C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types.

Introduction: A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis. Methods: We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, and cerebellum) with average gene expression values for 15,633 protein-coding genes, including 54 genes known to be associated with ALS, FTD, or ALS-FTD. We then performed imaging transcriptomic analyses to evaluate whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n = 19) compared to controls (n = 23). Lastly, we explored whether genes with significant C9orf72 imaging transcriptomic correlations (i.e., "C9orf72 imaging transcriptomic network") were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways. Results: A total of 2,120 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 imaging transcriptomic network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic neurons in the spinal cord and brainstem and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with protein ubiquitination, autophagy, cellular response to DNA damage, endoplasmic reticulum to Golgi vesicle-mediated transport, among others. Conclusion: Considered together, we identified a network of C9orf72 associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.

Expansion of highly interferon-responsive T cells in early-onset Alzheimer's disease.

INTRODUCTION: Altered immune signatures are emerging as a central theme in neurodegenerative disease, yet little is known about immune responses in early-onset Alzheimer's disease (EOAD). METHODS: We examined single-cell RNA-sequencing (scRNA-seq) data from peripheral blood mononuclear cells (PBMCs) and droplet digital (dd)PCR data from CD4 T cells from participants with EOAD and clinically normal controls. RESULTS: We analyzed ~182,000 PBMCs by scRNA-seq and discovered increased interferon signaling-associated gene (ISAG) expression and striking expansion of antiviral-like ISAGhi T cells in EOAD. We isolated CD4 T cells from additional EOAD cases and confirmed increased expression of ISAGhi marker genes. Publicly available cerebrospinal fluid leukocyte scRNA-seq data from late-onset mild cognitive impairment and AD also revealed increased expression of interferon-response genes. DISCUSSION: ISAGhi T cells, apparently primed for antiviral activity, are expanded in EOAD. Additional research into these cells and the role of heightened peripheral IFN signaling in neurodegeneration is warranted.

FTLD targets brain regions expressing recently evolved genes.

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation is associated with a decline in human-specialized social-emotional and language functions. Most disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD targets brain regions that express genes containing human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and normative human regional transcriptomic data to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions expressing recently evolved genes. In addition, we asked whether genes expressed in FTLD-targeted brain regions are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions that express overlapping and distinct genes, including many linked to neuromodulatory functions. Genes whose normative brain regional expression pattern correlated with FTLD cortical atrophy were strongly associated with HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes.

Early-onset Alzheimer's disease explained by polygenic risk of late-onset disease?

Early-onset Alzheimer's disease (AD) is highly heritable, yet only 10% of cases are associated with known pathogenic mutations. For early-onset AD patients without an identified autosomal dominant cause, we hypothesized that their early-onset disease reflects further enrichment of the common risk-conferring single nucleotide polymorphisms associated with late-onset AD. We applied a previously validated polygenic hazard score for late-onset AD to 193 consecutive patients diagnosed at our tertiary dementia referral center with symptomatic early-onset AD. For comparison, we included 179 participants with late-onset AD and 70 healthy controls. Polygenic hazard scores were similar in early- versus late-onset AD. The polygenic hazard score was not associated with age-of-onset or disease biomarkers within early-onset AD. Early-onset AD does not represent an extreme enrichment of the common single nucleotide polymorphisms associated with late-onset AD. Further exploration of novel genetic risk factors of this highly heritable disease is warranted.Highlights: There is a unique genetic architecture of early- versus late-onset Alzheimer's disease (AD).Late-onset AD polygenic risk is not an explanation for early-onset AD.Polygenic risk of late-onset AD does not predict early-onset AD biology.Unique genetic architecture of early- versus late-onset AD parallels AD heterogeneity.

C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types.

Introduction: A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis. Methods: We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, cerebellum) with average gene expression values for 15,633 protein-coding genes, including 50 genes known to be associated with ALS, FTD, or ALS-FTD. We then evaluated whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n=19). Lastly, we explored whether genes with significant C9orf72 radiogenomic correlations (i.e., 'C9orf72 gene network') were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways. Results: A total of 1,748 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 gene network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic motor neurons in the spinal cord, and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with multiple neurotransmitter systems, protein ubiquitination, autophagy, and MAPK signaling, among others. Conclusions: Considered together, we identified a network of C9orf72-associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.

Single-cell RNA-seq reveals alterations in peripheral CX3CR1 and nonclassical monocytes in familial tauopathy.

BACKGROUND: Emerging evidence from mouse models is beginning to elucidate the brain's immune response to tau pathology, but little is known about the nature of this response in humans. In addition, it remains unclear to what extent tau pathology and the local inflammatory response within the brain influence the broader immune system. METHODS: To address these questions, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from carriers of pathogenic variants in MAPT, the gene encoding tau (n = 8), and healthy non-carrier controls (n = 8). Primary findings from our scRNA-seq analyses were confirmed and extended via flow cytometry, droplet digital (dd)PCR, and secondary analyses of publicly available transcriptomics datasets. RESULTS: Analysis of ~ 181,000 individual PBMC transcriptomes demonstrated striking differential expression in monocytes and natural killer (NK) cells in MAPT pathogenic variant carriers. In particular, we observed a marked reduction in the expression of CX3CR1-the gene encoding the fractalkine receptor that is known to modulate tau pathology in mouse models-in monocytes and NK cells. We also observed a significant reduction in the abundance of nonclassical monocytes and dysregulated expression of nonclassical monocyte marker genes, including FCGR3A. Finally, we identified reductions in TMEM176A and TMEM176B, genes thought to be involved in the inflammatory response in human microglia but with unclear function in peripheral monocytes. We confirmed the reduction in nonclassical monocytes by flow cytometry and the differential expression of select biologically relevant genes dysregulated in our scRNA-seq data using ddPCR. CONCLUSIONS: Our results suggest that human peripheral immune cell expression and abundance are modulated by tau-associated pathophysiologic changes. CX3CR1 and nonclassical monocytes in particular will be a focus of future work exploring the role of these peripheral signals in additional tau-associated neurodegenerative diseases.

Association of Optic Nerve Head and Macular Optical Coherence Tomography Measures With Glaucoma-Related Disability.

PRCIS: Optical coherence tomography (OCT) estimated retinal nerve fiber layer (RNFL) thickness associated with glaucoma-related disability independent of the visual field (VF) damage and thus may provide additional patient-relevant disability information beyond what is captured by standard VF testing. PURPOSE: To examine whether OCT metrics [peripapillary RNFL thickness and macular ganglion cell/inner plexiform layer (GCIPL) thickness] are associated with quality of life (QoL) measures and additional disability metrics, and whether these associations are independent of VF damage. METHODS: In this cross-sectional study, 156 patients with glaucoma or suspected glaucoma received VF testing and OCT scans to measure RNFL and GCIPL thickness. QoL was assessed using the Glaucoma Quality-of-Life 15 and additional disability measures including fear of falling, reading speed, and steps per day were assessed. Multivariable regression models adjusting for relevant covariates tested whether RNFL or GCIPL thickness from the less-impaired eye were associated with disability measures and whether associations were independent of VF damage. RESULTS: Greater VF damage is associated with worse QoL (95% CI=0.4-1.4; P <0.001) and slower reading speed (CI=-0.06 to -0.02; P <0.001). Lower RNFL and GCIPL thicknesses were associated with lower QoL scores, but not with QoL scores or other disability metrics after correcting for VF damage. However, post hoc analyses in patients with better eye thicknesses between 55 and 75 µm demonstrated associations between lower RNFL thickness and worse QoL (CI=-2.2 to -0.1; P =0.04) and greater fear of falling (CI=-6.1 to -0.4; P =0.03) even after accounting for VF damage. No such associations were observed for GCIPL thickness. CONCLUSIONS: OCT RNFL, but not GCIPL, thickness is associated with multiple disability measures independent of VF damage severity.

Prevalence, Timing, and Network Localization of Emergent Visual Creativity in Frontotemporal Dementia.

Importance: The neurological substrates of visual artistic creativity (VAC) are unknown. VAC is demonstrated here to occur early in frontotemporal dementia (FTD), and multimodal neuroimaging is used to generate a novel mechanistic hypothesis involving dorsomedial occipital cortex enhancement. These findings may illuminate a novel mechanism underlying human visual creativity. Objective: To determine the anatomical and physiological underpinnings of VAC in FTD. Design, Setting, and Participants: This case-control study analyzed records of 689 patients who met research criteria for an FTD spectrum disorder between 2002 and 2019. Individuals with FTD and emergence of visual artistic creativity (VAC-FTD) were matched to 2 control groups based on demographic and clinical parameters: (1) not visually artistic FTD (NVA-FTD) and (2) healthy controls (HC). Analysis took place between September 2019 to December 2021. Main Outcomes and Measures: Clinical, neuropsychological, genetic, and neuroimaging data were analyzed to characterize VAC-FTD and compare VAC-FTD with control groups. Results: Of 689 patients with FTD, 17 (2.5%) met VAC-FTD inclusion criteria (mean [SD] age, 65 [9.7] years; 10 [58.8%] female). NVA-FTD (n = 51; mean [SD] age, 64.8 [7] years; 25 [49.0%] female) and HC (n = 51; mean [SD] age, 64.5 [7.2] years; 25 [49%] female) groups were well matched to VAC-FTD demographically. Emergence of VAC occurred around the time of onset of symptoms and was disproportionately seen in patients with temporal lobe predominant degeneration (8 of 17 [47.1%]). Atrophy network mapping identified a dorsomedial occipital region whose activity inversely correlated, in healthy brains, with activity in regions found within the patient-specific atrophy patterns in VAC-FTD (17 of 17) and NVA-FTD (45 of 51 [88.2%]). Structural covariance analysis revealed that the volume of this dorsal occipital region was strongly correlated in VAC-FTD, but not in NVA-FTD or HC, with a volume in the primary motor cortex corresponding to the right-hand representation. Conclusions and Relevance: This study generated a novel hypothesis about the mechanisms underlying the emergence of VAC in FTD. These findings suggest that early lesion-induced activation of dorsal visual association areas may predispose some patients to the emergence of VAC under certain environmental or genetic conditions. This work sets the stage for further exploration of enhanced capacities arising early in the course of neurodegeneration.

Genetic overlap between cortical brain morphometry and frontotemporal dementia risk.

Frontotemporal dementia (FTD) has a complex genetic etiology, where the precise mechanisms underlying the selective vulnerability of brain regions remain unknown. We leveraged summary-based data from genome-wide association studies (GWAS) and performed LD score regression to estimate pairwise genetic correlations between FTD risk and cortical brain imaging. Then, we isolated specific genomic loci with a shared etiology between FTD and brain structure. We also performed functional annotation, summary-data-based Mendelian randomization for eQTL using human peripheral blood and brain tissue data, and evaluated the gene expression in mice targeted brain regions to better understand the dynamics of the FTD candidate genes. Pairwise genetic correlation estimates between FTD and brain morphology measures were high but not statistically significant. We identified 5 brain regions with a strong genetic correlation (rg > 0.45) with FTD risk. Functional annotation identified 8 protein-coding genes. Building upon these findings, we show in a mouse model of FTD that cortical N-ethylmaleimide sensitive factor (NSF) expression decreases with age. Our results highlight the molecular and genetic overlap between brain morphology and higher risk for FTD, specifically for the right inferior parietal surface area and right medial orbitofrontal cortical thickness. In addition, our findings implicate NSF gene expression in the etiology of FTD.

Radiogenomics of C9orf72 Expansion Carriers Reveals Global Transposable Element Derepression and Enables Prediction of Thalamic Atrophy and Clinical Impairment.

Hexanucleotide repeat expansion (HRE) within C9orf72 is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread derepression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including C9orf72 HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral C9orf72 expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used FreeSurfer software to assess the effects of C9orf72 HRE and clinical diagnosis (n = 78 individuals, male and female) on atrophy of thalamic nuclei. We also generated a novel, human, whole-blood RNA-sequencing dataset to determine the relationships among peripheral C9orf72 expression, TE activation, thalamic atrophy, and clinical severity (n = 114 individuals, male and female). We confirmed global thalamic atrophy and reduced C9orf72 expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that C9orf72 expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element L1HS L1HS levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from human HRE carriers revealed atrophy of specific thalamic nuclei, demonstrated that C9orf72 levels relate to clinical severity, and identified marked derepression of TEs, including L1HS, which predicted atrophy of FTD-relevant thalamic nuclei.SIGNIFICANCE STATEMENT Pathogenic repeat expansion in C9orf72 is the most frequent genetic cause of FTD and amyotrophic lateral sclerosis (ALS; C9-FTD/ALS). The clinical, neuroimaging, and pathologic features of C9-FTD/ALS are well characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we used a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction of C9orf72 in blood and found broad dysregulation of transposable elements-genetic elements typically repressed in the human genome-in symptomatic C9orf72 expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD. C9orf72 expression was also associated with clinical severity, suggesting that peripheral C9orf72 levels capture disease-relevant information.

Case Report: Novel CSF1R Variant in a Patient With Behavioral Variant Frontotemporal Dementia Syndrome With Prodromal Repetitive Scratching Behavior.

CSF1R-related leukoencephalopathy is an autosomal dominant neurodegenerative disease caused by mutations in the tyrosine kinase domain of the colony stimulating factor 1 receptor (CSF1R). Several studies have found that hematogenic stem cell transplantation is an effective disease modifying therapy however the literature regarding prodromal and early symptoms CSF1R-related leukoencephalopathy is limited. We describe a 63-year-old patient with 4 years of repetitive scratching and skin picking behavior followed by 10 years of progressive behavioral, cognitive, and motor decline in a pattern suggesting behavioral variant of frontotemporal dementia. Brain MRI demonstrated prominent frontal and parietal atrophy accompanied by underlying bilateral patchy white matter hyperintensities sparing the U fibers and cavum septum pellucidum. Whole-exome sequencing revealed a novel, predicted deleterious missense variant in a highly conserved amino acid in the tyrosine kinase domain of CSF1R (p.Gly872Arg). Given this evidence and the characteristic clinical and radiological findings this novel variant was classified as likely pathogenic according to the American College of Medical Genetics standard guidelines. Detailed description of the prodromal scratching and skin picking behavior and possible underlying mechanisms in this case furthers knowledge about early manifestations of CSF1R-related leukoencephalopathy with the hope that early detection and timely administration of disease modifying therapies becomes possible.

Dissecting the clinical heterogeneity of early-onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) is a rare but particularly devastating form of AD. Though notable for its high degree of clinical heterogeneity, EOAD is defined by the same neuropathological hallmarks underlying the more common, late-onset form of AD. In this review, we describe the various clinical syndromes associated with EOAD, including the typical amnestic phenotype as well as atypical variants affecting visuospatial, language, executive, behavioral, and motor functions. We go on to highlight advances in fluid biomarker research and describe how molecular, structural, and functional neuroimaging can be used not only to improve EOAD diagnostic acumen but also enhance our understanding of fundamental pathobiological changes occurring years (and even decades) before the onset of symptoms. In addition, we discuss genetic variation underlying EOAD, including pathogenic variants responsible for the well-known mendelian forms of EOAD as well as variants that may increase risk for the much more common forms of EOAD that are either considered to be sporadic or lack a clear autosomal-dominant inheritance pattern. Intriguingly, specific pathogenic variants in PRNP and MAPT-genes which are more commonly associated with other neurodegenerative diseases-may provide unexpectedly important insights into the formation of AD tau pathology. Genetic analysis of the atypical clinical syndromes associated with EOAD will continue to be challenging given their rarity, but integration of fluid biomarker data, multimodal imaging, and various 'omics techniques and their application to the study of large, multicenter cohorts will enable future discoveries of fundamental mechanisms underlying the development of EOAD and its varied clinical presentations.

