Diagnostic accuracy of virtual cognitive assessment and testing: Systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: Virtual (i.e., telephone or videoconference) care was broadly implemented because of the COVID-19 pandemic. Our objectives were to compare the diagnostic accuracy of virtual to in-person cognitive assessments and tests and barriers to virtual cognitive assessment implementation. DESIGN: Systematic review and meta-analysis. SETTING: MEDLINE, EMBASE, CDSR, CENTRAL, PsycINFO, and gray literature (inception to April 1, 2020). PARTICIPANTS AND INTERVENTIONS: Studies describing the accuracy or reliability of virtual compared with in-person cognitive assessments (i.e., reference standard) for diagnosing dementia or mild cognitive impairment (MCI), identifying virtual cognitive test cutoffs suggestive of dementia or MCI, or describing correlations between virtual and in-person cognitive test scores in adults. MEASUREMENTS: Reviewer pairs independently conducted study screening, data abstraction, and risk of bias appraisal. RESULTS: Our systematic review included 121 studies (15,832 patients). Two studies demonstrated that virtual cognitive assessments could diagnose dementia with good reliability compared with in-person cognitive assessments: weighted kappa 0.51 (95% confidence interval [CI] 0.41-0.62) and 0.63 (95% CI 0.4-0.9), respectively. Videoconference-based cognitive assessments were 100% sensitive and specific for diagnosing dementia compared with in-person cognitive assessments in a third study. No studies compared telephone with in-person cognitive assessment accuracy. The Telephone Interview for Cognitive Status (TICS; maximum score 41) and modified TICS (maximum score 50) were the only virtual cognitive tests compared with in-person cognitive assessments in >2 studies with extractable data for meta-analysis. The optimal TICS cutoff suggestive of dementia ranged from 22 to 33, but it was 28 or 30 when testing was conducted in English (10 studies; 1673 patients). Optimal modified TICS cutoffs suggestive of MCI ranged from 28 to 31 (3 studies; 525 patients). Sensory impairment was the most often voiced condition affecting assessment. CONCLUSION: Although there is substantial evidence supporting virtual cognitive assessment and testing, we identified critical gaps in diagnostic certainty.

Comparative efficacy of interventions for reducing symptoms of depression in people with dementia: systematic review and network meta-analysis.

OBJECTIVE: To describe the comparative efficacy of drug and non-drug interventions for reducing symptoms of depression in people with dementia who experience depression as a neuropsychiatric symptom of dementia or have a diagnosis of a major depressive disorder. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, the Cochrane Library, CINAHL, PsycINFO, and grey literature between inception and 15 October 2020. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised trials comparing drug or non-drug interventions with usual care or any other intervention targeting symptoms of depression in people with dementia. MAIN OUTCOME MEASURES: Pairs of reviewers screened studies, abstracted aggregate level data, and appraised risk of bias with the Cochrane risk of bias tool, which facilitated the derivation of standardised mean differences and back transformed mean differences (on the Cornell scale for depression in dementia) from bayesian random effects network meta-analyses and pairwise meta-analyses. RESULTS: Of 22 138 citations screened, 256 studies (28 483 people with dementia) were included. Missing data posed the greatest risk to review findings. In the network meta-analysis of studies including people with dementia without a diagnosis of a major depressive disorder who were experiencing symptoms of depression (213 studies; 25 177 people with dementia; between study variance 0.23), seven interventions were associated with a greater reduction in symptoms of depression compared with usual care: cognitive stimulation (mean difference -2.93, 95% credible interval -4.35 to -1.52), cognitive stimulation combined with a cholinesterase inhibitor (-11.39, -18.38 to -3.93), massage and touch therapy (-9.03, -12.28 to -5.88), multidisciplinary care (-1.98, -3.80 to -0.16), occupational therapy (-2.59, -4.70 to -0.40), exercise combined with social interaction and cognitive stimulation (-12.37, -19.01 to -5.36), and reminiscence therapy (-2.30, -3.68 to -0.93). Except for massage and touch therapy, cognitive stimulation combined with a cholinesterase inhibitor, and cognitive stimulation combined with exercise and social interaction, which were more efficacious than some drug interventions, no statistically significant difference was found in the comparative efficacy of drug and non-drug interventions for reducing symptoms of depression in people with dementia without a diagnosis of a major depressive disorder. Clinical and methodological heterogeneity precluded network meta-analysis of studies comparing the efficacy of interventions specifically for reducing symptoms of depression in people with dementia and a major depressive disorder (22 studies; 1829 patients). CONCLUSIONS: In this systematic review, non-drug interventions were found to be more efficacious than drug interventions for reducing symptoms of depression in people with dementia without a major depressive disorder. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017050130.

Safety of pharmacologic interventions for neuropsychiatric symptoms in dementia: a systematic review and network meta-analysis.

