 22 videos were created in which the model turned the head horizontally and vertically. We created a questionnaire asking raters how acceptable the face is, on a linear scale from 0 to 10., Results: Results showed a correlation between the degree of asymmetry and the acceptability score of the raters. Enophthalmos of ≥6 mm, palpebral fissure width ≤79% compared with the other eye, and 2 mm or more downward displacement of the eye resulted in a significant different acceptability score. The desire for correction was strongly increased when these thresholds were exceeded. Adjusting the vertical palpebral fissure height to the horizontal palpebral fissure width resulted in a worse acceptability score., Conclusion: A unilateral sunken eye (enophthalmos) of 6 mm or more, asymmetric horizontal palpebral fissure length of ≤79%, and a lower position of one eye of more than 2 mm resulted in unacceptable judgment. These data can be used to evaluate treatment outcome in children treated for congenital microphthalmia and anophthalmia., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of he American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

This retrospective multicenter study examines therapy-induced orbital and ocular MRI findings in retinoblastoma patients following selective intra-arterial chemotherapy (SIAC) and quantifies the impact of SIAC on ocular and optic nerve growth. Patients were selected based on medical chart review, with inclusion criteria requiring the availability of posttreatment MR imaging encompassing T2-weighted and T1-weighted images (pre- and post-intravenous gadolinium administration). Qualitative features and quantitative measurements were independently scored by experienced radiologists, with deep learning segmentation aiding total eye volume assessment. Eyes were categorized into three groups: eyes receiving SIAC (Rb-SIAC), eyes treated with other eye-saving methods (Rb-control), and healthy eyes. The most prevalent adverse effects post-SIAC were inflammatory and vascular features, with therapy-induced contrast enhancement observed in the intraorbital optic nerve segment in 6% of patients. Quantitative analysis revealed significant growth arrest in Rb-SIAC eyes, particularly when treatment commenced ≤ 12 months of age. Optic nerve atrophy was a significant complication in Rb-SIAC eyes. In conclusion, this study highlights the vascular and inflammatory adverse effects observed post-SIAC in retinoblastoma patients and demonstrates a negative impact on eye and optic nerve growth, particularly in children treated ≤ 12 months of age, providing crucial insights for clinical management and future research.

Purpose: Choroidal venous overload was recently suggested to be a pathogenetic factor in central serous chorioretinopathy (CSC). Manifestations of venous overload on ultrawidefield indocyanine green angiography (UWF ICGA) include asymmetric arterial choroidal filling (AACF), enlarged choroidal vessels ("pachyvessels"), and asymmetric venous drainage (AVD) leading to choroidal intervortex venous anastomoses (CVAs) accompanied by choroidal vascular hyperpermeability (CVH). The purpose of the current study is to assess the presence of these signs of venous overload in a large cohort of CSC patients., Design: Monocentric retrospective cohort study., Participants: Consecutive CSC patients seen at a large tertiary referral center., Methods: For the CERTAIN study, patients underwent a standardized imaging protocol including UWF ICGA. Features of choroidal venous overload were graded for each eye individually by 2 independent graders and, in case of disagreement, by a third grader., Main Outcome Measures: Presence of AAFC, pachyvessels, AVD, CVA, and CVH., Results: In total, 178 eyes of 91 patients were included in this study. Mean patient age was 47.6 (± 12.0) years and 75 patients (82%) were male. The 116 eyes (65%) that showed subretinal fluid were considered affected (bilateral disease in 29 patients). In affected eyes, AACF was present in 62 eyes (85% of gradable eyes), pachyvessels in 102 eyes (88%), AVD in 81 eyes (74%), CVA in 107 eyes (94%), and CVH in 100% of affected eyes. For fellow eyes, prevalence of pachyvessels (94%), AVD (67%), and CVA (90%) was similar to affected eyes, whereas CVH was present in 85% of fellow eyes. Intergrader agreement was excellent for CVH (94%), and 74%-82% for all other criteria. Patients with pachyvessels and AVD in 1 eye were more likely to also show the same characteristic in the fellow eye (odds ratios 22.2 and 9.9, P < 0.01)., Conclusions: Signs of venous overload are seen in the vast majority of CSC patients, both in affected and unaffected eyes. Although pachyvessels, AVD, and CVA are observed frequently, CVH was observed in all affected eyes, showed excellent intergrader reliability, and is diagnostic for CSC. This supports the concept of choroidal venous overload as a major factor in CSC pathogenesis., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objectives: To validate associations between MRI features and gene expression profiles in retinoblastoma, thereby evaluating the repeatability of radiogenomics in retinoblastoma., Methods: In this retrospective multicenter cohort study, retinoblastoma patients with gene expression data and MRI were included. MRI features (scored blinded for