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Background: The temporal relationship between sleep, Alzheimer’s disease (AD), and cognitive impairment remains to be further elucidated. Objective: First, we aim to determine whether the Neuropsychiatric Inventory–Questionnaire (NPI-Q) assessed nighttime behaviors prior to cognitive decline influence the rate of cognitive deterioration in pathologically confirmed AD, and second, to assess the possible interactions with APOE allele and cerebral amyloid angiopathy (CAA). Methods: The rate of cognitive decline between cognitively asymptomatic participants from the National Alzheimer Coordinating Center who eventually received a neuropathologic diagnosis of AD with (+NTB) or without (−NTB) nighttime behaviors were compared using independent samples t-test. Participants were stratified by APOE carrier and CAA status. Demographic and patient characteristics were assessed using descriptive statistics, and the independent samples t-test was used for continuous variables and chi-square test for categorical variables. The significance level was set at p≤0.05. Results: The rate of cognitive decline was greater in +NTB (n = 74; 3.30 points/year) than −NTB (n = 330; 2.45 points/year) (p = 0.016), even if there was no difference in cognitive status at onset. This difference was restricted to APOE ɛ4 carriers (p = 0.049) and positive CAA participants (p = 0.020). Significance was not reached in non-carriers (p = 0.186) and negative CAA (p = 0.364). APOE and CAA were not differentially distributed between the NTB groups. Conclusion: NPI-Q assessed nighttime behaviors, a surrogate for sleep disturbances, are associated with more rapidly deteriorating cognition in patients with AD neuropathology who are also carriers of APOE ɛ4 or show CAA.

Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap.This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes.We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation.Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

Measurement of ID1 half-life by cycloheximide chase assays. U251 cells were pretreated with or without TMZ for 3 days, followed by treatment with cycloheximide for the indicated times. The cell lysates were then analyzed by Western blots.

Table S1. Sampling events, signal strength and signal persistence of data points used to build the MB subgroup model; Table S2. MB subgroup classifying peak list from PCA-LDA modeling;Table S3. PCA-LDA prediction results of the blind MB subgrouping test; Figure S1. The collection geometry of PIRL-MS setup used in this study; Figure S2. Representative PIRL-MS spectra of MB subgroups; Figure S3. The PCA-LDA model of the 4 MB subgroups upon application of non-subjective data exclusion criteria; Figure S4. The 'low complexity' PCA-LDA model of the 4 MB subgroups utilizing only the top 44 MB subgroup distinguishing m/z values; Figure S5. Hematoxylin and Eosin (H&E) staining of the misclassified and unclassifiable data points; Figure S6. PCA-LDA analysis of the misclassified/unclassifiable data points; Figure S7. Liquid Chromatography (LC) elution profiles of laser plume and tissue extract; Figure S8. The envisioned use scenarios for PIRL-MS technology. We have also per request of the reviewers included information on identification of MB classifying molecules with LC-MS, Intrasample variability in correct subgroup assignment as well as Sample collection and handling prior to access for PIRL-MS sampling

Glioblastoma is the most common primary brain tumor in adults. While the introduction of temozolomide chemotherapy has increased long-term survivorship, treatment failure and rapid tumor recurrence remains universal. The transcriptional regulatory protein, inhibitor of DNA-binding-1 (ID1), is a key regulator of cell phenotype in cancer. We show that CRISPR-mediated knockout of ID1 in glioblastoma cells, breast adenocarcinoma cells, and melanoma cells dramatically reduced tumor progression in all three cancer systems through transcriptional downregulation of EGF, which resulted in decreased EGFR phosphorylation. Moreover, ID1-positive cells were enriched by chemotherapy and drove tumor recurrence in glioblastoma. Addition of the neuroleptic drug pimozide to inhibit ID1 expression enhanced the cytotoxic effects of temozolomide therapy on glioma cells and significantly prolonged time to tumor recurrence. Conclusively, these data suggest ID1 could be a promising therapeutic target in patients with glioblastoma.Significance:These findings show that the transcriptional regulator ID1 is critical for glioblastoma initiation and chemoresistance and that inhibition of ID1 enhances the effect of temozolomide, delays tumor recurrence, and prolongs survival.

