Volumetric growth rate of incidental asymptomatic meningiomas: a single-center prospective cohort study.

BACKGROUND: Decision about treatment of incidentally found intracranial meningiomas is controversial and conditioned by the growth potential of these tumors. We aimed to evaluate the growth rate of a cohort of incidentally found asymptomatic meningiomas and to analyze their natural course and the need for eventual treatment. METHODS: A total of 193 patients harboring intracranial meningiomas (85 with 109 incidental and 108 with 112 symptomatic) were included between 2015 and 2019. In the prospective cohort of incidental meningiomas, we measured size at diagnosis, volumetric growth rate (by segmentation software), appearance of symptoms, and need for surgery or radiotherapy. Progression-free survival and risk factors for growth were assessed with Kaplan-Meier survival and Cox regression analyses. RESULTS: Among incidental meningiomas, 94/109 (86.2%) remained untreated during a median follow-up of 49.3 months. Tumor growth was observed in 91 (83.5%) and > 15% growth in 40 (36.7%). Neurological symptoms developed in 1 patient (1.2%). Volume increased an average of 0.51 cm3/year (95% CI, 0.20-0.82). Nine patients were operated (9.2%) and 4 underwent radiotherapy (4.7%). Treatment-related complication rates of incidental and symptomatic meningiomas were 0% and 35.4%, respectively. Persistent neurological defects occurred in 46 (40.7%) of symptomatic versus 2 (2.3%) of incidental meningiomas. Among covariates, only brain edema resulted in an increased risk of significant tumor growth in the female subgroup (Cox regression HR 2.96, 95% CI 1.02-8.61, p = 0.046). Size at diagnosis was significantly greater in the symptomatic meningioma group (37.33 cm3 versus 4.74 cm3, p < 0.001). CONCLUSIONS: Overall, 86% of incidentally found meningiomas remained untreated over the first 4 years of follow-up. The majority grew within the 20% range, yet very few developed symptoms. Treatment-related morbidity was absent in the incidental meningioma group.

Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor.

Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole-exome sequencing and targeted resequencing in three ET families. In vitro and in vivo experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole-exome sequencing revealed a missense mutation in TENM4 segregating in an autosomal-dominant fashion in an ET family. Subsequent targeted resequencing of TENM4 led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic TENM4 alleles across the three families. Consistent with a dominant mode of inheritance, in vitro analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a Tenm4 knockout mouse displaying an ET phenotype, implicates TENM4 in ET. Together with previous studies of TENM4 in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorder.

Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease.

Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD.

Delta-amino-levulinic acid dehydratase gene and essential tremor.

BACKGROUND: Several reports found a relationship between increased serum lead levels and the risk for essential tremor (ET), especially in carriers of the minor allele of the single nucleotide polymorphism (SNP) rs1800435 in the aminolevulinate dehydratase (ALAD) gene, which is involved in the synthesis of haem groups. Our group reported decreased risk for ET in carriers of the minor alleles of the rs2071746 and rs1051308 SNPs in the haem-oxygenases 1 and 2 (HMOX1 and HMOX2), respectively, involved in haem metabolism. We analysed whether ALAD rs1800435 alone and their interactions with the four common SNPs in the HMOX1 and HMOX2 genes are associated with the risk for ET. MATERIALS AND METHODS: We analysed the genotype and allele variants frequencies of ALAD rs1800435 in 202 patients with familial ET and 218 healthy controls using a TaqMan method. We also analysed the role of the interaction between ALAD rs1800435 and the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363 and HMOX2 rs1051308 with the risk of developing ET. RESULTS: The frequencies of genotype and allelic variants of ALAD rs1800435 did not differ significantly between patients with ET and controls, and were not influenced by gender. Subjects carrying the ALAD rs1800435CC genotype (wild-type) and the HMOX2 rs1051308GG genotype or the HMOX2 rs1051308G allele had significantly decreased risk for ET. CONCLUSIONS: These results suggest that the ALAD rs1800435 SNP is not related with the risk for ET, but its interaction with the HMOX2 rs1051308 SNP could be weakly associated with the risk for this disease.