clinical data) and matched genome-wide gene expression data were used to perform radiogenomic analysis. Expression data from each center were first separately processed and analyzed. The end product normalized expression values from different sites were subsequently merged by their Z-score to permit cross-sites validation analysis. The MRI features were non-parametrically correlated with expression of photoreceptorness (radiogenomic analysis), a gene expression signature informing on disease progression. Outcomes were compared to outcomes in a previous described cohort., Results: Thirty-six retinoblastoma patients were included, 15 were female (42%), and mean age was 24 (SD 18) months. Similar to the prior evaluation, this validation study showed that low photoreceptorness gene expression was associated with advanced stage imaging features. Validated imaging features associated with low photoreceptorness were multifocality, a tumor encompassing the entire retina or entire globe, and a diffuse growth pattern (all p < 0.05). There were a number of radiogenomic associations that were also not validated., Conclusions: A part of the radiogenomic associations could not be validated, underlining the importance of validation studies. Nevertheless, cross-center validation of imaging features associated with photoreceptorness gene expression highlighted the capability radiogenomics to non-invasively inform on molecular subtypes in retinoblastoma., Clinical Relevance Statement: Radiogenomics may serve as a surrogate for molecular subtyping based on histopathology material in an era of eye-sparing retinoblastoma treatment strategies., Key Points: • Since retinoblastoma is increasingly treated using eye-sparing methods, MRI features informing on molecular subtypes that do not rely on histopathology material are important. • A part of the associations between retinoblastoma MRI features and gene expression profiles (radiogenomics) were validated. • Radiogenomics could be a non-invasive technique providing information on the molecular make-up of retinoblastoma., (© 2023. The Author(s).)

Objective: Valid estimates of premorbid cognitive functioning (PMIQ) are crucial for the assessment of older adults at risk for Alzheimer's disease. We investigated the relationship between the NIH Toolbox-Cognition Battery's (NIHTB-CB) Oral Reading Recognition (ORR) subtest and Wechsler Test of Adult Reading scores (WTAR, convergent validity). We also compared ORR to NIHTB-CB Flanker scores, where null relationships were expected (discriminant validity)., Methods: The WTAR and NIHTB-CB were administered to 130 cognitively normal (CN) and 113 participants with mild cognitive impairment (MCI). Participants were community-dwelling, older Black and White adults, ages 55-88 years. Data analysis used uncorrected standard scores and Bayesian bivariate correlations. Supplemental materials include intraclass correlations., Results: ORR and WTAR scores were strongly positively associated, while ORR and Flanker scores were unrelated. This pattern held when restricting analyses to the two cognitive status groups, the two racial groups, and the four race-by-diagnosis subgroups., Conclusion: The findings demonstrate convergent and discriminant validity and support NIHTB-CB ORR scores as valid estimates of scores on a PMIQ measure in older Black and White adults with and without MCI.

Objective: Word list-learning tasks are commonly used to evaluate auditory-verbal learning and memory. However, different frequencies of word usage, subtle meaning nuances, unique word phonology, and different preexisting associations among words make translation across languages difficult. We administered lists of consonant-vowel-consonant (CVC) nonword trigrams to independent American and Italian young adult samples. We evaluated whether an auditory list-learning task using CVC nonword trigrams instead of words could be applied cross-culturally to evaluate similar learning and associative memory processes., Participants and Methods: Seventy-five native English-speaking (USA) and 104 native Italian-speaking (Italy) university students were administered 15-item lists of CVC trigrams using the Rey Auditory Verbal Learning Test paradigm with five study-test trials, an interference trial, and short- and long-term delayed recall. Bayesian t tests and mixed-design ANOVAs contrasted the primary learning indexes across the two samples and biological sex., Results: Performance was comparable between nationalities on all primary memory indices except the interference trial (List B), where the Italian group recalled approximately one item more than the American sample. For both nationalities, recall increased across the five learning trials and declined significantly on the postinterference trial, demonstrating susceptibility to retroactive interference. No effects of sex, age, vocabulary, or depressive symptoms were observed., Conclusions: Using lists of unfamiliar nonword CVC trigrams, Italian and American younger adults showed a similar performance pattern across immediate and delayed recall trials. Whereas word list-learning performance is typically affected by cultural, demographic, mood, and cognitive factors, this trigram list-learning task does not show such effects, demonstrating its utility for cross-cultural memory assessment.