The Role of Microglia in Inherited White-Matter Disorders and Connections to Frontotemporal Dementia.

Microglia play a critical but poorly understood role in promoting white-matter homeostasis. In this review, we leverage advances in human genetics and mouse models of leukodystrophies to delineate our current knowledge and identify outstanding questions regarding the impact of microglia on central nervous system white matter. We first focus on the role of pathogenic mutations in genes, such as TREM2, TYROBP, and CSF1R, that cause leukodystrophies in which the primary deficit is thought to originate in microglia. We next discuss recent advances in disorders such as adrenoleukodystrophy and Krabbe disease, in which microglia play an increasingly recognized role. We conclude by reviewing the roles of GRN and related genes, such as TMEM106B, PSAP, and SORT1, that affect microglial biology and associate with several types of disease, including multiple leukodystrophies as well as forms of frontotemporal dementia (FTD) presenting with white-matter abnormalities. Taken together, mouse and human data support the notion that loss of microglia-facilitated white-matter homeostasis plays an important role in the development of leukodystrophies and suggest novel mechanisms contributing to FTD.

A second X chromosome contributes to resilience in a mouse model of Alzheimer's disease.

A major sex difference in Alzheimer's disease (AD) is that men with the disease die earlier than do women. In aging and preclinical AD, men also show more cognitive deficits. Here, we show that the X chromosome affects AD-related vulnerability in mice expressing the human amyloid precursor protein (hAPP), a model of AD. XY-hAPP mice genetically modified to develop testicles or ovaries showed worse mortality and deficits than did XX-hAPP mice with either gonad, indicating a sex chromosome effect. To dissect whether the absence of a second X chromosome or the presence of a Y chromosome conferred a disadvantage on male mice, we varied sex chromosome dosage. With or without a Y chromosome, hAPP mice with one X chromosome showed worse mortality and deficits than did those with two X chromosomes. Thus, adding a second X chromosome conferred resilience to XY males and XO females. In addition, the Y chromosome, its sex-determining region Y gene (Sry), or testicular development modified mortality in hAPP mice with one X chromosome such that XY males with testicles survived longer than did XY or XO females with ovaries. Furthermore, a second X chromosome conferred resilience potentially through the candidate gene Kdm6a, which does not undergo X-linked inactivation. In humans, genetic variation in KDM6A was linked to higher brain expression and associated with less cognitive decline in aging and preclinical AD, suggesting its relevance to human brain health. Our study suggests a potential role for sex chromosomes in modulating disease vulnerability related to AD.

Diagnostic and interventional magnetic resonance neurography diagnosis of brachytherapy seed-mediated pudendal nerve injury: a case report.

Injury to the pudendal nerve in men presents with pain, paresthesia, or numbness of the perineum, and/or scrotum, and/or penis. There is evidence implicating the brachytherapy seeds used to treat prostate cancer as source of pudendal nerve injury. Compared to surgical prostatectomy, brachytherapy has the advantage of being less invasive, but seeds may not only lead to well-established complications such as urinary, bowel, and erectile dysfunction, but also injury to the sensory branches of the pudendal nerve. We report and document a case of pudendal nerve injury secondary to brachytherapy seeds diagnosed with magnetic resonance (MR) neurography, nerve blocks, and histopathological examination; and successful treatment via sensory branch neurectomy.

Needle Heating During Interventional Magnetic Resonance Imaging at 1.5- and 3.0-T Field Strengths.

