Citations

AbstractThis case report underlines the importance of molecular characterization of genomic duplications and other structural variants in the prenatal setting to guide clinical interpretation, genetic counseling, and perinatal medical care.

Abstract The utility of ultrasound in sports medicine is improving the sports medicine physician's ability to rapidly diagnose and treat a multitude of sports related pathologies. In this article, we clearly outline the current status of the evidence in support of using sports ultrasound in the setting of acute ocular injury, evaluation of elevated intracranial pressures, deep venous thrombosis, and soft tissue complaints.

Abstract Background: Dysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers, crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.Methods: The plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTL with amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERTL protein was employed to study interaction of CERTL with amyloid-β (Aβ), Aβ aggregation process in presence of CERTL, and the resulting changes in Aβ toxicity in neuroblastoma cells. CERTL was overexpressed in neurons by adeno associated virus (AAV) in a familial mouse model of familial AD (5xFAD). Ten weeks after transduction, animals were challenged with behavior tests for memory, anxiety and locomotion. At week twelve, brains were investigated for sphingolipid levels by mass spectrometry, plaques and neuroinflammation by immunohistochemistry, gene expression and/or immunoassay.Results: Here, we report that CERTL, binds to APP, modifies Aβ aggregation and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male 5xFAD mice. CERTL in vivo over-expression has a mild effect on animal locomotion, decreases Aβ formation and modulates microglia by decreasing their pro-inflammatory phenotype.Conclusion: Our results demonstrate a crucial role of CERTL in regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.

Abstract Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

AbstractBackgroundHeterozygous progranulin (GRN) mutations are an important cause of familial Frontotemporal Lobar Degeneration (f‐FTLD) associated with TDP‐43 pathology. The cellular role of progranulin remains unclear, but alterations in lipid metabolism and lysosomal function have been suggested. Better understanding the pathophysiology of progranulin deficiency is critical as several clinical trials are underway in this population, and fluid biomarkers are urgently needed to assess pharmacodynamic effects. Therefore, we conducted an unbiased metabolomic analysis in GRN mutation carriers and family member controls, and identified at least two classes of lipids altered in symptomatic GRN carriers.MethodsMatched plasma and CSF samples were obtained from GRN mutation carriers (46 plasma, 36 CSF) and age‐matched blood relatives (36 plasma, 18 CSF). Untargeted metabolite detection was conducted via LC‐MS/MS in both plasma (1389 compounds) and CSF (508 compounds) by Metabolon. To identify important compounds in differentiating these groups, we conducted an unbiased analysis between family controls, asymptomatic carriers, and symptomatic carriers using univariate one‐way ANOVA with post‐hoc Fisher’s LSD corrected for false discovery rate (FDR) and partial least squares ‐ discriminant analysis (PLS‐DA, Metaboanalyst). For compounds identified by this unbiased approach, correlation with measures of disease severity was analyzed via linear regression, controlling for age and gender.ResultsIn plasma, 22 compounds were identified as significant in discriminating between groups via ANOVA (FDR<0.05), and 17/22 were also identified by PLS‐DA (VIP>2.4). Of these, 21/22 compounds were lipids; 11 were sphingomyelins. Comparatively, in the relatively lipid‐poor CSF samples, 6/15 compounds identified by PLS‐DA (VIP>2.0) were phosphatidylcholines. Pathway impact analysis revealed a large impact from the GRN mutation on sphingolipids in plasma and glycerophospholipids in CSF. In secondary analyses, sphingomyelins were elevated in plasma from symptomatic carriers, while phosphatidylcholines were decreased in CSF. Secondary analyses showed these compounds were correlated with clinical measures of disease severity, including MoCA and CDR+NACC‐FTLD.ConclusionIncreased plasma concentration of sphingomyelin and decreased CSF phosphatidylcholines are both associated with worse clinical status in FTLD‐GRN. These findings suggest that impaired lipid metabolism could play a pathogenic role in FTLD‐GRN. Targeted lipidomic measures in plasma and CSF may potentially reveal useful clinical trial biomarkers.