Background/aims: To evaluate treatment with custom, three-dimensional (3D) printed conformers for socket expansion in congenital microphthalmia and anophthalmia (MICA)., Methods: Retrospective analysis of prospective cohort from 2016 to 2020. All children received custom-made 3D-printed conformers increasing in size. We measured height, width, thickness, surface and volume of first and consecutive conformers, as well as horizontal palpebral fissure length (HPF) at start and follow-up visits. We analysed these parameters for severely (<45%) and moderately (>45%-75%) affected children, based on affected axial length on ultrasonography., Results: We included 18 cases (9 severe, 9 moderate) with a total of 174 conformers (88 severe, 86 moderate) and a mean follow-up of 2.8 years (range 1.3-4.8). The mean relative HPF increased from 77% to 93% with 16/17 cases reaching >80%, and 12/17 cases >90% symmetry. Horizontal and vertical conformer dimensions increased up to 10 months of treatment, with a steeper slope for the severe group (10.5% vs 5.5% for height and 9.0% vs 6.1% for width gain per treatment month, for severe and moderate MICA, respectively). After 10 months of treatment conformer height and width increased only slightly. No serious complications were observed., Conclusion: 3D-design and printing of solid conformers results in highly acceptable horizontal eyelid symmetry in the treatment of congenital MICA. The mean increase in conformer height and width in the first 10 months should be about 170% for moderate and about 200% for severe MICA. The presented conformer size formulas can aid ophthalmologists and ocularists to plan conformer treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background MYCN -amplified RB1 wild-type ( MYCN A RB1 +/+ ) retinoblastoma is a rare but clinically important subtype of retinoblastoma due to its aggressive character and relative resistance to typical therapeutic approaches. Because biopsy is not indicated in retinoblastoma, specific MRI features might be valuable to identify children with this genetic subtype. Purpose To define the MRI phenotype of MYCN A RB1 +/+ retinoblastoma and evaluate the ability of qualitative MRI features to help identify this specific genetic subtype. Materials and Methods In this retrospective, multicenter, case-control study, MRI scans in children with MYCN A RB1 +/+ retinoblastoma and age-matched children with RB1 -/- subtype retinoblastoma were included (case-control ratio, 1:4; scans acquired from June 2001 to February 2021; scans collected from May 2018 to October 2021). Patients with histopathologically confirmed unilateral retinoblastoma, genetic testing ( RB1/MYCN status), and MRI scans were included. Associations between radiologist-scored imaging features and diagnosis were assessed with the Fisher exact test or Fisher-Freeman-Halton test, and Bonferroni-corrected P values were calculated. Results A total of 110 patients from 10 retinoblastoma referral centers were included: 22 children with MYCN A RB1 +/+ retinoblastoma and 88 control children with RB1 -/- retinoblastoma. Children in the MYCN A RB1 +/+ group had a median age of 7.0 months (IQR, 5.0-9.0 months) (13 boys), while children in the RB1 -/- group had a median age of 9.0 months (IQR, 4.6-13.4 months) (46 boys). MYCN A RB1 +/+ retinoblastomas were typically peripherally located (in 10 of 17 children; specificity, 97%; P < .001) and exhibited plaque or pleomorphic shape (in 20 of 22 children; specificity, 51%; P = .011) with irregular margins (in 16 of 22 children; specificity, 70%; P = .008) and extensive retina folding with vitreous enclosure (specificity, 94%; P < .001). MYCN A RB1 +/+ retinoblastomas showed peritumoral hemorrhage (in 17 of 21 children; specificity, 88%; P < .001), subretinal hemorrhage with a fluid-fluid level (in eight of 22 children; specificity, 95%; P = .005), and strong anterior chamber enhancement (in 13 of 21 children; specificity, 80%; P = .008). Conclusion MYCN A RB1 +/+ retinoblastomas show distinct MRI features that could enable early identification of these tumors. This may improve patient selection for tailored treatment in the future. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Rollins in this issue.