BACKGROUND: Prescribing trends suggest that pharmacologic alternatives to antipsychotics are gaining in popularity, but randomized trial (RCT) data of their comparative safety is scarce. Our objective was to describe the comparative safety of pharmacologic interventions for treating neuropsychiatric symptoms in dementia. METHODS: We searched MEDLINE, EMBASE, CENTRAL, CINAHL, and PsycINFO, from inception to May 28, 2019, for studies of pharmacologic interventions used to treat neuropsychiatric symptoms in dementia. Dementia care partners selected fracture risk as our primary outcome. Pairs of reviewers, working independently, conducted all study screening, data abstraction, and risk of bias appraisal. We conducted Bayesian random-effects network meta-analyses (NMAs) using data from RCTs to derive odds ratios (ORs). In secondary analyses, we conducted frequentist random-effects NMAs using data from RCTs and Bayesian three-level hierarchical random-effects NMAs incorporating data from RCTs and non-randomized studies. RESULTS: Our systematic review included 209 randomized and non-randomized studies (889,378 persons with dementia). In NMAs of data from randomized trials, there were no increased odds of fracture associated with any intervention in primary analyses; however, data were sparse. We found increased odds of cerebrovascular events associated with antipsychotics (odds ratio [OR] 2.12, 95% credible interval [CrI] 1.29 to 3.62; number needed to harm [NNH] = 99) and increased odds of falls associated with dextromethorphan-quinidine (OR 4.16, 95% CrI 1.47 to 14.22; NNH = 55) compared to placebo in persons with dementia. In a subgroup of persons with Alzheimer disease, antipsychotics were associated with increased odds of fracture compared to anticonvulsants (OR 54.1, 95% CrI 1.15 to 38,300; NNH = 18). In older persons (mean age ≥ 80 years) with dementia, anticonvulsants were associated with increased odds of death compared to placebo (OR 8.36, 95% CrI 1.17 to 203.4; NNH = 35) and antipsychotics were associated with increased odds of death compared to antidepressants (OR 5.28, 95% CrI 1.06 to 3.51; NNH = 47). CONCLUSION: Although antipsychotics were associated with greater harm than antidepressants and anticonvulsants in subgroups of persons with dementia, medications used in lieu of antipsychotics for treating neuropsychiatric symptoms in dementia, such as anticonvulsants and dextromethorphan-quinidine, were also associated with harm. Decision-making concerning treatments prescribed in lieu of antipsychotics should include potential harms. PROSPERO REGISTRATION: CRD42017050130.

Comparative Efficacy of Interventions for Aggressive and Agitated Behaviors in Dementia: A Systematic Review and Network Meta-analysis.

Background: Both pharmacologic and nonpharmacologic interventions are used to treat neuropsychiatric symptoms in persons with dementia. Purpose: To summarize the comparative efficacy of pharmacologic and nonpharmacologic interventions for treating aggression and agitation in adults with dementia. Data Sources: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, and PsycINFO between inception and 28 May 2019 without language restrictions; gray literature; and reference lists scanned from selected studies and systematic reviews. Study Selection: Randomized controlled trials comparing interventions for treating aggression and agitation in adults with dementia. Data Extraction: Pairs of reviewers independently screened studies, abstracted data, and appraised risk of bias. Data Synthesis: After screening of 19 684 citations, 163 studies (23 143 patients) were included in network meta-analyses. Analysis of interventions targeting aggression and agitation (148 studies [21 686 patients]) showed that multidisciplinary care (standardized mean difference [SMD], -0.5 [95% credible interval {CrI}, -0.99 to -0.01]), massage and touch therapy (SMD, -0.75 [CrI, -1.12 to -0.38]), and music combined with massage and touch therapy (SMD, -0.91 [CrI, -1.75 to -0.07]) were clinically more efficacious than usual care. Recreation therapy (SMD, -0.29 [CrI, -0.57 to -0.01]) was statistically but not clinically more efficacious than usual care. Limitations: Forty-six percent of studies were at high risk of bias because of missing outcome data. Harms and costs of therapies were not evaluated. Conclusion: Nonpharmacologic interventions seemed to be more efficacious than pharmacologic interventions for reducing aggression and agitation in adults with dementia. Primary Funding Source: Alberta Health Services Critical Care Strategic Clinical Network. (PROSPERO: CRD42017050130).

A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases.

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling.

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1). Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.

Intertumoral Heterogeneity within Medulloblastoma Subgroups.

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

Spatial heterogeneity in medulloblastoma.

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

Divergent clonal selection dominates medulloblastoma at recurrence.

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

Posterior fossa ependymoma: current insights.

BACKGROUND: Ependymoma is the third most common malignant tumor of the posterior fossa and is a major cause of neurological morbidity and mortality in children. Current treatments, particularly surgery and external beam irradiation result in relatively poor outcomes with significant neurological and cognitive sequelae from treatment. Historical approaches have considered all ependymomas as similar entities based on their morphological appearance. RESULTS: Recent advances in genomics and epigenetics have revealed, however, that ependymomas from different CNS locations represent distinct entities. Moreover, ependymoma of the posterior fossa, the most common location in children, is actually comprised of two distinct molecular variants. These two variants have marked differences in demographics, transcriptomes, structure, methylation patterns, and clinical outcomes. This allows for the development of new biology-based clinical risk stratification, which can both prioritize patients for de-escalation of therapy and identify those who will benefit from novel therapeutic strategies. Indeed, the identification of these two variants allows an opportunity for robust preclinical modeling for development of novel therapeutic strategies. CONCLUSIONS: Herein, we have summarized our current clinical approach to diagnosis and treatment of posterior fossa ependymoma, recent advances in understanding the biology of posterior fossa ependymoma and how these new insights can be translated into the clinic to form the basis of the next generation of clinical trials.

Spinal Myxopapillary Ependymomas Demonstrate a Warburg Phenotype.

PURPOSE: Myxopapillary ependymoma (MPE) is a distinct histologic variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently, the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. EXPERIMENTAL DESIGN: Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling was done on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumor lysates consisting of assays measuring pyruvate kinase M activity (PKM), hexokinase activity (HK), and lactate production. RESULTS: At a gene expression level, we demonstrate that spinal grade II and MPE are molecularly and biologically distinct. These are supported by specific copy number alterations occurring in each histologic variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with upregulation of HIF1α. These findings were validated by Western blot analysis demonstrating increased protein expression of HIF1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. CONCLUSIONS: Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small-molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE.