Efficacy and safety of transcranial magnetic stimulation on cognition in mild cognitive impairment, Alzheimer's disease, Alzheimer's disease-related dementias, and other cognitive disorders: a systematic review and meta-analysis.

OBJECTIVE: We aim to analyze the efficacy and safety of TMS on cognition in mild cognitive impairment (MCI), Alzheimer's disease (AD), AD-related dementias, and nondementia conditions with comorbid cognitive impairment. DESIGN: Systematic review, Meta-Analysis. SETTING: We searched MEDLINE, Embase, Cochrane database, APA PsycINFO, Web of Science, and Scopus from January 1, 2000, to February 9, 2023. PARTICIPANTS AND INTERVENTIONS: RCTs, open-label, and case series studies reporting cognitive outcomes following TMS intervention were included. MEASUREMENT: Cognitive and safety outcomes were measured. Cochrane Risk of Bias for RCTs and MINORS (Methodological Index for Non-Randomized Studies) criteria were used to evaluate study quality. This study was registered with PROSPERO (CRD42022326423). RESULTS: The systematic review included 143 studies (n = 5,800 participants) worldwide, encompassing 94 RCTs, 43 open-label prospective, 3 open-label retrospective, and 3 case series. The meta-analysis included 25 RCTs in MCI and AD. Collectively, these studies provide evidence of improved global and specific cognitive measures with TMS across diagnostic groups. Only 2 studies (among 143) reported 4 adverse events of seizures: 3 were deemed TMS unrelated and another resolved with coil repositioning. Meta-analysis showed large effect sizes on global cognition (Mini-Mental State Examination (SMD = 0.80 [0.26, 1.33], p = 0.003), Montreal Cognitive Assessment (SMD = 0.85 [0.26, 1.44], p = 0.005), Alzheimer's Disease Assessment Scale-Cognitive Subscale (SMD = -0.96 [-1.32, -0.60], p < 0.001)) in MCI and AD, although with significant heterogeneity. CONCLUSION: The reviewed studies provide favorable evidence of improved cognition with TMS across all groups with cognitive impairment. TMS was safe and well tolerated with infrequent serious adverse events.

LGI1 antibody encephalitis: acute treatment comparisons and outcome.

OBJECTIVE: To compare acute treatment responses and long-term outcome in leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis. METHODS: Retrospective case series of 118 patients with LGI1 antibody encephalitis evaluated at Mayo Clinic across all US sites from 1 May 2008 to 31 March 2019. Patient clinical data were identified and analysed through the neuroimmunology laboratory and electronic medical record. LGI1 antibody detection was by cell-based indirect immunofluorescence assay of serum, cerebrospinal fluid or both. Clinical outcomes were faciobrachial dystonic seizure (FBDS) resolution, modified Rankin Scale (mRS) score, Kokmen Short Test of Mental Status (STMS) score (0-38 point scale) and neuropsychometric testing results. RESULTS: Compared with intravenous immunoglobulin (IVIg) (n=21), patients treated with single-agent acute corticosteroids (intravenous, oral or both) (n=49) were more likely to experience resolution of FBDS (61% vs 7%, p=0.002) and improvements in mRS score (ΔmRS score 2 vs 0, p=0.008) and median Kokmen STMS scores (ΔKokmen STMS score 5 points vs 0 points, p=0.01). In 54 patients with long-term follow-up (≥2 years), the median mRS score was 1 (range 0-6) and the median Kokmen STMS score was 36 (range 24-38) after all combinations of immunotherapy. Neuropsychometric testing in 32 patients with long-term follow-up (≥2 years) demonstrated short-term memory impairments in 37%. CONCLUSIONS: Corticosteroids appeared more effective acutely than IVIg in improving LGI1 antibody encephalitis in this retrospective comparison of immunotherapies. While improvement with immunotherapy is typical and long-term outcome is favourable, short-term memory deficits are noted in approximately a third of the patients.

Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase.

Myeloperoxidase (MPO) is a heme peroxidase found in neutrophils, monocytes and macrophages that efficiently catalyzes the oxidation of endogenous chloride into hypochlorous acid for antimicrobial activity. Chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. Triazolopyrimidine 5 is a reversible MPO inhibitor; however it suffers from poor stability in acid, and is an irreversible inhibitor of the DNA repair protein methyl guanine methyl transferase (MGMT). Structure-based drug design was employed to discover benzyl triazolopyridines with improved MPO potency, as well as acid stability, no reactivity with MGMT, and selectivity against thyroid peroxidase (TPO). Structure-activity relationships, a crystal structure of the MPO-inhibitor complex, and acute in vivo pharmacodynamic data are described herein.

Linking (Pyr)1apelin-13 pharmacokinetics to efficacy: Stabilization and measurement of a high clearance peptide in rodents.

Apelin, the endogenous ligand for the APJ receptor, has generated interest due to its beneficial effects on the cardiovascular system. Synthesized as a 77 amino acid preproprotein, apelin is post-translationally cleaved to a series of shorter peptides. Though (Pyr)1apelin-13 represents the major circulating form in plasma, it is highly susceptible to proteolytic degradation and has an extremely short half-life, making it challenging to quantify. Literature reports of apelin levels in rodents have historically been determined with commercial ELISA kits which suffer from a lack of selectivity, recognizing a range of active and inactive isoforms of apelin peptide. (Pyr)1apelin-13 has demonstrated beneficial hemodynamic effects in humans, and we wished to evaluate if similar effects could be measured in pre-clinical models. Despite development of a highly selective LC/MS/MS method, in rodent studies where (Pyr)1apelin-13 was administered exogenously the peptide was not detectable until a detailed stabilization protocol was implemented during blood collection. Further, the inherent high clearance of (Pyr)1apelin-13 required an extended release delivery system to enable chronic dosing. The ability to deliver sustained doses and stabilize (Pyr)1apelin-13 in plasma allowed us to demonstrate for the first time the link between systemic concentration of apelin and its pharmacological effects in animal models.

Identification of substituted benzothiazole sulfones as potent and selective inhibitors of endothelial lipase.

A low level of high density lipoprotein (HDL) is an independent risk factor for cardiovascular disease. HDL reduces inflammation and plays a central role in reverse cholesterol transport, where cholesterol is removed from peripheral tissues and atherosclerotic plaque. One approach to increase plasma HDL is through inhibition of endothelial lipase (EL). EL hydrolyzes phospholipids in HDL resulting in reduction of plasma HDL. A series of benzothiazole sulfone amides was optimized for EL inhibition potency, lipase selectivity and improved pharmacokinetic profile leading to the identification of Compound 32. Compound 32 was evaluated in a mouse pharmacodynamic model and found to show no effect on HDL cholesterol level despite achieving targeted plasma exposure (Ctrough > 15 fold over mouse plasma EL IC50 over 4 days).

Occlusal Pressure Analysis of Complete Dentures after Microwave Disinfection: A Clinical Study.

PURPOSE: This clinical study evaluated the effect of microwave disinfection protocols on the occlusal pressure pattern of dentures. MATERIALS AND METHODS: Dentures were constructed for 40 patients and evaluated as follows (n = 20). Group 1: Patients had the maxillary dentures submitted to microwave disinfection, once a week, for 4 weeks. Group 2: Patients had the maxillary dentures submitted to microwave disinfection, three times a week, for 4 weeks. Occlusal contacts were recorded on five occasions: 30 days after denture insertion and before first disinfection (baseline or control group); 1 week after disinfection; 2 weeks after disinfection; 3 weeks after disinfection; 4 weeks after disinfection. Occlusal contacts were analyzed by T-Scan III. Intergroup analysis was performed using the Mann-Whitney test and intragroup analysis using the Friedman test with significance of 5%. RESULTS: The results showed no significant difference between groups during the periods. The data on parameters loss of denture adaptation or complaints showed that patients used their dentures regularly for eating and expressed comfort and satisfaction in all experimental periods. The evaluation of functional occlusion revealed that the distribution of the occlusal contacts remained unaltered after disinfection. CONCLUSION: Microwave disinfection protocols as studied in this report did not influence occlusal contacts of the complete dentures.