Purpose: Pathological conditions associated with the optic nerve (ON) can cause structural changes in the nerve. Quantifying these changes could provide further understanding of disease mechanisms. We aim to develop a framework that automatically segments the ON separately from its surrounding cerebrospinal fluid (CSF) on magnetic resonance imaging (MRI) and quantifies the diameter and cross-sectional area along the entire length of the nerve., Approach: Multicenter data were obtained from retinoblastoma referral centers, providing a heterogeneous dataset of 40 high-resolution 3D T2-weighted MRI scans with manual ground truth delineations of both ONs. A 3D U-Net was used for ON segmentation, and performance was assessed in a tenfold cross-validation ( n = 32 ) and on a separate test-set ( n = 8 ) by measuring spatial, volumetric, and distance agreement with manual ground truths. Segmentations were used to quantify diameter and cross-sectional area along the length of the ON, using centerline extraction of tubular 3D surface models. Absolute agreement between automated and manual measurements was assessed by the intraclass correlation coefficient (ICC)., Results: The segmentation network achieved high performance, with a mean Dice similarity coefficient score of 0.84, median Hausdorff distance of 0.64 mm, and ICC of 0.95 on the test-set. The quantification method obtained acceptable correspondence to manual reference measurements with mean ICC values of 0.76 for the diameter and 0.71 for the cross-sectional area. Compared with other methods, our method precisely identifies the ON from surrounding CSF and accurately estimates its diameter along the nerve's centerline., Conclusions: Our automated framework provides an objective method for ON assessment in vivo ., (© 2023 The Authors.)

Importance: To improve diagnostics of cancer predisposition syndromes (CPSs) in children with cancer, it is essential to evaluate the effect of CPS gene sequencing among all children with cancer and compare it with genetic testing based on clinical selection. However, a reliable comparison is difficult because recent reports on a phenotype-first approach in large, unselected childhood cancer cohorts are lacking., Objective: To describe a national children's cancer center's experience in diagnosing CPSs before introducing routine next-generation sequencing., Design, Setting, and Participants: This retrospective cohort study was conducted at the National Retinoblastoma Treatment Center (Amsterdam, the Netherlands) and the Princess Máxima Center for Pediatric Oncology (Utrecht, Netherlands) and included Dutch pediatric patients with a new diagnosis of neoplasm between June 1, 2018, and December 31, 2019. Follow-up was at least 18 months after neoplasm diagnosis. Data analysis was conducted from July 2021 to February 2022., Exposures: As part of routine diagnostics, pediatric oncologists and ophthalmologists checked for characteristics of CPSs and selected children for referral to clinical geneticists and genetic testing., Main Outcomes and Measures: Detected cancer predisposition syndromes., Results: A total of 824 patients (median [range] age at diagnosis 7.5 [0-18.9] years; 361 girls [44%]) were assessed, including 335 children with a hematological neoplasm (41%) and 489 (59%) with a solid tumor. In 71 of 824 children (8.6%), a CPS was identified, of which most (96%) were identified by a phenotype-driven approach. Down syndrome and neurofibromatosis type 1 were the most common CPSs diagnosed. In 42 of 71 patients (59%), a CPS was identified after these children developed a neoplasm. The specific type of neoplasm was the most frequent indicator for genetic testing, whereas family history played a minor role., Conclusions and Relevance: In this cohort study of children with a neoplasm, the prevalence of CPSs identified by a phenotype-driven approach was 8.6%. The diagnostic approach for identifying CPSs is currently shifting toward a genotype-first approach. Future studies are needed to determine the diagnostic value, as well as possible disadvantages of CPS gene sequencing among all children with cancer compared with the phenotype-driven approach.