AbstractBackgroundComputed tomography (CT) is the most commonly used brain examination tool for the initial assessment of neurodegenerative diseases such as dementia disorders. It is widely available, affordable and provides short scan times, however, it is mainly used for visual assessment of brain integrity and exclusion of co‐pathologies while magnetic resonance imaging (MRI) is the preferred modality for the extraction of regional brain volumetric measures, obtained by brain segmentation into tissue classes and anatomical regions. We developed an automated, deep learning‐based approach to segment CT scans into intracranial volume (ICV), grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF).Method139 CT and T1‐weighted MRI scans acquired on the same day in participants of the Gothenburg H70 Birth Cohort Study (70% female) were included in this study. SPM12 was used to extract GM, WM and CSF tissue class labels and Pincram for creating ICV masks from the MRIs. These labels were used as training input and as the reference criteria for subsequent volumetric and similarity comparisons. In a training subcohort (n=120), CT scans were co‐registered to their corresponding MRI. A U‐Net deep learning model was developed using the Keras software package which underwent two training sessions: 1. Predict ICVs in CT and extract brain; 2. Predict GM, WM and CSF volumes with extracted CT images as input, preserving the predictions in individual space. MRI labels were incorporated during the training sessions including 120 datasets.ResultNineteen validation datasets which were not included in the training were used for the prediction process without MRI intervention. Continuous Dice scores between ICV, GM, WM and CSF predictions from the model in the validation datasets and independently MRI‐derived labels were 0.97, 0.79, 0.81 and 0.72 with a volumetric Pearson correlation coefficient, r of 0.93, 0.84, 0.73 and 0.71, respectively.ConclusionOur pilot study developed a deep learning model that enables the automated segmentation and volumetric measure extraction from cranial CT. With further optimization, training on larger and more diverse datasets, we aim at improving the model to execute predictions comparable to MRI‐based approaches, thus, developing a diagnostic support tool based on routinely acquired CT scans.

AbstractBackgroundImmune dysregulation may influence disease pathogenesis in familial frontotemporal dementia (fFTD), but the utility of peripheral biomarkers of inflammation remains unclear in this cohort. We sought to investigate candidate plasma biomarkers of immune function within a large cohort of fFTD kindreds from the ARTFL and LEFFTDS Consortia.MethodsWe examined plasma samples from 148 non‐carrier healthy controls and 256 asymptomatic and symptomatic individuals carrying autosomal dominant fFTD‐associated mutations (n=73 MAPT, n=120 C9ORF72, and n=63 GRN). ELISA was used to measure three plasma biomarkers of inflammation (YKL‐40, TNF‐α,IL‐6). We used Mann–Whitney U tests to compare concentrations amongst controls and subgroups of fFTD differing in disease severity, defined by the Clinical Dementia Rating Scale plus National Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR® plus NACC FTLD) global score (asymptomatic=0, early symptomatic=0.5, late symptomatic ≥1). We also used linear mixed models to assess the utility of baseline inflammatory biomarkers in predicting the subsequent annual rate of decline in functional clinical severity (CDR® plus NACC FTLD sum of boxes) and psychomotor speed (Trails A).ResultsPlasma YKL‐40 concentrations were elevated in late symptomatic fFTD (59.3ng/ml [50.1]) relative to controls (32.9ng/ml [24.0]) (p=0.0003) and asymptomatic mutation carriers (30.9ng/ml [25.4], p=0.0001). Plasma TNF‐α concentrations were relatively low in asymptomatic mutation carriers (1.96pg/ml [0.56]) compared to early symptomatic fFTD (2.35pg/ml [0.83], p= 0.009). Amongst mutation carriers (including 140 with follow up clinical data), higher baseline plasma IL‐6 and YKL‐40 concentrations were associated with greater increase in functional clinical severity and declines in psychomotor speed, respectively.ConclusionPlasma biomarkers of inflammation increase with disease severity in fFTD and predict worse clinical trajectories. While the role of inflammation remains unclear in familial FTD, plasma markers of inflammation appear to reflect the processes influencing disease trajectory in patients carrying mutations associated with familial frontotemporal dementia.

AbstractBackgroundPlasma NfL is a sensitive marker of axonal injury that is elevated in symptomatic FTLD and asymptomatic carriers of FTLD‐associated genetic mutations at short‐term risk of phenoconversion to mild behavioral or cognitive impairment or dementia. In carriers of FTLD‐associated genetic mutations, NfL is associated with clinical measures of disease severity.MethodPlasma NfL was measured using single molecule array technology in baseline blood samples from 290 participants in the ARTFL/LEFFTDS consortia. Participants included 181 asymptomatic mutation carriers (C9orf72, GRN, and MAPT); 45 with mild impairment (MBI/MCI), and 64 with dementia. 103 family members without FTLD‐associated mutations served as asymptomatic controls. Social cognition scales were obtained through clinical evaluation at baseline, year 1, and year 2. Stepwise linear regressions assessed NfL relationships with baseline social cognition measures. Linear mixed models were used to test the ability of baseline NfL to predict longitudinal changes. Analyses corrected for age, sex, and genotype.ResultAt baseline, plasma NfL correlated with all measures of social cognition, regardless of genotype. Associations were strongest for the Revised Self‐monitoring Scale (RSMS;β = ‐.50, p < .001), total score of the Social Norms questionnaire (β= .48, p < .001), and caregiver burden (Zarit burden;β = .55, p < .001). Regardless of disease severity, baseline NfL related to worse RSMS scores over time (‐3.7 points at year 2/ LogNfL unit increase, 95% CI ‐1.7 to ‐5.7, p < .001). In MBI/MCI, higher baseline NfL was associated with worse longitudinal scores on the Social Norms questionnaire (‐5.9 points at year 2/LogNfL unit increase, 95% CI ‐1.1 to ‐10.7, p = .016). No associations were seen in asymptomatic non‐carriers.ConclusionIn this familial FTLD cohort, plasma NfL is correlated with clinical measures of social cognition and caregiver burden. Higher baseline plasma NfL concentrations are associated with worsening self‐monitoring and social norms scores over time. These associations suggest that NfL is correlated with clinically meaningful measures that may be relevant to therapeutic development.