Use of perceptual memory as a performance validity indicator: initial validation with simulated mild traumatic brain injury.

INTRODUCTION: Many commonly employed performance validity tests (PVTs) are several decades old and vulnerable to compromise, leading to a need for novel instruments. Because implicit/non-declarative memory may be robust to brain damage, tasks that rely upon such memory may serve as an effective PVT. Using a simulation design, this experiment evaluated whether novel tasks that rely upon perceptual memory hold promise as PVTs. METHOD: Sixty healthy participants were provided instructions to simulate symptoms of mild traumatic brain injury (TBI), and they were compared to a group of 20 honest responding individuals. Simulator groups received varying levels of information concerning TBI symptoms, resulting in naïve, sophisticated, and test-coached groups. The Word Memory Test, Test of Memory Malingering, and California Verbal Learning Test-II Forced Choice Recognition Test were administered. To assess perceptual memory, selected images from the Gollin Incomplete Figures and Mooney Closure Test were presented as visual perception tasks. After brief delays, memory for the images was assessed. RESULTS: No group differences emerged on the perception trials of the Gollin and Mooney figures, but simulators remembered fewer images than the honest responders. Simulator groups differed on the standard PVTs, but they performed equivalently on the Gollin and Mooney figures, implying robustness to coaching. Relying upon a criterion of 90% specificity, the Gollin and Mooney figures achieved at least 90% sensitivity, comparing favorably to the standard PVTs. CONCLUSIONS: The Gollin and Mooney figures hold promise as novel PVTs. As perceptual memory tests, they may be relatively robust to brain damage, but future research involving clinical samples is necessary to substantiate this assertion.

The relationship between performance validity testing, external incentives, and cognitive functioning in long COVID.

INTRODUCTION: Performance validity test (PVT) failures occur in clinical practice and at higher rates with external incentives. However, little PVT research has been applied to the Long COVID population. This study aims to address this gap. METHODS: Participants were 247 consecutive individuals with Long COVID seen for neuropsychological evaluation who completed 4 PVTs and a standardized neuropsychological battery. The sample was 84.2% White and 66% female. The mean age was 51.16 years and mean education was 14.75 years. Medical records were searched for external incentive (e.g., disability claims). Three groups were created based on PVT failures (Pass [no failures], Intermediate [1 failure], and Fail [2+ failures]). RESULTS: A total of 8.9% participants failed 2+ PVTs, 6.4% failed one PVT, and 85% passed PVTs. From the full sample, 25.1% were identified with external incentive. However, there was a significant difference between the rates of external incentives in the Fail group (54.5%) compared to the Pass (22.1%) and Intermediate (20%) groups. Further, the Fail group had lower cognitive scores and higher frequency of impaired range scores, consistent with PVT research in other populations. External incentives were uncorrelated with cognitive performance. CONCLUSIONS: Consistent with other populations, results suggest Long COVID cases are not immune to PVT failure and external incentives are associated with PVT failure. Results indicated that individuals in the Pass and Intermediate groups showed no evidence for significant cognitive deficits, but the Fail group had significantly poorer cognitive performance. Thus, PVTs should be routinely administered in Long COVID cases and research.

Executive function in eating disorders: the role of state anxiety.

