Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer’s Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer’s disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7

ABSTRACTLimited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer’s Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/nearCR1,BIN1,TREM2,CD2AP,PTK2B,CLU,SHARPIN,MS4A6A,PICALM,ABCA7,APOEand two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). Reflecting the power of diverse ancestry in GWAS, we observed theSHARPINlocus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near (PTPRK(P=2.4×10-8) andGRB14(P=1.7×10-8) in HIS), andKIAA0825(P=2.9×10-8in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest withPadjusted=1.6×10-4) and the classical complement pathway (Padjusted=1.3×10-3). Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, andPTPRK) and insulin receptor activity regulation (GRB14). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Background Carotid body tumors (CBTs) are rare neuroendocrine neoplasms arising near the carotid bifurcation with a reported incidence of 1 to 2 cases in 100,000 patients. Most CBTs are sporadic, benign, slow-growing, and non-secreting, but untreated CBTs can grow locally to compress the nearby blood vessels, esophagus, and airway. Regional metastases can occur in 5% to 10% of cases, but distant metastases are exceedingly rare, occurring in roughly 1–2% of cases. As such, the optimal treatment for metastatic CBTs is not well-defined. We report a rare case of a patient with CBT distant metastases causing spinal cord compression. Case presentation A 40-year-old African American female presented with a right neck mass, headaches, vertigo, tinnitus, hoarseness, and dysphagia. Imaging demonstrated a Shamblin II right neck mass; subsequent transcervical resection and pathology showed a carotid body paraganglioma. The patient recurred locally near the carotid bifurcation, so she underwent Stereotactic Body Radiation Therapy to the recurrent right neck disease. She later re-presented with new onset bilateral lower extremity weakness, dysmetria, and numbness. She was found to have metastatic disease to the thoracic spine causing spinal cord compression. She underwent laminectomy, tumor resection, and posterior fixation followed by adjuvant radiation therapy. She was started on systemic therapy with sunitinib. She eventually progressed with metastatic disease to the right iliac bone, which was treated with palliative radiotherapy. Second line systemic therapy with capecitabine and temozolomide was started. At last follow up, the patient was asymptomatic with stable persistent disease. Conclusions Paragangliomas often exhibit a prolonged interval to the development of progression; locoregional recurrences or rare distant metastases have been reported to occur as many as 20 years from diagnosis. The natural course of CBTs in other cases as well as the present case call into question the idea that CBTs are truly benign; instead CBTs may be indolent tumors with metastatic potential. Treatment choices for CBTs include surgical resection, radiation therapy, and systemic therapy, though the optimal treatment regimen for metastatic CBTs is not well-defined. A more advanced understanding of CBT pathophysiology, disease classification, risk stratification, and treatment options is needed to improve outcomes for patients.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near (PTPRK (P=2.4E10-8) and GRB14 (P=1.7E10-8) in HIS), and KIAA0825 (P=2.9E10-8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with Padjusted=1.6E10-4) and the classical complement pathway (Padjusted=1.3E10-3). Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

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Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease. We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Patient: Male, 44 Final Diagnosis: Cerebral toxoplasmosis after HSCT Symptoms: Hemiparesis • muscle weakness Medication: — Clinical Procedure: — Specialty: Hematology Objective: Unusual clinical course Background: Toxoplasmosis is an uncommon but potentially fatal complication following allogeneic hematopoietic stem cell transplantation (HCT). Post-transplant toxoplasmosis is often a reactivation of prior infection and typically occurs within the first 6 months of transplant. Herein, we report that cerebral toxoplasmosis may occur 22 months after allogeneic hematopoietic stem cell transplantation. Case Report: We describe a case of cerebral toxoplasmosis that occurred 22 months after an allogeneic HCT while the patient was on aerosolized pentamidine for Pneumocystis jiroveci pneumonia (PCP) prophylaxis. The disease was only diagnosed after brain biopsy because of atypical MRI appearance of the cerebral lesion and negative Toxoplasma gondii IgG antibody test result in the cerebrospinal fluid (CSF). The patient received pyrimethamine and sulfadiazine treatment, with dramatic improvement after several months. The patient is alive 2 years after infection diagnosis, with no evidence of disease and is off Toxoplasma prophylaxis. Conclusions: Cerebral toxoplasmosis can occur late after allogeneic HCT while patients are on immunosuppression therapy, with atypical features on imaging studies and negative Toxoplasma gondii IgG antibody test result in the CSF. Pre-transplant serologic screening for T. gondii antibodies in allogeneic transplant candidates is warranted. Brain biopsy can be a helpful diagnostic tool for cerebral lesions.

