Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

A comprehensive screening of copy number variability in dementia with Lewy bodies.

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.

Copy number loss in SFMBT1 is common among Finnish and Norwegian patients with iNPH.

OBJECTIVE: To evaluate the role of the copy number loss in SFMBT1 in a Caucasian population. METHODS: Five hundred sixty-seven Finnish and 377 Norwegian patients with idiopathic normal pressure hydrocephalus (iNPH) were genotyped and compared with 508 Finnish elderly, neurologically healthy controls. The copy number loss in intron 2 of SFMBT1 was determined using quantitative PCR. RESULTS: The copy number loss in intron 2 of SFMBT1 was detected in 10% of Finnish (odds ratio [OR] = 1.9, p = 0.0078) and in 21% of Norwegian (OR = 4.7, p < 0.0001) patients with iNPH compared with 5.4% in Finnish controls. No copy number gains in SFMBT1 were detected in patients with iNPH or healthy controls. The carrier status did not provide any prognostic value for the effect of shunt surgery in either population. Moreover, no difference was detected in the prevalence of hypertension or T2DM between SFMBT1 copy number loss carriers and noncarriers. CONCLUSIONS: This is the largest and the first multinational study reporting the increased prevalence of the copy number loss in intron 2 of SFMBT1 among patients with iNPH, providing further evidence of its role in iNPH. The pathogenic role still remains unclear, requiring further study.

Molecular alterations in pediatric brainstem gliomas.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis. Previously, diagnosis was based on a typical clinical presentation and magnetic resonance imaging findings. After the start of the era of biopsies, DIPGs bearing H3 K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group. METHODS: We studied tumor samples obtained at diagnosis or upon autopsy from 23 children, including two long-term survivors. Based on clinical, radiological, and histological findings, all tumors were previously diagnosed as DIPGs. All samples were analyzed for genetic alterations by next-generation sequencing (NGS) and for protein expression by immunohistochemistry (IHC). RESULTS: H3 K27 was mutated in NGS or IHC in 20 patients, excluding both long-term survivors. One of these long-term survivors harbored a mutation in IDH1, formerly considered to be an alteration absent in pediatric diffuse brainstem gliomas. Other altered genes in NGS included TP53 (10 patients), MET and PDGFRA (3 patients each), VEGFR and SMARCA4 (2 patients each), and PPARγ, PTEN and EGFR in 1 patient, respectively. IHC revealed cMYC expression in 15 of 24 (63%) of all samples, exclusively in the biopsies. CONCLUSIONS: Eighty-seven percent of the tumors formerly diagnosed as DIPGs could be reclassified as H3 K27-mutated diffuse midline gliomas. Both long-term survivors lacked this alteration. Contrary to former conceptions, IDH1 mutations may occur also in pediatric brainstem gliomas.

The developing management of esthesioneuroblastoma: a single institution experience.

Esthesioneuroblastoma remains a challenging disease because of its rarity, the complexity of surrounding structures, missing opinions of optimal treatment protocol, and complications associated with necessary surgery. Our objective was to analyse the management and outcome of a cohort of patients with esthesioneuroblastoma from 1990 to 2009 in a tertiary medical centre. There were 17 eligible patients (8 males and 9 females) with the median age of 53 years (range 20-75 years). An obvious inconsistency was noted in the management of the various tumours of the present series during the two decades due to a lack of a uniform treatment protocol. The median follow-up time was 57.5 months (range 3-158 months). Nine patients (seven with curative treatment intent) died of the disease with the median time from diagnosis to death of 60 months (range 3-161 months). Eight patients had no evidence of the disease at last follow-up visit (median 76 months, range 24-119 months). Recurrences were documented in seven of the patients. The median time from end of primary treatment to a recurrence was 57 months (range 6-110 months). The 5-year overall survival and disease-free survival was 68 and 62%, respectively. The management of ENB should be planned by an experienced head and neck surgeon as part of a multidisciplinary team in a tertiary referral setting. Multimodality therapy with long-term follow-up is preferable and should be set based on the available disease-specific classifications for clinical staging and histopathological grading.

MRI-validation of SEP monitoring for ischemic events during microsurgical clipping of intracranial aneurysms.

OBJECTIVE: During surgical clipping of intracranial aneurysms, reduction in SEP amplitude is thought to indicate cortical ischemia and subsequent neurological deficits. Since the sensitivity of SEP is questioned, we investigated SEP with respect to post-operative ischemia. METHODS: In 36 patients with 51 intracranial aneurysms, clinical evaluation and diffusion-weighted MRI (DWI) was performed before and within 24h after surgery. During surgery, time of temporary occlusion was recorded. MRI images were reviewed for signs of ischemia. RESULTS: For 43 clip applications (84%), we observed neither pathologic SEP events nor ischemia in MRI. In two cases where reduction lasted >10 min after clip release, SEP events correlated with ischemia in the MRI. Only one of the ischemic patients was symptomatic and developed a transient hemiparesis. CONCLUSIONS: While pathologic SEP events correlated with visible ischemia in MRI only in two cases with late SEP recovery, ischemia in MRI may have been transient or may not have reached detection threshold in the other cases, in agreement with the absence of permanent neurological deficits. SIGNIFICANCE: In complex aneurysm cases, where prolonged temporary occlusion is expected, SEP should be used to detect ischemia at a reversible stage to improve the safety of aneurysm clipping.

The impact of minimizing brain retraction in aneurysm surgery: evaluation using magnetic resonance imaging.

BACKGROUND: Recent advances in skull base and microsurgical techniques minimize the need for brain retraction. OBJECTIVE: We studied the impact of such techniques in 36 patients (51 aneurysms) using magnetic resonance imaging (MRI). METHODS: Preoperative and 24 hours postoperative MR imaging was performed in patients undergoing microsurgical clipping of intracranial aneurysms. Images were evaluated for parenchymal signal changes. During surgery, use and time of brain retraction were recorded. The degree of cortical injury was quantified using a 0 to 3 scale (grade 0 = normal surface; 1 = pial/arachnoidal damage; 2 = gray matter injury; 3 = contusion/necrosis). RESULTS: Brain retraction by use of a brain spatula was used in all patients. Retraction times ranged from 14 to 290 minutes (mean, 84.1). Cortical surface changes were grade 0 in 86% and grade 1 in 14%; none showed grade 2 or 3 changes. In the postoperative MRI, 4 patients presented with parenchymal alterations, 4 with edema (11.1%), and 1 patient had additional contusion (2.8%). All lesions were confined to the temporal pole. The grade of cortical surface changes was not related to lesions found on MR imaging. No patients showed retraction-related neurological deficits. CONCLUSION: The incidence of evident mechanical parenchymal injury (infarction or contusion) is very low when appropriate microsurgical and skull base techniques are used. Minor pia-arachnoid injury should nevertheless continue to be attended through future advances.

Symptomatic and silent ischemia associated with microsurgical clipping of intracranial aneurysms: evaluation with diffusion-weighted MRI.

BACKGROUND AND PURPOSE: Silent ischemic events are known to occur during diagnostic and interventional endovascular procedures between 10% and 69% of the time. The occurrence of silent and symptomatic ischemic events in the surgically treated population is not known, although atherosclerotic changes of intracranial vessels or within the aneurysms wall or neck area are seen often during surgery. METHODS: Patients with unruptured and ruptured intracranial aneurysms treated by microsurgical clipping were prospectively evaluated with MRI using diffusion-weighted imaging sequences before and within 24 hours after surgery. Patients were evaluated clinically before and after surgery. During surgery, the overall and maximal time of temporary occlusion as well as the total number of temporary and finally applied clips was noted. Diffusion-weighted images were analyzed with determination and characterization of diffusion-weighted imaging abnormalities. RESULTS: Thirty-six patients with 51 aneurysms were included. One symptomatic and 5 silent ischemic lesions were found in 5 patients. This represents a risk of silent ischemia of 9.8% per treated aneurysm and a risk of symptomatic stroke of 2%. The most significant risk factor in increasing order was: age (P<0.05), presence of thrombus (P<0.05), number of final clips applied (P<0.05), number of temporary clips used (P<0.01), total time of temporary clip occlusion (P<0.001), and maximal time of temporary occlusion (P<0.001). CONCLUSIONS: The risk of silent and symptomatic ischemic events during microsurgical clipping of intracranial aneurysms seems to be low. Microsurgical clipping is safe and should continue to be strongly considered as a treatment option.