Recent work suggests that APOEɛ4/4 females with Alzheimer's disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS).To examine the interaction of sex and APOEɛ4 status on NPS burden using two independent cohorts: 1) patients at risk for AD with mild cognitive impairment and/or major depressive disorder (n = 252) and 2) patients with probable AD (n = 7,261).Regression models examined the interactive effects of sex and APOEɛ4 on the number of NPS experienced and NPS Severity. APOEɛ3/4 and APOEɛ4/4 were pooled in the at-risk cohort due to the sample size.In the at-risk cohort, there was a significant sex*APOEɛ4 interaction (p = 0.007) such that the association of APOEɛ4 with NPS was greater in females than in males (incident rate ratio (IRR) = 2.0). APOEɛ4/4 females had the most NPS (mean = 1.9) and the highest severity scores (mean = 3.5) of any subgroup. In the clinical cohort, APOEɛ4/4 females had significantly more NPS (IRR = 1.1, p = 0.001, mean = 3.1) and higher severity scores (b = 0.31, p = 0.015, mean = 3.7) than APOEɛ3/3 females (meanNPS = 2.9, meanSeverity = 3.3). No association was found in males.Our study suggests that sex modifies the association of APOEɛ4 on NPS burden. APOEɛ4/4 females may be particularly susceptible to increased NPS burden among individuals with AD and among individuals at risk for AD. Further investigation into the mechanisms behind these associations are needed.

The analysis of nuclear morphology plays an important role in glioma diagnosis and grading. We previously described intranuclear rods (rods) labeled with the SDL.3D10 monoclonal antibody against class III beta-tubulin (TUBB3) in human ependymomas. In a cohort of adult diffuse gliomas, we identified nuclear rods in 71.1% of IDH mutant lower-grade gliomas and 13.7% of IDH wild-type glioblastomas (GBMs). The presence of nuclear rods was associated with significantly longer postoperative survival in younger (≤65) GBM patients. Consistent with this, nuclear rods were mutually exclusive with Ki67 staining and their prevalence in cell nuclei inversely correlated with the Ki67 proliferation index. In addition, rod-containing nuclei showed a relative depletion of lamin B1, suggesting a possible association with senescence. To gain insight into their functional significance, we addressed their antigenic properties. Using a TUBB3-null mouse model, we demonstrate that the SDL.3D10 antibody does not bind TUBB3 in rods but recognizes an unknown antigen. In the present study, we show that rods show immunoreactivity for the nucleotide synthesizing enzymes inosine monophosphate dehydrogenase (IMPDH) and cytidine triphosphate synthetase. By analogy with the IMPDH filaments that have been described previously, we postulate that rods regulate the activity of nucleotide-synthesizing enzymes in the nucleus by sequestration, with important implications for glioma behavior.

Rosai-Dorfman disease (RDD) is a rare histiocytosis that typically presents with painless lymphadenopathy but can also present with neurologic symptoms.

Background Prediction of early progression in glioblastoma may provide an opportunity to personalize treatment. Simplified intravoxel incoherent motion (IVIM) MRI offers quantitative estimates of diffusion and perfusion metrics. We investigated whether these metrics, during chemoradiation, could predict treatment outcome. Methods 38 patients with newly diagnosed IDH-wildtype glioblastoma undergoing 6-week/30-fraction chemoradiation had standardized post-operative MRIs at baseline (radiation planning), and at the 10th and 20th fractions. Non-overlapping T1-enhancing (T1C) and non-enhancing T2-FLAIR hyperintense regions were independently segmented. Apparent diffusion coefficient (ADCT1C, ADCT2-FLAIR) and perfusion fraction (fT1C, fT2-FLAIR) maps were generated with simplified IVIM modelling. Parameters associated with progression before or after 6.9 months (early vs late progression, respectively), overall survival (OS) and progression-free survival (PFS) were investigated. Results Higher ADCT2-FLAIR at baseline [Odds Ratio (OR) = 1.06, 95% CI 1.01–1.15, p = 0.025], lower fT2-FLAIR at fraction 10 (OR = 2.11, 95% CI 1.04–4.27, p = 0.018), and lack of increase in ADCT2-FLAIR at fraction 20 compared to baseline (OR = 1.12, 95% CI 1.02–1.22, p = 0.02) were associated with early progression. Combining ADCT2-FLAIR at baseline, fT2-FLAIR at fraction 10, ECOG and MGMT promoter methylation status significantly improved AUC to 90.3% compared to a model with only ECOG and MGMT promoter methylation status (p = 0.001). Using multivariable analysis, neither IVIM metrics were associated with OS but higher fT2-FLAIR at fraction 10 (HR = 0.72, 95% CI 0.56–0.95, p = 0.018) was associated with longer PFS. Conclusion ADCT2-FLAIR at baseline, its lack of increase from baseline to fraction 20, or fT2-FLAIR at fraction 10 significantly predicted early progression. fT2-FLAIR at fraction 10 was associated with PFS.