IMPORTANCE:Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States. OBJECTIVE:To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden. DESIGN, SETTING, AND PARTICIPANTS:Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources. MAIN OUTCOMES AND MEASURES:Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies). RESULTS:The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673. CONCLUSIONS AND RELEVANCE:The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations.

Pleomorphic xanthoastrocytoma (PXA) is an uncommon low grade astrocytic tumor and molecular alterations commonly observed in other WHO grade II gliomas, such as TP53 mutation, EGFR amplification, 1p19q deletion, are rarely seen. A 25-year-old woman experienced generalized seizures; a left temporal lesion in was identified in 2001. Resections were performed in 2004 and 2011 with a diagnosis of PXA, WHO grade II. The patient was treated with radiation and chemotherapy, but recurrence was found in 2013. The pathology of the craniotomy resection showed tumor necrosis and increased proliferation index (25% by Ki-67), and the diagnosis of PXA with anaplastic features exhibiting leptomeningeal infiltration was rendered, which likely represented malignant transformation. Targeted next-generation sequencing analysis was performed at Genomic Pathology Service (Washington University). A potentially actionable BRAF gene mutation (p.V600E) as well as potentially relevant TP53 gene p.R158H mutation was identified. The patient is on Vemurafenib and the lesion is stable on MRI. PXA has been shown to have BRAF mutations in 60–70% of cases. PXA with anaplastic features is a rare entity and has significantly worse prognosis. Vemurafenib is suggested to cross the blood-brain barrier and the patients with BRAF mutated brain tumors would benefit from BRAF targeted therapies. Pleomorphic xanthoastrocytoma (PXA) is an uncommon low grade astrocytic tumor and molecular alterations commonly observed in other WHO grade II gliomas, such as TP53 mutation, EGFR amplification, 1p19q deletion, are rarely seen. A 25-year-old woman experienced generalized seizures; a left temporal lesion in was identified in 2001. Resections were performed in 2004 and 2011 with a diagnosis of PXA, WHO grade II. The patient was treated with radiation and chemotherapy, but recurrence was found in 2013. The pathology of the craniotomy resection showed tumor necrosis and increased proliferation index (25% by Ki-67), and the diagnosis of PXA with anaplastic features exhibiting leptomeningeal infiltration was rendered, which likely represented malignant transformation. Targeted next-generation sequencing analysis was performed at Genomic Pathology Service (Washington University). A potentially actionable BRAF gene mutation (p.V600E) as well as potentially relevant TP53 gene p.R158H mutation was identified. The patient is on Vemurafenib and the lesion is stable on MRI. PXA has been shown to have BRAF mutations in 60–70% of cases. PXA with anaplastic features is a rare entity and has significantly worse prognosis. Vemurafenib is suggested to cross the blood-brain barrier and the patients with BRAF mutated brain tumors would benefit from BRAF targeted therapies.

Whipple disease (WD) is usually a systemic infectious disease that can have central nervous system (CNS) involvement. WD confined to the CNS is extremely rare and difficult to diagnose, but can be fatal if not treated in a timely fashion. We present the case of a 42-year-old man with a subacute dementia accompanied by a movement disorder consisting of progressive supranuclear gaze palsy, myoclonus, and ataxia. Our patient lacked the typical magnetic resonance imaging (MRI) findings reported with isolated CNS WD and had a false-positive cerebrospinal fluid (CSF) 14-3-3 protein. The patient expired, and definitive diagnosis of isolated CNS WD was made by autopsy with characteristic macrophage accumulations found in the brain but not in the gastrointestinal tract. We examine the literature on isolated CNS WD and discuss how these previously unreported findings make a rare diagnosis even more challenging. The reported patient is the first in the literature with tissue diagnosis of isolated CNS WD in the setting of normal brain MRI and positive CSF 14-3-3 protein. Isolated CNS WD should be added to the list of considerations for a false-positive CSF 14-3-3 protein. Even in the absence of typical MRI lesions, a patient with subacute progressive dementia, supranuclear gaze palsy, and other various neurologic abnormalities should have the diagnosis of isolated CNS WD considered.