AbstractBackgroundCSF neurofilament light protein (NfL) is an important biomarker in several neurologic diseases. CSF NfL concentrations are known to increase with age, but sex differences have been less examined. The CSF/serum albumin ratio (QAlb) is a biomarker for blood‐brain barrier integrity, which has previously been found to be higher in men. As NfL and QAlb are used in clinical routine, the impact of demographic factors on these biomarkers is important to understand.MethodParticipants were derived from two samples. The first was a population‐based cohort of 308 70‐year olds from the Gothenburg H70 Birth Cohort Study, Sweden. The second data set comprised CSF NfL and QAlb results from 8995 and 39252 subjects respectively, generated in clinical practice between 2005‐2012 in Gothenburg, Sweden. In the population‐based study, QAlb and NfL concentrations were examined in relation to sex, cardiovascular risk factors, and MRI signs of cerebral white matter lesions. In the clinical routine cohort, sex differences in QAlb and NfL were tested in relation to age.ResultIn the population‐based sample, men had higher QAlb and NfL concentrations than women. NfL was not related to cerebral vascular pathology, but QAlb correlated positively with several measures of white matter lesions. In the clinical routine cohort, men also had higher QAlb and NfL concentrations from adolescence and throughout life.ConclusionQAlb ratios and CSF NfL levels are higher in men throughout life. The CSF NfL sex difference could not be explained by vascular pathology. Future studies should consider using different reference limits for men and women.

AbstractBackgroundThe LEFFTDS Consortium involves investigators at 8 centers in North America evaluating individuals in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72) genes using a standardized battery of measures. Participants are evaluated annually. We sought to determine possible correlations between FTLD disease progression and neuropsychiatric features.MethodThe Neuropsychiatric Inventory Questionnaire (NPI‐Q) scale is an informant‐based instrument that measures the presence and severity of 12 neuropsychiatric features in patients with dementia. The NPI‐Q was completed at each LEFFTDS visit. The individual NPI questions and total score were analyzed in those with CDR® Dementia Staging Instrument PLUS National Alzheimer Coordinating Center Frontotemporal Lobar Degeneration (CDR®+ NACC FTLD) ratings of 0 (i.e., clinically normal), 0.5 (i.e., questionably/minimally abnormal), 1, 2, and 3.ResultThe 472 participants enrolled to date with a baseline (Visit 1) assessment have the following characteristics: 261 (55.5%) female, mean age 48 (range 18‐80) years, mean education 16 (range 11‐22) years, and 275 participants with a CDR®+NACC FTLD=0 (58%) and known genetic status. Participants with a CDR®+NACC FTLD=0 plus a genetic mutation were compared to those without a mutation and found to have increased severity of apathy (mean score of 0.116 versus 0.035, p=0.0302). Regardless of the specific mutation, those with a CDR®+NACC FTLD=0.5 were reported to have increased severity of apathy, disinhibition, and irritability. For most domains, mean NPI‐Q severity scores increase between groups up to CDR®+NACC FTLD=2. Depression increases in severity up to CDR®+NACC FTLD=1, whereas apathy severity continues to increase with increasing disease severity through CDR®+NACC FTLD=3. Twenty participants converted from CDR®+NACC FTLD 0 to >0 between their baseline and most recent visit; apathy severity almost tripled in these participants. For those that converted, disinhibition, irritability, and NPI total score were different between baseline and most recent visit (Wilcoxon signed rank test, p<0.05).ConclusionKey neuropsychiatric features measured by the NPI‐Q demonstrate differences in apathy severity between clinically normal mutation vs non‐mutation carriers. Key domains differ at different levels of FTLD severity and show dynamic changes with increasing level of FTLD severity. Supported by AG063911, AG045390, NS092089, AG016976.