Thr105Ile (rs11558538) polymorphism in the histamine-1-methyl-transferase (HNMT) gene and risk for restless legs syndrome.

A recent meta-analysis suggests an association between the rs11558538 single nucleotide polymorphism in the histamine-N-methyl-transferase (HNMT) gene and the risk for Parkinson's disease. Based on the possible relationship between PD and restless legs syndrome (RLS), we tried to establish whether rs11558538 SNP is associated with the risk for RLS. We studied the genotype and allelic variant frequencies of HNMT rs11558538 SNP 205 RLS patients and 410 healthy controls using a TaqMan assay. The frequencies of the HNMT rs11558538 genotypes allelic variants were similar between RLS patients and controls, and were not influenced by gender, family history of RLS, or RLS severity. RLS patients carrying the genotype rs11558538TT had an earlier age at onset, but this finding was based on three subjects only. These results suggest a lack of major association between HNMT rs11558538 SNP and the risk for RLS.

Genome-wide association study in essential tremor identifies three new loci.

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.

Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia.

Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotide repeat number and clinical phenotype. Here we characterize, through a new non-radioactive Southern blot protocol, the expansion size range in a series of 38 ALS and 22 FTD heterozygous carriers of >30 copies of the repeat. Maximum, median and modal hexanucleotide repeat number were higher in ALS patients than in FTD patients (P< 0.05 in all comparisons). A higher median number of repeats correlated with a bigger range of repeat sizes (Spearman's ρ = 0.743, P = 1.05 × 10(-11)). We did not find any correlation between age of onset or disease duration with the repeat size in neither ALS nor FTD mutation carriers. Clinical presentation (bulbar or spinal) in ALS patients did not correlate either with the repeat length. We finally analyzed two families with affected and unaffected repeat expansion carriers, compared the size of the repeat expansion between two monozygotic (MZ) twins (one affected of ALS and the other unaffected), and examined the expansion size in two different tissues (cerebellum and peripheral blood) belonging to the same FTD patient. The results suggested that the length of the C9orf72 repeat varies between family members, including MZ twins, and among different tissues from the same individual.

Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies.

Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.

A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease.

The sortilin-related receptor 1 (SORL1) gene has been associated with increased risk for Alzheimer's disease (AD). Rare genetic variants in the SORL1 gene have also been implicated in autosomal dominant early-onset AD (EOAD). Here we report a large-scale investigation of the contribution of genetic variability in SORL1 to EOAD in a European EOAD cohort. We performed massive parallel amplicon-based re-sequencing of the full coding region of SORL1 in 1255 EOAD patients and 1938 age- and origin-matched control individuals in the context of the European Early-Onset Dementia (EOD) consortium, originating from Belgium, Spain, Portugal, Italy, Sweden, Germany, and Czech Republic. We identified six frameshift variants and two nonsense variants that were exclusively present in patients. These mutations are predicted to result in haploinsufficiency through nonsense-mediated mRNA decay, which could be confirmed experimentally for SORL1 p.Gly447Argfs*22 observed in a Belgian EOAD patient. We observed a 1.5-fold enrichment of rare non-synonymous variants in patients (carrier frequency 8.8 %; SkatOMeta p value 0.0001). Of the 84 non-synonymous rare variants detected in the full patient/control cohort, 36 were only detected in patients. Our findings underscore a role of rare SORL1 variants in EOAD, but also show a non-negligible frequency of these variants in healthy individuals, necessitating the need for pathogenicity assays. Premature stop codons due to frameshift and nonsense variants, have so far exclusively been found in patients, and their predicted mode of action corresponds with evidence from in vitro functional studies of SORL1 in AD.

Rare Variants in PLD3 Do Not Affect Risk for Early-Onset Alzheimer Disease in a European Consortium Cohort.

Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole-genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and two splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta-analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (P = 0.43; OR = 1.53, 95% CI 0.60-3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated.