Background: Cognitive assessment of older adults typically includes symptom reports and objective evaluations. However, there is often poor agreement between these measures. Cultural norms, stress, and anxiety may also influence cognitive self-appraisal and performance. Little research describes how other factors affect the self-report/objective test discrepancies noted in the literature., Objective: This study investigated whether the disparity between subjective cognitive concerns and objective cognitive performance is related to measures of anxiety and stress in older Black and African American adults., Methods: Telephone screenings were administered to 206 older adults (ages 64-94) during the first year of the pandemic. Demographic data, objective memory (Telephone Interview for Cognitive Status [TICS-m]), an adaptation of the subjective memory measure, the Cognitive Change Questionnaire, emphasizing executive functioning in everyday life [CCQ-e]), Generalized Anxiety Disorder-7 (GAD-7), and Perceived Stress Scale-4 (PSS4) were measured. Metacognition Discrepancy Index (MDI) was calculated from the standardized residual after regressing TICS-m on CCQ-e scores to quantify the discrepancy between cognitive self-appraisal and objective cognitive functioning., Results: Neither GAD-7 nor PSS-4 moderated the relationship between TICS-m and CCQ-e, and TICS-m scores weakly predicted subjective CCQ-e scores (F(1, 197)=4.37, p = 0.038, R2 = 0.022). The MDI correlated with stress and anxiety (rs = 0.294, 0.396, ps < 0.001)., Conclusion: Discrepancies exist between objectively measured and self-evaluated cognition. Elevations in stress and anxiety are associated with greater overestimation of cognitive difficulties relative to objective performance. Pandemic-related stressors may have worsened anxiety and diminished self-appraisal of cognitive abilities for some individuals, while others may remain reluctant to acknowledge impairments. Social and emotional factors are meaningful considerations in assessing cognitive difficulties.

Purpose: To investigate the prevalence and magnetic resonance imaging (MRI) phenotype of retinoblastoma-associated orbital cellulitis. Additionally, this study aimed to identify postlaminar optic nerve enhancement (PLONE) patterns differentiating between inflammation and tumor invasion., Design: A monocenter cohort study assessed the prevalence of orbital cellulitis features on MRI in retinoblastoma patients. A multicenter case-control study compared MRI features of the retinoblastoma-associated orbital cellulitis cases with retinoblastoma controls., Participants: A consecutive retinoblastoma patient cohort of 236 patients (311 eyes) was retrospectively investigated. Subsequently, 30 retinoblastoma cases with orbital cellulitis were compared with 30 matched retinoblastoma controls without cellulitis., Methods: In the cohort study, retinoblastoma MRI scans were scored on presence of inflammatory features. In the case-control study, MRI scans were scored on intraocular features and PLONE patterns. Postlaminar enhancement patterns were compared with histopathologic assessment of postlaminar tumor invasion. Interreader agreement was assessed, and exact tests with Bonferroni correction were adopted for statistical comparisons., Main Outcome Measures: Prevalence of retinoblastoma-associated orbital cellulitis on MRI was calculated. Frequency of intraocular MRI features was compared between cases and controls. Sensitivity and specificity of postlaminar optic nerve patterns for detection of postlaminar tumor invasion were assessed., Results: The MRI prevalence of retinoblastoma-associated orbital cellulitis was 6.8% (16/236). Retinoblastoma with orbital cellulitis showed significantly more tumor necrosis, uveal abnormalities (inflammation, hemorrhage, and necrosis), lens luxation (all P &lt; 0.001), and a larger eye size (P = 0.012). The inflammatory pattern of optic nerve enhancement (strong enhancement similar to adjacent choroid) was solely found in orbital cellulitis cases, of which none (0/16) showed tumor invasion on histopathology. Invasive pattern enhancement was found in both cases and controls, of which 50% (5/10) showed tumor invasion on histopathology. Considering these different enhancement patterns suggestive for either inflammation or tumor invasion increased specificity for detection of postlaminar tumor invasion in orbital cellulitis cases from 32% (95% confidence interval [CI], 16-52) to 89% (95% CI, 72-98)., Conclusions: Retinoblastoma cases presenting with orbital cellulitis show MRI findings of a larger eye size, extensive tumor necrosis, uveal abnormalities, and lens luxation. Magnetic resonance imaging contrast-enhancement patterns within the postlaminar optic nerve can differentiate between tumor invasion and inflammatory changes., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Hypertension impacts approximately 65% of persons over 60 years of age. Although previous studies have proposed an association between mid-life hypertension and late-life cognition, reports of associations between late-life hypertension and cognition have been mixed in the direction and magnitude of the observed associations and in the cognitive domains that may be affected. This study contrasted older adults with and without self-reported hypertension at two time