Medulloblastoma with myogenic differentiation (MMD), previously termed medullomyoblastoma, is a distinctive subtype of medulloblastoma. It is an uncommon neoplasm in children and very rare in adults, with oldest reported case being 49-years of age. We present a case of large cell/anaplastic medulloblastoma with myogenic differentiation arising in the right cerebellar hemisphere of a 54-year-old man treated by surgical resection and radiotherapy. Despite C-MYC amplification in the tumor, he survived tumor-free for nearly 2 years (726 days), which greatly exceeded the expected total survival. His death was attributed to complications of treatment rather than recurrence.

Mitochondrial dysfunction is a recognized cause of autosomal recessive Parkinson disease (PD) and may contribute to idiopathic disease.1 Twinkle protein is a DNA helicase coded by the C10orf2 gene, which, along with polymerase gamma and other proteins, is responsible for regulating mitochondrial replication. Heterozygous C10orf2 mutations are a recognized cause of chronic progressive ophthalmoplegia (CPEO) and other neurologic manifestations, but their relationship with parkinsonism is unclear. Here, we report a case (along with postmortem examination findings) of familial parkinsonism associated with a heterozygous mutation in C10orf2 , alongside reviewing previously published cases.

Background Meningiomas are the most common tumors occurring in the central nervous system, with variable recurrence rates depending on World Health Organization grading. Atypical (Grade II) meningioma has a higher rate of recurrence than benign (Grade I) meningioma. The efficacy of adjuvant radiotherapy (RT) to improve tumor control has been questioned. Objective To investigate clinical and histopathological predictors of tumor recurrence and radio-resistance in atypical meningiomas. Methods This cohort study retrospectively reviewed all patients in St. Michael's Hospital CNS tumor patient database who underwent surgical resection of a Grade II meningioma from 1995 to 2015. Cases with neurofibromatosis type II, multiple satellite tumors, spinal cord meningioma, radiation-induced meningioma, and perioperative death were excluded. Patient demographics, neuropathological diagnosis, tumor location, extent of resection, radiation therapy, and time to recurrence or progression were recorded. Cox univariate regression and Kaplan-Meier survival analysis were employed to identify risk factors for recurrence and radio-resistance. Results Among 181 patients, the combination of necrosis and brain invasion was associated with an increased recurrence risk (hazard ratio [HR] = 4.560, P = .001) and the lowest progression-free survival (PFS) relative to other pathological predictors. This trend was maintained after gross total resection (GTR, P = .001). RT was associated with decreased PFS (P = .001), even in patients who received GTR (P = .001). Conclusion The combination of necrosis and brain invasion is a strong predictor of tumor recurrence and radio-resistance in meningioma, regardless of EOR or adjuvant RT. Our findings question the sensibility of brain invasion as an absolute criterion for Grade II status.