Metabolic patterns in prion diseases: an FDG PET voxel-based analysis.

PURPOSE: Clinical diagnosis of human prion diseases can be challenging since symptoms are common to other disorders associated with rapidly progressive dementia. In this context, (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) might be a useful complementary tool. The aim of this study was to determine the metabolic pattern in human prion diseases, particularly sporadic Creutzfeldt-Jakob disease (sCJD), the new variant of Creutzfeldt-Jakob disease (vCJD) and fatal familial insomnia (FFI). METHODS: We retrospectively studied 17 patients with a definitive, probable or possible prion disease who underwent FDG PET in our institution. Of these patients, 12 were diagnosed as sCJD (9 definitive, 2 probable and 1 possible), 1 was diagnosed as definitive vCJD and 4 were diagnosed as definitive FFI. The hypometabolic pattern of each individual and comparisons across the groups of subjects (control subjects, sCJD and FFI) were evaluated using a voxel-based analysis. RESULTS: The sCJD group exhibited a pattern of hypometabolism that affected both subcortical (bilateral caudate, thalamus) and cortical (frontal cortex) structures, while the FFI group only presented a slight hypometabolism in the thalamus. Individual analysis demonstrated a considerable variability of metabolic patterns among patients, with the thalamus and basal ganglia the most frequently affected areas, combined in some cases with frontal and temporal hypometabolism. CONCLUSION: Patients with a prion disease exhibit a characteristic pattern of brain metabolism presentation in FDG PET imaging. Consequently, in patients with rapidly progressive cognitive impairment, the detection of these patterns in the FDG PET study could orient the diagnosis to a prion disease.

Automated neuromelanin imaging as a diagnostic biomarker for Parkinson's disease.

BACKGROUND: We aimed to analyze the diagnostic accuracy of an automated segmentation and quantification method of the SNc and locus coeruleus (LC) volumes based on neuromelanin (NM)-sensitive MRI (NM-MRI) in patients with idiopathic (iPD) and monogenic (iPD) Parkinson's disease (PD). METHODS: Thirty-six patients (23 idiopathic and 13 monogenic PARKIN or LRRK2 mutations) and 37 age-matched healthy controls underwent 3T-NM-MRI. SNc and LC volumetry were performed using fully automated multi-image atlas segmentation. The diagnostic performance to differentiate PD from controls was measured using the area under the curve (AUC) and likelihood ratios based on receiver operating characteristic (ROC) analyses. RESULTS: We found a significant reduction of SNc and LC volumes in patients, when compared to controls. ROC analysis showed better diagnostic accuracy when using SNc volume than LC volume. Significant differences between ipsilateral and contralateral SNc volumes, in relation to the more clinically affected side, were found in patients with iPD (P = 0.007). Contralateral atrophy in the SNc showed the highest power to discriminate PD subjects from controls (AUC, 0.93-0.94; sensitivity, 91%-92%; specificity, 89%; positive likelihood ratio: 8.4-8.5; negative likelihood ratio: 0.09-0.1 at a single cut-off point). Interval likelihood ratios for contralateral SNc volume improved the diagnostic accuracy of volumetric measurements. CONCLUSION: SNc and LC volumetry based on NM-MRI resulting from the automated segmentation and quantification technique can yield high diagnostic accuracy for differentiating PD from health and might be an unbiased disease biomarker. © 2015 International Parkinson and Movement Disorder Society.

No evidence of association between common European mitochondrial DNA variants in Alzheimer, Parkinson, and migraine in the Spanish population.