Gerard Schellenberg and colleagues report a genome-wide association study of late-onset Alzheimer's disease (LOAD), as part of the Alzheimer Disease Genetics Consortium. They identify common variants in MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 associated with LOAD. The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (PM) = 1.7 × 10−9, joint analysis P (PJ) = 1.7 × 10−9; stages 1, 2 and 3, PM = 8.2 × 10−12), CD2AP (rs9349407; stages 1, 2 and 3, PM = 8.6 × 10−9), EPHA1 (rs11767557; stages 1, 2 and 3, PM = 6.0 × 10−10) and CD33 (rs3865444; stages 1, 2 and 3, PM = 1.6 × 10−9). We also replicated previous associations at CR1 (rs6701713; PM = 4.6 × 10−10, PJ = 5.2 × 10−11), CLU (rs1532278; PM = 8.3 × 10−8, PJ = 1.9 × 10−8), BIN1 (rs7561528; PM = 4.0 × 10−14, PJ = 5.2 × 10−14) and PICALM (rs561655; PM = 7.0 × 10−11, PJ = 1.0 × 10−10), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility1,2,3.

Although 1p/19q codeletions define “genetically favorable” oligodendrogliomas, eventual tumor progression and patient death remain constant. Genetic testing is often performed at the time of recurrence, though it is unclear whether these or other genetic alterations provide useful prognostic information. We characterized 138 of 189 (73%) available primary and recurrent oligodendroglial neoplasms from 80 patients, utilizing paired FISH probes for 1p32/1q42, 19p13/19q13, CEP7/ EGFR, CEP9/p16, and PTEN/DMBT1. Patients were followed until death (49%), or a median follow-up of 8.9 years. Patients with 1p/19q codeleted tumors (71%) had an estimated overall median survival of 14.9 years with an estimated 3.9 years from first recurrence. In contrast, those lacking deletions had significantly lower estimated overall median survivals of 4.7 years and 1.0 year after first recurrence (both p < 0.001). This increased survival in patients with 1p/19q codeleted tumors remained significant when adjustments were made for age, tumor grade, type of surgical procedure, and treatment with radiation or chemotherapy. Only 1 recurrence showed focal EGFR amplification, while 5 developed 10q deletions, mostly in high-grade mixed oligoastrocytomas lacking 1p/19q deletions. In contrast, p16 (9p21) deletions were common and associated with both high grade (p < 0.001) and recurrence (p = 0.002). Our data suggest that in classic oligodendrogliomas: 1) 1p/19q tumor status is a powerful predictor of patient survival, even after recurrence; 2) p16 deletions are common progression-associated alterations; and 3) 10q deletions and EGFR amplifications are sufficiently rare to suggest the possibility of alternate diagnoses.

Neuregulin-1 (NRG-1) proteins, acting through their erbB receptors, promote the differentiation, survival and/or proliferation of many cell types in the developing nervous system, including neural crest cells and neural crest-derived Schwann cells. We have recently found that the proliferation of a neoplastic Schwann cell line is dependent on constitutive activation of the NRG-1/erbB signaling pathway and that overexpression of NRG-1 in myelinating Schwann cells induces the formation of malignant peripheral nerve sheath tumors. These observations suggested that NRG-1 might similarly promote mitogenesis in a variety of neural neoplasms including peripheral neuro-epitheliomas, aggressive neural crest-derived neoplasms that arise in nerves and soft tissues. To test this hypothesis, we examined the expression of NRG-1 and its erbB receptors in SK-N-MC neuroepithelioma cells. SK-N-MC cells expressed multiple NRG-1 proteins and mRNAs encoding several α and β isoforms from the sensory and motor neuron-derived factor NRG-1 subfamily as well as the NRG-1 receptor subunits erbB2, erbB3, and erbB4. The erbB receptors expressed by SK-N-MC cells were constitutively tyrosine phosphorylated and inhibiting these kinases with the erbB specific inhibitor PD158780 reduced SK-N-MC DNA synthesis in a dose-dependent manner. We conclude that constitutive activation of the NRG-1/erbB signaling pathway promotes the proliferation of SK-N-MC neuroepithelioma cells in vitro and hypothesize that NRG-1/erbB autocrine, paracrine or juxtacrine signaling may contribute to the development and/or progression of neuroepitheliomas in vivo.

Intravascular malignant lymphomatosis (IML) is a lymphoma, usually of B-cell phenotype, confined to intravascular spaces. IML is a relatively rare disease that is usually diagnosed at autopsy. We report a biopsy-proven case and review 15 published cases that were diagnosed antemortem by muscle, nerve biopsy, or both.