BACKGROUND The relationship between sleep, neuropathology, and clinical manifestations of Alzheimer's disease (AD) remains controversial. OBJECTIVE To determine whether nighttime behaviors (NTB) are associated with the development of AD histopathology or cognitive decline. METHODS We compared NTB prevalence in subjects with or without AD lesions, and with or without progressive cognitive decline. Subjects with either absent or severe plaques and tangles were identified from the National Alzheimer's Disease Coordinating Center data sets and classified as cognitively declining if the standard deviation from their individual mean Mini-Mental Status Examination score was ≥2, and stable if

The use of standard next generation sequencing (NGS) technologies to detect key mutations in isocitrate dehydrogenase (IDH) genes for glioma diagnosis imposes several challenges including high capital cost and turnaround delays associated with the need for batch testing. Both for glioma testing, as well as for testing in other tumor types where highly specific mutation identification is required, the high throughput nature of NGS limits the feasibility of using it as a primary approach in clinical laboratories. We hypothesized that third generation nanopore sequencing by Oxford Nanopore Technologies (ONT) has the capability to overcome these limitations. This study aimed to develop and validate a nanopore-based IDH mutation detection assay for clinical practice using glioma formalin-fixed paraffin-embedded (FFPE) tissue. Glioma FFPE (n=66) samples with confirmed IDH gene mutational status were sequenced on ONT's MinION device using an amplicon-based approach. All cases were concordant when compared to the reference results. Limit of blank and limit of detection for the variant allele fraction were 1.5% and 3.3% respectively at 500x read depth per gene. Total sequencing cost per sample was $50-$134 CAD with results being available in 9-15 hours. These findings demonstrate that nanopore-sequencing technology can be leveraged to develop low cost, high performance clinical sequencing-based assays with quick turn-around times, to support the detection of targeted mutations in FFPE tumor tissue.

INTRODUCTION: Spinal hemangiomas are benign vascular tumors that most commonly originate from the osseous structures of the spinal column. Epidural spinal hemangiomas without osseous involvement are uncommon and are classified as pure epidural spinal hemangiomas. Extraosseous spinal epidural cavernous hemangiomas are rarely described and among available reports; most patients present with slowly progressive neurological symptoms. Herein, we present a novel case of acute neurological dysfunction from a pure spinal epidural hemangioma that was managed through surgical resection with good neurological recovery at follow-up. CASE PRESENTATION: A 45-year-old previously healthy man presented to the emergency room with sudden inability to ambulate and was found to have bilateral lower extremity weakness. Magnetic resonance imaging of the spine demonstrated an epidural mass extending out of the right T5/6 neural foramen. The mass enhanced heterogeneously, and the preoperative diagnosis favored an atypical schwannoma. The lesion was surgically removed en-bloc through a midline posterior decompression with instrumentation. Histopathologic examination confirmed cavernous hemangioma pathology. Within 6 weeks of the surgical intervention, the patient had regained full sensorimotor function and these effects were durable through long term follow-up. DISCUSSION: Pure spinal epidural hemangiomas are rare and generally have an insidious clinical course. This case report highlights that these uncommon lesions may present with substantial and acute neurological dysfunction requiring urgent neurosurgical intervention. This should prompt clinicians to consider cavernous hemangioma in the differential diagnosis of patients presenting with acute neurological deterioration and an epidural spinal tumor.