Certain mitochondrial DNA (mtDNA) variants and haplogroups have been found to be associated with neurological disorders. Several studies have suggested that mtDNA variation could have an etiologic role in these disorders by affecting the ATP production on high-energy demanding organs, such as the brain. We have analyzed 15 mtDNA SNPs (mtSNPs) in five cohorts of cases presenting Alzheimer disease (AD), Parkinson disease (PD), and migraine, and in controls, to evaluate the role mtDNA variation in disease risk. Association tests were undertaken both for mtSNPs and mitochondrial haplogroups. No significant association was detected for any mtSNP or haplogroup in AD and PD cohorts. Two mtSNPs were associated with one migraine cohort after correcting for multiple tests, namely, T4216C and G13708A and haplogroup J (FDR q-value = 0.02; Santiago's cohort). However, this association was not confirmed in a second replication migraine series. A review of the literature reveals the existence of inconsistent findings and methodological shortcomings affecting a large proportion of mtDNA association studies on AD, PD, and migraine. A detailed inspection of the literature highlights the need for performing more rigorous methodological and statistical standards in mtDNA genetic association studies aimed to avoid false positive results of association between mtDNA variants and neurological diseases.

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.

No association of the SLC1A2 rs3794087 allele with risk for essential tremor in the Spanish population.

BACKGROUND/AIMS: A recent genome-wide association study and other replication studies have suggested that the rs3794087 single nucleotide polymorphism in the solute carrier family 1 - glial affinity glutamate transporter-member 2 (SLC1A2) gene is associated with an increased risk for essential tremor (ET), and a replication study in an Asian cohort has shown a decreased risk for ET associated with the rs3794087T allele. We tried to replicate this association in a White Spanish population. MATERIALS AND METHODS: We analyzed the distribution of allelic and genotypic frequencies of rs3794087 in 202 patients with familial ET and 308 healthy controls using a TaqMan-based quantitative PCR assay. RESULTS: Genotypic and allelic frequencies of rs3794087 did not differ significantly between patients with ET and controls and were unrelated with the age at onset of tremor or sex. CONCLUSION: Our study suggests that SLC1A2 rs3794087 is not associated with the risk for developing familial ET in the Spanish population, thus subtracting relevance to SLC1A2 rs3794087 as a risk biomarker for ET.

Exome-wide rare variant analysis in familial essential tremor.

INTRODUCTION: Essential tremor (ET) is one of the most common movement disorders. Despite its high prevalence and heritability, its genetic etiology remains elusive with only a few susceptibility genes identified and poorly replicated. Our aim was to find novel candidate genes involved in ET predisposition through whole exome sequencing. METHODS: We studied eight multigenerational families (N = 40 individuals) with an autosomal-dominant inheritance using a comprehensive strategy combining whole exome sequencing followed by case-control association testing of prioritized variants in a separate cohort comprising 521 ET cases and 596 controls. We further performed gene-based burden analyses in an additional dataset comprising 789 ET patients and 770 healthy individuals to investigate whether there was an enrichment of rare deleterious variants within our candidate genes. RESULTS: Fifteen variants co-segregated with disease status in at least one of the families, among which rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050 in GPR151 showed a nominal association with ET. However, we found no significant enrichment of rare variants within these genes in cases compared with controls. Interestingly, MMP10 protein is involved in the inflammatory response to neuronal damage and has been previously associated with other neurological disorders. CONCLUSIONS: We prioritized a set of promising genes, especially MMP10, for further genetic and functional studies in ET. Our study suggests that rare deleterious coding variants that markedly increase susceptibility to ET are likely to be found in many genes. Future studies are needed to replicate and further infer biological mechanisms and potential disease causality for our identified genes.

Vancomycin powder for the prevention of surgical site infection in posterior elective spinal surgery. / Polvo de vancomicina tópico para la prevención de infección de herida quirúrgica en cirugía electiva de columna por vía posterior.

OBJECTIVE: To assess the effectiveness and safety of vancomycin powder as surgical site infection (SSI) prophylaxis in posterior bilateral elective spinal surgery. MATERIALS AND METHODS: Single-center quasi-experimental pre and postintervention comparative cohort study. The post-intervention group received standard intravenous antibiotic prophylaxis plus 1g of vancomycin powder into the surgical field before wound closure, and the pre-intervention group only the intravenous prophylaxis. RESULTS: 150 patients were included in each group. Twelve SSI (7 superficial and 5 deep) occurred in the post-intervention group and 16 SSI (7 superficial and 9 deep) in the pre-intervention group. The risk of deep SSI decreased from 6.0% to 3.3% (OR 0,54, 95%CI 0.17-1.65, p=0.411) with vancomycin powder. The percentage of deep SSI due to gram negative-positive germs were 80%-20% and 33%-67% for the post- and pre-intervention groups, respectively (p=0.265). No local or systemic adverse effects occurred attributable to vancomycin powder. CONCLUSION: In posterior elective spinal surgery, prophylaxis with vancomycin powder did not result in a significantly reduced incidence of superficial and deep SSI. There was a trend towards a higher incidence of deep SSI caused by gram negative microorganisms among those treated with vancomycin.

Cauda equina syndrome due to disk herniation: Long-term functional prognosis.

OBJECTIVE: Cauda equina syndrome (CES) caused by lumbar disk extrusion is classically considered an indication of urgent surgery. CES can be subdivided into CESI (incomplete CES) and CESR (complete CES with urinary retention and incontinence). This paper evaluates the long-term functional outcome of a CES cohort operated on due to disk herniation. METHODS: Single-center retrospective observational study. CES patients due to disk herniation that underwent surgery between 2000 and 2016 were included in the study. Demographic data, time intervals to diagnosis and surgery, preoperative neurologic status and outcome at the end of follow up were recorded. RESULTS: Twenty-two patients were included (median age 44 years). Eight patients were CESR and 14 CESI. Median time from symptom onset to diagnosis was 78h (range, 12-720h), and from diagnosis to surgery 24h (range, 5-120h). Median follow up was 75 months (range, 20-195 months). At the end of follow up, in the CESR group (median time from diagnosis to surgery, 23h) only pain significantly improved after surgery (p=0.007). In the CESI group (median time from diagnosis to surgery 23h) low back pain, sciatica and urinary sphincter function significantly improved (p<0.001). There were no significant differences between early (<48h) operation (n=4) and late (n=18) in terms of sphincter recovery (Fisher's Exact Test, p=0.076). CONCLUSION: Pain associated to CES improved both in the CESI and CESR groups. However, urinary sphincter impairment significantly improved only in the CESI group. No significant differences were found regarding long-term functional outcome between early and late surgery.

Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease.

Background: The prevalence of dementia in Parkinson disease (PD) increases dramatically with advancing age, approaching 80% in patients who survive 20 years with the disease. Increasing evidence suggests clinical, pathological and genetic overlap between Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia with PD. However, the contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established. Objective: To assess the contribution of coding variants in Mendelian dementia-causing genes on the risk of developing PD and the effect on cognitive performance of PD patients. Methods: We analyzed the coding regions of the amyloid-beta precursor protein (APP), Presenilin 1 and 2 (PSEN1, PSEN2), and Granulin (GRN) genes from 1,374 PD cases and 973 controls using pooled-DNA targeted sequence, human exome-chip and whole-exome sequencing (WES) data by single variant and gene base (SKAT-O and burden tests) analyses. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). The effect of coding variants in dementia-causing genes on cognitive performance was tested by multiple regression analysis adjusting for gender, disease duration, age at dementia assessment, study site and APOE carrier status. Results: Known AD pathogenic mutations in the PSEN1 (p.A79V) and PSEN2 (p.V148I) genes were found in 0.3% of all PD patients. There was a significant burden of rare, likely damaging variants in the GRN and PSEN1 genes in PD patients when compared with frequencies in the European population from the ExAC database. Multiple regression analysis revealed that PD patients carrying rare variants in the APP, PSEN1, PSEN2, and GRN genes exhibit lower cognitive tests scores than non-carrier PD patients (p = 2.0 × 10-4), independent of age at PD diagnosis, age at evaluation, APOE status or recruitment site. Conclusions: Pathogenic mutations in the Alzheimer disease-causing genes (PSEN1 and PSEN2) are found in sporadic PD patients. PD patients with cognitive decline carry rare variants in dementia-causing genes. Variants in genes causing Mendelian neurodegenerative diseases exhibit pleiotropic effects.