OBJECTIVE: We examined the influence of depression and anxiety on executive function in individuals with a DSM-IV diagnosis of anorexia nervosa-restricting type, anorexia nervosa-binge-eating/purging type, bulimia nervosa, or eating disorder not otherwise specified. METHOD: We assessed 106 women after their inpatient treatment in an eating disorders program. All participants were nutritionally stable at the time of testing. RESULTS: Thirty percent of the total sample showed impaired performance on one or more tests of executive function. No differences in executive function were observed among diagnostic groups. Anxiety scores accounted for significant variance in performance for all groups. DISCUSSION: Executive function deficits were found in a minority of our sample, with significant variance in performance accounted for by self-reported anxiety. State anxiety appears to contribute to diminished executive function in women with eating disorders.

Social cognition and social functioning in nonclinical paranoia.

INTRODUCTION: Persons with nonclinical paranoia show many of the same biases as those with clinical paranoia, suggesting that paranoia exists on a continuum. However, little is known about the various social cognitive processes found in paranoia and how these relate to social functioning and social behaviours in general. This study will examine performance on emotion perception and attributional style measures and their relationship to social functioning, social problem solving, and social skill. A key element in this study will be the incorporation of ambiguity in the perception of emotional expressions and the assignment of attributional blame, which appears to be an important, yet neglected, construct in paranoia. METHODS: Twenty-six persons with high levels of nonclinical paranoia and 31 persons with low levels of paranoia completed measures of emotion perception, attributional style, social functioning, and social problem solving. Salient and subtle emotional expressions were used to examine how ambiguity impacts emotion perception in paranoia. RESULTS: The group high in nonclinical paranoia showed reduced accuracy for subtle negative emotional expressions and showed more perceived hostility and blame for ambiguous social situations as compared to the group low in nonclinical paranoia. Also, the high nonclinical paranoia group reported less social engagement, fewer social contacts, and more problems in social perception and social skill than the group low in nonclinical paranoia. CONCLUSION: Social cognitive and social functioning biases are found in persons with high levels of nonclinical paranoia. Possible mechanisms of these biases and relevance for treatment approaches are discussed.

Examination of the relationship between symptom and performance validity measures across referral subtypes.

INTRODUCTION: The extent to which performance validity (PVT) and symptom validity (SVT) tests measure separate constructs is unclear. Prior research using the Minnesota Multiphasic Personality Inventory (MMPI-2 & RF) suggested that PVTs and SVTs are separate but related constructs. However, the relationship between Personality Assessment Inventory (PAI) SVTs and PVTs has not been explored. This study aimed to replicate previous MMPI research using the PAI, exploring the relationship between PVTs and overreporting SVTs across three subsamples, neurodevelopmental (attention deficit-hyperactivity disorder (ADHD)/learning disorder), psychiatric, and mild traumatic brain injury (mTBI). METHODS: Participants included 561 consecutive referrals who completed the Test of Memory Malingering (TOMM) and the PAI. Three subgroups were created based on referral question. The relationship between PAI SVTs and the PVT was evaluated through multiple regression analysis. RESULTS: The results demonstrated the relationship between PAI symptom overreporting SVTs, including Negative Impression Management (NIM), Malingering Index (MAL), and Cognitive Bias Scale (CBS), and PVTs varied by referral subgroup. Specifically, overreporting on CBS but not NIM and MAL significantly predicted poorer PVT performance in the full sample and the mTBI sample. In contrast, none of the overreporting SVTs significantly predicted PVT performance in the ADHD/learning disorder sample but conversely, all SVTs predicted PVT performance in the psychiatric sample. CONCLUSIONS: The results partially replicated prior research comparing SVTs and PVTs and suggested that constructs measured by SVTs and PVTs vary depending upon population. The results support the necessity of both PVTs and SVTs in clinical neuropsychological practice.

COVID-19 Vaccine Hesitancy Among Deployed Personnel in a Joint Environment.