Background and Purpose: To quantitatively compare the recurrence patterns of glioblastoma (isocitrate dehydrogenase-wild type) versus grade 4 isocitrate dehydrogenase-mutant astrocytoma (wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase, respectively) following primary chemoradiation. Materials and Methods: A retrospective matched cohort of 22 wild type isocitrate dehydrogenase and 22 mutant isocitrate dehydrogenase patients were matched by sex, extent of resection, and corpus callosum involvement. The recurrent gross tumor volume was compared to the original gross tumor volume and clinical target volume contours from radiotherapy planning. Failure patterns were quantified by the incidence and volume of the recurrent gross tumor volume outside the gross tumor volume and clinical target volume, and positional differences of the recurrent gross tumor volume centroid from the gross tumor volume and clinical target volume. Results: The gross tumor volume was smaller for wild type isocitrate dehydrogenase patients compared to the mutant isocitrate dehydrogenase cohort (mean ± SD: 46.5 ± 26.0 cm3 vs 72.2 ± 45.4 cm3, P = .026). The recurrent gross tumor volume was 10.7 ± 26.9 cm3 and 46.9 ± 55.0 cm3 smaller than the gross tumor volume for the same groups ( P = .018). The recurrent gross tumor volume extended outside the gross tumor volume in 22 (100%) and 15 (68%) ( P= .009) of wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase patients, respectively; however, the volume of recurrent gross tumor volume outside the gross tumor volume was not significantly different (12.4 ± 16.1 cm3 vs 8.4 ± 14.2 cm3, P = .443). The recurrent gross tumor volume centroid was within 5.7 mm of the closest gross tumor volume edge for 21 (95%) and 22 (100%) of wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase patients, respectively. Conclusion: The recurrent gross tumor volume extended beyond the gross tumor volume less often in mutant isocitrate dehydrogenase patients possibly implying a differential response to chemoradiotherapy and suggesting isocitrate dehydrogenase status might be used to personalize radiotherapy. The results require validation in prospective randomized trials.

To evaluate the difference in temporal artery biopsy length before and after formalin fixation and identify any correlations with pathologic diagnosis.Prospective case series.Patients undergoing temporal artery biopsy between June 2020 and October 2021.The pre- and postfixation biopsy lengths were compared. The primary outcome was the difference in temporal artery length as measured before fixation by the surgeon versus the postfixation measurement by the pathologist.Forty-seven consecutive biopsies in 46 patients were included. One patient had a repeat biopsy. Mean age was 75.3 ± 8.4 years (range, 49-94 years); 74% of patients (34 of 46 patients) were female. Mean prefixation biopsy length was 2.36 ± 0.58 cm (range, 1.1-4.5 cm). Mean postfixation biopsy length was 2.09 ± 0.59 cm (range, 0.6-3.8 cm). Mean difference (postfixation shrinkage) was 0.27 ± 0.24 cm (p = 0.0298), and 36% of biopsies (17 of 47 biopsies) were positive. There was no significant difference in prefixation temporal artery biopsy length (p = 0.38) or postfixation shrinkage (p = 0.24) between positive and negative biopsies. In a univariate analysis, elevated erythrocyte sedimentation rate was 31.3 mm/h (range, 4-88 mm/h) in negative biopsies versus 54.5 mm/h (range, 29-98 mm/h) in positive biopsies (p = 0.01), C-reactive protein was 17.4 mg/L (range, 0.2-145 mg/L) in negative biopsies versus 78.56 mg/L (range, 5-244.4 mg/L) in positive biopsies (p = 0.003), and platelets were 254.9 × 10The average temporal artery biopsy was approximately 0.27 cm shorter on pathologic reports compared with before fixation measurements. Surgeons should account for this shrinkage with a buffer of at least 0.3 cm, aiming for excision of at least 2.3 cm, if they desire a postfixation size of 2 cm.