OBJECTIVES: The aim of this study was to test the hypothesis that clinically used magnetic resonance (MR)-conditional needles of varying lengths, orientations, locations, and pulse sequences can result in excessive heating during MR imaging (MRI)-guided interventions that can be minimized to physiological ranges with proper selection of the needle length, needle position, and modification of pulse sequence parameters. MATERIALS AND METHODS: We simulated a clinical interventional MRI setting with 2 standard American Society for Testing and Materials F2182-11A phantoms and measured temperatures with fiber optic sensors. Temperature profiles were monitored for commercial 10, 15 and 20 cm MR-conditional cobalt-chromium needles in clinically relevant perpendicular, 45-degree oblique, and parallel orientations relative to the static magnetic field (B0) and center, right off-center, and left off-center needle tip locations in the z = 0 plane. Clinically available interventional MRI pulse sequences including turbo spin echo (TSE), fast TSE, slice encoding for metal artifact correction, compressed sensing slice encoding for metal artifact correction, half-Fourier acquisition single-shot TSE (HASTE), HASTE inversion recovery, fluoroscopic steady-state gradient echo (3.0 T only), fast low-angle shot gradient echo, and volumetric interpolated breath-hold examination gradient echo pulse sequences were tested at 1.5 and 3.0 T field strengths. Acquired temperature data were analyzed using Friedman and Wilcoxon signed-rank tests with Bonferroni correction. RESULTS: After 5-minute of continuous MRI, less than 2.5°C heating occurred when needles were oriented perpendicular and 45-degree oblique to B0, regardless of field strengths. Higher temperature rises capable of causing permanent tissue damage were observed when needles were oriented in parallel to B0 (1.5 T: 22°C with 20 cm needles, 3.0 T: 8°C with 10 and 15 cm needles) using higher radiofrequency energy pulse sequences, such as TSE and HASTE. Left off-center location, parallel orientation, and needle lengths close to half of the radiofrequency pulse wavelength were positively associated with higher temperature rises. CONCLUSIONS: Under the herein used experimental conditions, clinically used MR-conditional needles can heat to supraphysiologic temperatures during prolonged MRI at 1.5 and 3.0 T field strengths; however, the temperature rise can be balanced to physiological ranges with proper selection of needle length, needle orientation, and pulse sequence parameters. Caution must be exercised when using different MRI systems, as results may not directly translate.

Non-coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases.

We conducted genome sequencing to search for rare variation contributing to early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 435 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than one in 10,000 or private), computational prediction of deleteriousness (CADD) (10 or 15 thresholds), and molecular function (protein loss-of-function [LoF] only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory regions). Replication analysis was conducted on 16,434 independent cases and 15,587 independent controls. Rare variants in TET2 were enriched in the discovery combined EOAD and FTD cohort (p = 4.6 × 10-8, genome-wide corrected p = 0.0026). Most of these variants were canonical LoF or non-coding in predicted regulatory regions. This enrichment replicated across several cohorts of Alzheimer's disease (AD) and FTD (replication only p = 0.0029). The combined analysis odds ratio was 2.3 (95% confidence interval [CI] 1.6-3.4) for AD and FTD. The odds ratio for qualifying non-coding variants considered independently from coding variants was 3.7 (95% CI 1.7-9.4). For LoF variants, the combined odds ratio (for AD, FTD, and amyotrophic lateral sclerosis, which shares clinicopathological overlap with FTD) was 3.1 (95% CI 1.9-5.2). TET2 catalyzes DNA demethylation. Given well-defined changes in DNA methylation that occur during aging, rare variation in TET2 may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes. Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.

Exploring Patient Motivations and Impact of Asian Blepharoplasty.

To date, patient motivations for Asian blepharoplasty and the surgery's impact on quality of life have not been quantified. Here, we employed structured interviews and a web-based survey to better characterize patient motivations for Asian blepharoplasty and the impact of Asian blepharoplasty on self-reported domains of happiness, self-esteem, attractiveness, social life, and professional life. Structured interviews were conducted to inform a web-based survey regarding Asian blepharoplasty. Survey respondents used visual analog scales to rate their satisfaction with their eye shape, motivations for undergoing Asian blepharoplasty, and perceived outcomes after surgery. A total of 315 participants (mean 25.7 [18-58] years) of East or Southeast Asian descent were included. 185 participants expressed no desire for Asian blepharoplasty, 76 expressed some desire, and 54 had already undergone surgery. There were statistically significant differences regarding baseline satisfaction, perceived social limitation, and perceived professional limitations regarding eye shape (p < 0.0001). The Looking Glass Self index (comprised of media exposure, low self-esteem, and negative stereotypes related to eye shape) is negatively associated with preoperative satisfaction with eye shape (rho = -0.29, p < 0.01). The desire for social-professional advancement and the Looking Glass Self index significantly predict self-reported improvements in professional and social life, respectively (both p < 0.01). Asian blepharoplasty may be driven by functional, social, or economic patient motivations. Some patients may see Asian blepharoplasty as a potential solution for sociological concerns. These expectations should be further explored in physician-patient discussions regarding candidacy for surgery and establishing expectations for postoperative outcomes.