INTRODUCTION: In the United States, vaccine hesitancy has been identified as a major barrier to vaccination against COVID-19, but attitudes toward COVID-19 vaccination among military personnel are not well understood. We evaluated the prevalence and correlates of COVID-19 vaccine consent or refusal among deployed personnel in a joint environment. MATERIALS AND METHODS: Deidentified data were retrospectively extracted from the electronic medical record of the Military Health System in May 2021. All personnel currently assigned to the deployment area of operations were included in the analysis if their choice to receive the vaccine was known. Personnel characteristics were compared by vaccine acceptance status using chi-square tests, Fisher's exact tests, or correlation coefficients. This analysis was exempted from Institutional Review Board review. RESULTS: The sample included 1,809 individuals, primarily members of the Army (72%) and members of Reserve (53%) or National Guard (27%) units. In the overall sample, 61% accepted the vaccine, with vaccine acceptance rates being lowest among Black or African American personnel (54%; P = .03 for comparison across racial groups) and members of Reserve or National Guard units (59%; P < .001 for comparison by component). No differences in vaccine acceptance were found according to sex or health status (including prior COVID-19 infection). CONCLUSIONS: Overall vaccine acceptance was greater among deployed military personnel than that reported in the U.S. population as a whole. However, lower vaccine acceptance among personnel from marginalized populations suggests a need to ensure that all service members have sufficient opportunities to have a frank and ongoing discussion with health care providers to address concerns related to vaccination. Additionally, lower vaccine acceptance among Reserve and National Guard personnel indicates a need for innovative educational approaches to counter vaccine hesitancy in the premobilization phase of deployment.

Emotional functioning in long COVID: Comparison to post-concussion syndrome using the Personality Assessment Inventory.

Objective: Recent studies on Long COVID found that patients report prominent emotional distress and significant correlations between distress and cognitive performance have been identified, raising the question of how to manage or treat these issues. To understand psychological functioning in Long COVID further, this study examined personality responses on the Personality Assessment Inventory (PAI) to compare psychological functioning in a Long COVID group with a post-concussion syndrome (PCS) group, a syndrome with a significant psychological component. Participants and methods: Participants included 201 consecutive Long COVID outpatients (Mean age = 48.87 years, mean education = 14.82, 71.6% Female, 82.6% White) and a comparison group of 102 consecutively referred PCS outpatients (Mean age = 46.08, mean education = 14.17, 63.7% Female, 88.2% White). Effect sizes and t-tests were calculated using the PAI validity, clinical, interpersonal, and treatment consideration scales as well as clinical subscales. Results: The results replicated earlier findings on the PAI in Long COVID by demonstrating that both Long COVID and PCS groups had the highest mean elevations on SOM and DEP scales but no statistically significant between group differences in mean scale elevations. Results support similarities in psychological functioning between Long COVID and PCS patients emphasizing the importance of evaluating psychological functioning in neuropsychological evaluations for these populations. Further, results suggest that psychological treatment strategies for PCS patients may be helpful for Long COVID patients, but more research is needed.

Self-generation enhances verbal recall in individuals infected with HIV.

Despite the prevalence of HIV-associated episodic memory impairment and its adverse functional impact, there are no empirically validated cognitive rehabilitation strategies for HIV-infected persons. The present study examined the self-generation approach, which is theorized to enhance new learning by elaborating and deepening encoding. Participants included 54 HIV-infected and 46 seronegative individuals, who learned paired word associates in both self-generated and didactic encoding experimental conditions. Results revealed main effects of HIV serostatus and encoding condition, but no interaction. Planned comparisons showed that both groups recalled significantly more words learned in the self-generation condition, and that HIV+ individuals recalled fewer words overall compared to their seronegative counterparts at delayed recall. Importantly, HIV+ participants with clinical memory impairment evidenced similar benefits of self-generation compared to unimpaired HIV+ subjects. Self-generation strategies may improve verbal recall in individuals with HIV infection and may, therefore, be an appropriate and potentially effective cognitive rehabilitation tool in this population.

Evaluation of the occlusion vertical dimension of complete dentures after microwave disinfection.

OBJECTIVES: An increase in occlusal vertical dimension (OVD) after microwave disinfection may result in the need for adjustments in the complete dentures. This in vitro study evaluated the increase in OVD of maxillary complete dentures submitted to microwave disinfection protocols. MATERIAL AND METHODS: Thirty sets of complete dentures were evaluated as follows: Group 1-15 sets had the maxillary complete dentures submitted to microwave disinfection (650 W/3 min), once a week, for 4 weeks. Group 2-15 sets had the maxillary complete dentures submitted to microwave disinfection (650 W/3 min), three times a week, for 4 weeks. The vertical dimension was measured with a micrometre (in mm) before disinfection protocols (baseline readings) and after each week of disinfection. Data were analysed using Wilcoxon and Friedman tests (α = 0.05). RESULTS: For Group 1, no significant difference was found between the increases in OVD and zero, and no significant difference was found between the weeks. For Group 2, the increases in OVD were significantly greater than zero, and the Friedman test showed that weeks 3 and 4 had significantly greater changes than week 1 and that week 4 had significantly greater change than week 2. CONCLUSION: Microwave disinfection only promoted significant increase in OVD in Group 2, in which the values increased progressively.

Validation of the Personality Assessment Inventory (PAI) scale of scales in a mixed clinical sample.

Objective: This exploratory study examined the classification accuracy of three derived scales aimed at detecting cognitive response bias in neuropsychological samples. The derived scales are composed of existing scales from the Personality Assessment Inventory (PAI). A mixed clinical sample of consecutive outpatients referred for neuropsychological assessment at a large Midwestern academic medical center was utilized. Participants and Methods: Participants included 332 patients who completed study's embedded and free-standing performance validity tests (PVTs) and the PAI. PASS and FAIL groups were created based on PVT performance to evaluate the classification accuracy of the derived scales. Three new scales, Cognitive Bias Scale of Scales 1-3, (CB-SOS1-3) were derived by combining existing scales by either summing the scales together and dividing by the total number of scales summed, or by logistically deriving a variable from the contributions of several scales. Results: All of the newly derived scales significantly differentiated between PASS and FAIL groups. All of the derived SOS scales demonstrated acceptable classification accuracy (i.e. CB-SOS1 AUC = 0.72; CB-SOS2 AUC = 0.73; CB-SOS3 AUC = 0.75). Conclusions: This exploratory study demonstrates that attending to scale-level PAI data may be a promising area of research in improving prediction of PVT failure.

Replication and cross-validation of the personality assessment inventory (PAI) cognitive bias scale (CBS) in a mixed clinical sample.

Objective: This study is a cross-validation of the Cognitive Bias Scale (CBS) from the Personality Assessment Inventory (PAI), a ten-item scale designed to assess symptom endorsement associated with performance validity test failure in neuropsychological samples. The study utilized a mixed neuropsychological sample of consecutively referred patients at a large academic medical center in the Midwest. Participants and Methods: Participants were 332 patients who completed embedded and free-standing performance validity tests (PVTs) and the PAI. Pass and fail groups were created based on PVT performance to evaluate classification accuracy of the CBS. Results: The results were generally consistent with the initial study for overall classification accuracy, sensitivity, and cut-off score. Consistent with the validation study, CBS had better classification accuracy than the original PAI validity scales and a comparable effect size to that obtained in the original validation publication; however, the Somatic Complaints scale (SOM) and the Conversion subscale (SOM-C) also demonstrated good classification accuracy. The CBS had incremental predictive ability compared to existing PAI scales. Conclusions: The results supported the CBS, but further research is needed on specific populations. Findings from this present study also suggest the relationship between conversion tendencies and PVT failure may be stronger in some geographic locations or population types (forensic versus clinical patients).

Diagnosis of coexistent neurodegenerative dementias in multiple sclerosis.

Among people with multiple sclerosis, cognitive impairment occurs commonly and is a potent predictor of disability. Some multiple sclerosis patients present with severe cognitive impairment, and distinguishing multiple sclerosis-related cognitive impairment from co-existent progressive neurodegenerative diseases such as Alzheimer disease poses a diagnostic challenge. The use of biomarkers such as PET and CSF proteins may facilitate this distinction. The study was a retrospective, descriptive study on convenience samples of separate cohorts, one of cognitively impaired multiple sclerosis patients evaluated on autopsy to demonstrate coincidence of both multiple sclerosis and neurodegenerative cognitive diseases. The second cohort were cognitively impaired multiple sclerosis patients evaluated by biomarker to investigate possible additional neurodegenerative cognitive disorders contributing to the cognitive impairment. We investigated selected biomarkers among 31 severely impaired patients (biomarker cohort) and 12 severely impaired patients assessed at autopsy and selected 24 (23 biomarker cohort, 1 autopsy cohort) had comprehensive neurocognitive testing. Biomarker cohort investigations included 18F-Fluorodeoxyglucose PET and/or CSF amyloid Aß1-42, phospho-tau and total tau levels. The autopsy cohort was evaluated with comprehensive neuropathological assessment for aetiology of cognitive impairment. The cohorts shared similar sex, age at multiple sclerosis onset and multiple sclerosis clinical course. The autopsy-cohort patients were older at diagnosis (69.5 versus 57 years, P = 0.006), had longer disease duration [median (range) 20 years (3-59) versus 9 (1-32), P = 0.001] and had more impaired bedside mental status scores at last follow-up [Kokmen median (range) 23 (1-38) versus 31 (9-34) P = 0.01]. Autopsy-cohort patients confirmed, or excluded, coexistent neurogenerative disease by neuropathology gold standard. Most biomarker-cohort patients had informative results evaluating coexistent neurogenerative disease. Biomarkers may be useful in indicating a coexistent neurodegenerative disease earlier, and in life, in patients with multiple sclerosis and significant cognitive impairment.

The Alliance AMBUSH Trial: Rationale and Design.

Unlike medulloblastoma (MB) in children, robust prospective trials have not taken place for older patients due to the low incidence of MB in adults and adolescent and young adults (AYA). Current MB treatment paradigms for older patients have been extrapolated from the pediatric experience even though questions exist about the applicability of these approaches. Clinical and molecular classification of MB now provides better prognostication and is being incorporated in pediatric therapeutic trials. It has been established that genomic alterations leading to activation of the sonic hedgehog (SHH) pathway occur in approximately 60% of MB in patients over the age of 16 years. Within this cohort, protein patched homolog (PTCH) and smoothened (SMO) mutations are commonly found. Among patients whose tumors harbor the SHH molecular signature, it is estimated that over 80% of patients could respond to SHH pathway inhibitors. Given the advances in the understanding of molecular subgroups and the lack of robust clinical data for adult/AYA MB, the Alliance for Clinical Trial in Oncology group developed the AMBUSH trial: Comprehensive Management of AYA and Adult Patients with Medulloblastoma or Pineal Embryonal Tumors with a Randomized Placebo Controlled Phase II Focusing on Sonic Hedgehog Pathway Inhibition in SHH Subgroup Patients (Adult & Adolescent MedulloBlastoma Using Sonic Hedgehog Trial). This trial will enroll patients 18 years of age or older with MB (any molecular subgroup and risk stratification) or pineal embryonal tumor. Patients will be assigned to one of three cohorts: (1) average risk non-SHH-MB, (2) average risk SHH-MB, and (3) high risk MB or pineal embryonal tumors. All patients will receive protocol-directed comprehensive treatment with radiation therapy and chemotherapy. Patients with SHH-MB in cohort 1 will be randomized to a smoothened inhibitor or placebo as maintenance therapy for one year.