Introduction Psychosis is one of the most typical and persistent neuropsychiatric manifestations of AD where nearly half of AD patients experiences psychotic symptoms such as hallucinations and/or delusions (Ropacki & Jeste., 2005). Psychotic AD patients tend to have poorer overall health (Bassiony et al., 2000) and experience greater cognitive and functional impairments (Chui et al., 1994; Fischer et al., 2012). These qualities contribute to a reduced quality of life for patients and their caregivers. Researchers from our group found that psychosis risk in neuropathologically-diagnosed AD patients is significantly higher in females who are homozygous positive for APOE e4 with the presence of Lewy body pathology (Kim et al., 2017). These results point to a sexual dimorphism in AD psychosis where the e4 allele may play a larger role in influencing psychosis development in females. We hypothesize that AD patients with this high-risk profile (female and homozygous positive for APOE e4) are more susceptible to psychosis, potentially leading to more severe symptoms as well as earlier disease onset respectively. As such, this exploratory study aims to validate the sex-specific effect of APOE e4 status (i.e. high-risk profile) on psychosis in a clinical cohort. Methods We first obtained all required Research Ethics Board approval from St. Michael's Hospital and the National Alzheimer's Coordinating Centre (NACC). A series of parallel analyses were conducted via SPSS (Version 27.0.0.0). For each analysis, we first conducted a descriptive analysis of our sample including age, sex, cognitive status, psychosis status, and presence of the relevant alleles. Patients with CNS neoplasm, non-AD-induced dementia, and significant psychiatric co-morbidity were excluded as per the inclusion/exclusion criteria for NACC. Participants Selected participants from the NACC database had a presumptive etiological diagnosis of AD from a clinician. They also had available APOE e4 status and Neuropsychiatric Inventory Questionnaire (NPI-Q) data. Subjects were categorized by high-risk profile. Subjects with either hallucinations or delusions as defined by the NPI-Q were considered psychotic (Figure 1). Procedure & Analyses We investigated the effect of having a high-risk profile (female and homozygous positive for APOE e4) on age and neuropsychiatric test scores at initial visit, as well as presence and severity of psychotic symptoms (delusions or hallucinations). Results To investigate the effect of the high-risk profile on age, we conducted a one-way between-subjects analysis of variance in the high-risk vs. non-high-risk conditions. Subjects with the high-risk profile (M = 70.43, SD = 7.75) were significantly younger than those without the profile (M = 74.69, SD = 9.76) at the time of their initial visit [F(1, 16202) = 139.05, p To investigate the effect of the high-risk profile on the presence of delusions and hallucinations, we conducted a binary logistical regression for each psychotic symptom. We found that the high-risk profile significantly predicted the presence of delusions, b = 0.302, df = 1, p = .004. There was no significance for hallucinations. Lastly, to study the effect of the high-risk profile on the severity of delusions and hallucinations, we conducted an ordinal logistical regression for each psychotic symptom. Subjects with the high-risk profile had a predicted increase of 0.388 in the log-odds of being in a more severe category for delusions, p = .041. Similarly, high-risk individuals had a predicted increase of 0.638 in the log-odds of being in a more severe category for hallucinations, p = .046. Conclusions From our results, the high-risk profile of being female and homozygous positive for APOE e4 seems to be associated with an earlier age of initial visit, an increased presence of delusions and more severe psychotic symptoms. In terms of psychosis in AD, our findings are in line with our prior work suggesting APOE e4 may play a modulatory role in the development of psychosis in female patients with AD, leading to earlier onset of symptoms, increased prevalence of delusions and more severe psychotic symptoms (Kim et al., 2017). Taken together, we believe that this high-risk profile may be a significant step towards understanding the mechanisms that underly AD and psychosis in AD. Future directions include elucidating the sex-specific cellular mechanisms on APOE e4 status. Funding We wish to acknowledge the generosity of the St. Michael's Hospital Foundation and the Heather and Eric Donnelly endowment.

Purpose To quantitatively compare the recurrence pattern of glioblastoma (IDH-wild type) versus grade 4 IDH-mutant astrocytoma (herein referred to as wtIDH and mutIDH, respectively) following primary chemoradiation. Methods Twenty-two wtIDH and 22 mutIDH patients matched by sex, extent of resection, and corpus callosum involvement were enrolled. The recurrent gross tumor volume (rGTV) was compared with both the gross tumor volume (GTV) and clinical target volume (CTV) from radiotherapy planning. Failure patterns were quantified by the incidence and volume of the rGTV outside the GTV and CTV, and positional differences of the rGTV centroid from the GTV and CTV. Results The GTV was smaller in wtIDH compared to the mutIDH group (mean±SD: 46.5±26.0 cm3 v. 72.2±45.4 cm3, p=0.026). The rGTV was 10.7±26.9 cm3 and 46.9±55.0 cm3 smaller than the GTV for the same groups (p=0.018). The rGTV extended outside the GTV in 22 (100%) and 15 (68%) (p=0.009) of wtIDH and mutIDH patients, respectively; however, the volume of rGTV outside the GTV was not significantly different (12.4±16.1 cm3 vs. 8.4±14.2 cm3, p=0.443). The rGTV metrics extending outside the CTV was not different between the groups. The rGTV centroid was within 5.7 mm of the closest GTV edge for 21 (95%) and 22 (100%) of wtIDH and mutIDH patients, respectively. Conclusion The rGTV extended beyond the GTV less often in mutIDH patients, suggesting limited margin radiotherapy could be beneficial in this group. The results support the study of small margin adaptive radiotherapy per the ongoing UNITED MR-Linac 5 mm CTV trial (NCT04726397).