points in late life (M Baseline age  = 64.3 years, SD 1  = 0.7; M Follow-up age  = 71.2 years, SD 2  = 0.9), separated by approximately seven years. Participants included 4314 1957 high school graduates from the Wisconsin Longitudinal Study who were followed longitudinally until 2011. Cognitive, demographic, and health variables from the 2003-2005 and 2011 data collection waves were used. Cognitive measures included letter and category fluency, digit ordering, similarities, and immediate and delayed recall. Bayesian independent t tests and regressions examined the association between self-reported hypertension status and cognition at baseline and follow-up. Persons with self-reported hypertension over seven years showed slightly worse letter fluency and digit ordering performance at follow-up than persons without self-reported hypertension. No baseline cognitive differences were observed between groups. Participants with self-reported hypertension showed no improvement in letter fluency or digit ordering compared to persons without self-reported hypertension. After controlling for cardiovascular risk factors, hypertension was associated only with a slight decline in letter fluency. Finally, hypertension duration was not associated with cognitive performance. Self-reported hypertension was associated with minimal to no effects on cognition in older adults. Controlling for cardiovascular risk factors eliminated virtually all associations between self-reported hypertension and cognition., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Annually an estimated amount of 17.500 patients are admitted at the hospital with a fractured hip in the Netherlands. This often fragile population experiences many unwanted side effects with the use of strong painkillers. Currently used locoregional anesthetic techniques do not fully block pain in most hip fractures. In 2018 a novel technique was published, based on the innervation of the anterior hip capsule: 'The PEricapsular Nerve Group (PENG) block'. Based on current evidence, the PENG block seems a promising pain reducing technique in acute pain in pericapsular hip fractures and surgery. Due to the possibility of chemical denervation of the hip capsule, current literature and our own data show that long-term pain reduction is possible as well, without motor loss. This can lead to an increase of quality of life, and reduction of morbidity and mortality in the most fragile patients, who are not eligible for surgery.

Purpose: Retinoblastomas are malignant eye tumors diagnosed in young children. Most retinoblastomas are genetically characterized by biallelic inactivation of the RB1 gene. However, 1.5% of tumors demonstrate high-level amplification of the proto-oncogene MYCN . Patients with MYCN -amplified RB1 -proficient retinoblastoma receive a diagnosis at an earlier age and show a clinically and histologically more malignant phenotype. This study aimed to identify genome-wide molecular features that distinguish this subtype from other retinoblastomas., Design: Cohort study., Participants: Forty-seven retinoblastoma tumors, comprising 36 RB1 -/- , 4 RB1 +/- , and 7 RB1 +/+ tumors. In total, 5 retinoblastomas displayed high-level MYCN amplification, with 3 being RB1 +/+ , 1 being RB1 +/- , and 1 being RB1 -/- ., Methods: Integrated analysis, based on gene expression, methylation, and methylation-expression correlations, was performed to identify distinct molecular components of MYCN -amplified RB1 -proficient retinoblastomas compared with other retinoblastoma subtypes. The methylation and methylation-expression correlation analysis was initially conducted within a subset of samples (n = 15) for which methylation profiles were available. The significant findings were cross-validated in the entire cohort (n = 47) and in publicly available data., Main Outcome Measures: Differentially expressed genes/pathways, differentially methylated genes, and methylation-driven differential gene expression., Results: A large number of genes (n = 3155) were identified with distinct expression patterns in MYCN -amplified RB1 -proficient retinoblastomas. The upregulated and downregulated genes were associated with translation and cell-cycle processes, respectively. Methylation analysis revealed distinct methylated patterns in MYCN -amplified RB1 -proficient tumors, many of which showing significant impact on gene expression. Data integration identified a 40-gene expression signature with hypermethylated state resulting in a significant downregulation in MYCN -amplified RB1 -proficient retinoblastomas. Cross-validation using the entire cohort and the public domain expression data verified the overall lower expression of these genes not only in retinoblastomas with a MYCN -amplified RB1 -proficient background, but also in MYCN- amplified neuroblastomas. These include the metabolism-associated TSTD1 gene and the cyclin-dependent kinase inhibitor gene CDKN2C ., Conclusions: MYCN -amplified RB1 -proficient retinoblastomas display significantly distinct molecular features compared with other retinoblastomas, including a set of 40 hypermethylation-driven downregulated genes. This gene set can give insight into the biology of MYCN -amplified retinoblastomas and may help us to understand the more aggressive clinical behavior., (© 2022 by the American Academy of Ophthalmology.)