Evidence-Based Criteria for Determining Peripapillary OCT Reliability.

PURPOSE: To assess the impact of OCT signal strength (SS) and artifact on retinal nerve fiber layer (RNFL) measurement reliability and to understand whether glaucoma severity modifies this relationship. DESIGN: Retrospective, longitudinal cohort study. PARTICIPANTS: Two thousand nine hundred ninety-two OCT scans from 474 eyes of 241 patients with glaucoma or glaucoma suspect status. METHODS: We extracted mean RNFL thickness and SS and manually graded scans for artifact. To analyze the effect of SS and artifact on OCT reliability, we (1) created a multilevel linear model using measured RNFL thickness values and demographic and clinical data to estimate the true (predicted) RNFL thickness, (2) calculated model residuals (ΔRNFL) as our reliability measure, and (3) created a second multilevel linear model with splines and interaction terms that modeled overall and quadrant specific reliability (ΔRNFL) as the outcome, using SS and artifact as predictors. MAIN OUTCOME MEASURES: Impact of SS and artifact on ΔRNFL. RESULTS: For SS between 10 and 3, the impact of decreases in SS on OCT reliability is modest (-0.67 to -1.25 ΔRNFL per 1-point decrease in SS; P < 0.05). But at less than 3, changes in SS have a large impact on reliability (-15.70 to -16.34 ΔRNFL per 1-point decrease in SS; P < 0.05). At SS between 10 and 3, decreases in SS tend to have a larger impact on reliability in eyes with severe glaucoma (-1.25 per 1-point decrease in SS; P < 0.05) compared with eyes with mild or moderate glaucoma (-0.67 to -0.75 per 1-point decrease in SS; P < 0.05). The presence of artifact has a significant impact on OCT reliability independent of the effects of SS (-4.76 ΔRNFL; P < 0.05). Artifact affects reliability solely in the quadrant in which it occurs, with artifact in one quadrant showing no impact on ΔRNFL in the opposite quadrant (P > 0.05). CONCLUSIONS: Signal strength decreases down to 3 have relatively mild impacts on OCT reliability. At less than 3, the impact of further decreases in SS on reliability are substantial. The effect of SS on reliability is greater in severe glaucoma. Artifacts result in a decrease in reliability independent of the effect of SS. We propose evidence-based guidelines to guide physicians on whether to trust the results of an OCT scan.

The Radiogenomics of Late-onset Alzheimer Disease.

Radiogenomics, defined as the integrated analysis of radiologic imaging and genetic data, is a well-established tool shown to augment neuroimaging in the clinical diagnosis, prognostication, and scientific study of late-onset Alzheimer disease (LOAD). Early work using candidate single nucleotide polymorphisms (SNPs) identified genetic variation in APOE, BIN1, CLU, and CR1 as key modifiers of brain structure and function using magnetic resonance imaging (MRI). More recently, polygenic risk scores used in conjunction with MRI and positron emission tomography have shown great promise as a risk-stratification tool for clinical trials and care-management decisions. In addition, recent work using multimodal MRI and positron emission tomography as proxies of LOAD progression has identified novel risk variants that are enhancing our understanding of LOAD pathophysiology and progression. Herein, we highlight key studies and trends in the radiogenomics of LOAD over the past two decades and their implications for clinical practice and scientific research.