Intravascular papillary endothelial hyperplasia (IPEH) is a benign vascular lesion that is formally diagnosed on histopathology. IPEH seldom presents in periocular tissues and is even less commonly seen deep within the orbit. As with cavernous hemangioma, this lesion tends to distort surrounding structures and can cause a significant mass effect in the orbit. The authors present an unusual case of orbital IPEH that resulted in severe proptosis and progressive vision loss from optic nerve compression. In toto surgical excision of the lesion resulted in significant recovery of vision loss and resolution of symptoms associated with proptosis. To the best of our knowledge, this case is the first to illustrate the potential for visual recovery after surgery in a patient with compressive optic neuropathy from orbital IPEH.

We present a 47-year-old woman with a 10-year disease course consisting of episodic confusion, aphasia, psychosis, depression, migrainous headaches and seizures. There was mild elevation of protein levels in the cerebrospinal fluid, progressive cerebral atrophy, and numerous small T1 hypointensities appearing as central "holes" in the corpus callosum on magnetic resonance imaging. She eventually expired due to status epilepticus and subsequent significant respiratory complications. In the central nervous system, there was generalized brain atrophy, and patchy labeling of blood vessels by antibodies to complement component 4d (C4d) and membrane attack complex. Innumerable small patches with loss of cell bodies (neurons and glial cells in gray matter and glial cells in white matter) and demyelination were scattered throughout the brain and spinal cord. There was no cavitation and the passing axons were mostly preserved. Large solid calcified foci were present predominantly in the pons along with disseminated focal calcification involving neuron cell bodies, neurites, and capillaries. Patchy labeling of glial cells and linear structures suggestive of myelin sheaths with C4d antibodies was observed while immunostains for SV40, tau, β-amyloid, alpha synuclein, p62, and trans-activation response DNA-binding protein 43 kDa were negative. Whole-exome sequencing did not reveal any clinically significant variants. Although the radiological findings are suggestive of Susac's syndrome (a rare condition characterized by encephalopathy, hearing loss, and branch retinal artery occlusion), in the absence of audiovisual manifestations, a definitive diagnosis cannot be rendered and therefore, this case may be representing a new entity. Further reports of similar cases are needed for clarification.

Introduction Neuropsychiatric symptoms (NPS) are both common in mild cognitive impairment and Alzheimer disease (AD). Studies have shown that some NPS such as apathy and depression are a key indicator for progression to AD. Methods We compared Neuropsychiatric Inventory (NPI) total score and NPI subdomain score between mild cognitive impairment-converters (MCI-C) and mild cognitive impairment-nonconverters (MCI-NC) longitudinally for 6 years using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. In addition to the NPI, Mini-Mental State Examination (MMSE) scores were also compared to find out if MMSE scores would differ between different NPI groups. Lastly, a linear regression model was done on MMSE and NPI total score to establish a relationship between MMSE and NPI total score. Results The results in this study showed that NPI total scores between MCI-C and MCI-NC differed significantly throughout 6 years. MCI-C subjects had a higher mean NPI total score and lower MMSE score compared with MCI-NC subjects. In addition, MMSE scores were significantly different between the 3 groups of NPI total score. Subjects who have a high NPI score have the lowest mean MMSE score, thus demonstrating that NPI scores do indeed affect MMSE scores. Further analyses using a regression model revealed that a unit change in NPI total score lead to 0.1 to 0.3 decrease in MMSE. Discussion On the basis of the findings, this study showed evidence that increase in NPS burden (reflected by increase in NPI) over time predicts conversion to AD, whereas stability of symptoms (reflected by stable NPI score) favors nonconversion. Further study should investigate the underlying mechanisms that drive both NPS burden and cognitive decline.