Purpose: To determine the risk of patients with an early diagnosis of heritable retinoblastoma being diagnosed with TRb (or pineoblastoma) asynchronously in a later stage and its effect on screening., Methods: We updated the search (PubMed and Embase) for published literature as performed by our research group in 2014 and 2019. Trilateral retinoblastoma (TRb) patients were eligible for inclusion if identifiable as unique and the age at which TRb was diagnosed was available. The search yielded 97 new studies. Three new studies and eight new patients were included. Combined with 189 patients from the previous meta-analysis, the database included 197 patients. The main outcome was the percentage of asynchronous TRb in patients diagnosed before and after preset age thresholds of 6 and 12 months of age at retinoblastoma diagnosis., Results: Seventy-nine per cent of patients with pineoblastoma are diagnosed with retinoblastoma before the age of 12 months. However, baseline MRI screening at time of retinoblastoma diagnosis fails to detect the later diagnosed pineal TRb in 89% of patients. We modelled that an additional MRI performed at the age of 29 months picks up 53% of pineoblastomas in an asymptomatic phase. The detection rate increased to 72%, 87% and 92%, respectively, with 2, 3 and 4 additional MRIs., Conclusions: An MRI of the brain in heritable retinoblastoma before the age of 12 months misses most pineoblastomas, while retinoblastomas are diagnosed most often before the age of 12 months. Optimally timed additional MRI scans of the brain can increase the asymptomatic detection rate of pineoblastoma., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: Osteogenesis imperfecta (OI) is a rare inherited heterogeneous connective tissue disorder characterized by bone fragility, low bone mineral density, skeletal deformity and blue sclera. The dominantly inherited forms of OI are predominantly caused by mutations in either the COL1A1 or COL1A2 gene. Collagen type I is one of the major structural proteins of the eyes and therefore is the eye theoretically prone to alterations in OI. The aim of this systematic review was to provide an overview of the known ocular problems reported in OI., Methods: A literature search (in PubMed, Embase and Scopus), which included articles from inception to August 2020, was performed in accordance with the PRISMA guidelines., Results: The results of this current review show that almost every component of the eye could be affected in OI. Decreased thickness of the cornea and sclera is an important factor causing eye problems in patients with OI such as blue sclera. Findings that stand out are ruptures, lacerations and other eye problems that occur after minor trauma, as well as complications from standard surgical procedures., Discussion: Alterations in collagen type I affect multiple structural components of the eye. It is recommended that OI patients wear protective glasses against accidental eye trauma. Furthermore, when surgery is required, it should be approached with caution. The prevalence of eye problems in different types of OI is still unknown. Additional research is required to obtain a better understanding of the ocular defects that may occur in OI patients and the underlying pathology., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Background: The travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe., Methods: A cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries., Results: Capture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI -12.4 to -5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease., Conclusions: Fewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: While the apolipoprotein E ε 4 allele (ApoE- ε 4) is related to cognitive and brain decline in the general population, its effect on the brain in type 1 diabetes mellitus (T1DM) remains unclear. Therefore, the aim was to determine the interaction between ApoE- ε 4 and T1DM on cognitive performance and hippocampal structure and connectivity as the brain area most vulnerable to ApoE- ε 4 effects in adult patients with T1DM., Research Design and Methods: Blood sampling was performed in 104 patients with T1DM and 49 control subjects for ApoE genotyping, neuropsychology, and neuroimaging to determine hippocampal volume and resting-state connectivity. The interaction between T1DM status and ApoE- ε 4 presence was investigated and adjusted for age and mean systolic blood pressure., Results: ApoE genotyping could not be performed for three patients with T1DM. Significant interaction effects, indicating a differential effect of ApoE-ε4 between both groups, were found for overall cognitive functioning and for the subdomains of information processing speed and attention. Additionally, interaction effects were present for right hippocampal connectivity with the right posterior cingulate and supramarginal gyri. Subsequent group analysis showed that patients with T1DM with ApoE- ε 4 performed worse on these cognitive domains with increased connectivity, relative to their counterparts without ApoE- ε 4. In contrast, no cognitive effects, but decreased connectivity, were observed in control subjects with ApoE- ε 4. In patients with T1DM, higher right hippocampus connectivity with the posterior cingulate gyrus was related to poorer overall cognitive functioning., Conclusions: The results may suggest that ApoE-ε4 presence leaves our patients with T1DM more susceptible to cognitive decrements at a younger age, possibly through vascular pathways, warranting further longitudinal studies., (© 2021 by the American Diabetes Association.)