Citations

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.

AbstractBackgroundFrontotemporal dementia (FTD) is a rapidly progressive neurodegenerative disorder characterized by prominent atrophy of the frontal and temporal lobes and marked language and/or behavioral disturbances. Mislocalization of the TAR DNA‐binding protein 43 (TDP‐43) – characterized by both its nuclear loss and its cytosolic accumulation – occurs in up to 50% of FTD cases. Recent evidence from our group and others demonstrates that loss of TDP‐43‐dependent splicing activity occurs in FTD patient brains, is an early disease phenomenon, and contributes directly to neuronal death. Monitoring the products of TDP‐43 related mis‐splicing may, thus, yield promising biomarker candidates of early cellular dysfunction in FTD.MethodWe propose a series of proteogenomic studies in human iPSC neurons, post‐mortem brain, and patient biospecimens to identify and develop protein‐based biomarkers of RNA mis‐splicing in FTD. First, we will identify pathologic RNA splicing changes and protein products of mis‐splicing that occur in the context of TDP‐43 depletion in iPSC‐derived neurons. We will next determine which of these predicted transcripts and de novo proteins occur in post‐mortem human FTD brains, as a crucial first step in biomarker development. Finally, we will develop CSF biomarkers of FTD‐related mis‐splicing through a combination of targeted proteomics and ELISA‐based assays of lead candidate biomarkers.ResultUsing CRISPRi knockdown of TDP‐43 in i3Neurons followed by total RNAseq, we detected cryptic exon formation in STMN2 as well as hundreds of additional transcripts. We developed a proteogenomic informatic pipeline to detect de novo protein products of mis‐spliced transcripts in TDP‐43 deficient i3Neurons, revealing two in‐frame de novo peptides in the MYO18A transcript. Furthermore, we detected 38 of these mis‐spliced transcripts in ALS/FTD post‐mortem cortex, including MYO18A.ConclusionThese preliminary studies indicate that our i3Neuron CRISPRi pipeline can predict disease‐relevant markers of TDP‐43 mis‐splicing and suggest a proteogenomic workflow for development of novel protein‐based biomarkers of mis‐spliced transcripts.Together, these efforts will yield early biomarkers of TDP‐43 related cellular dysfunction that can act as surrogate measures of disease onset and progression in FTD.

How dipeptide repeats cause pathology A repeat expansion in the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the most common known cause of two neurodegenerative diseases: frontotemporal dementia and amyotrophic lateral sclerosis. This expansion leads to the abnormal production of proteins of repeating dipeptides, but their contribution to disease pathogenesis remains unclear. Zhang et al. engineered a mouse model to study the consequences of one of these dipeptides—prolinearginine dipeptide repeat protein, poly(PR)—in the brain. They found that poly(PR) caused neuron loss as well as motor and memory impairments. These detrimental effects resulted from poly(PR)-induced perturbation of heterochromatin function, a tightly packed form of DNA that represses gene expression. Science , this issue p. eaav2606

ObjectiveInflammatory back pain (IBP) is often an early manifestation of spondyloarthritis (SpA), but the prognosis of patients with incident IBP is unknown. This study was undertaken to investigate long‐term outcomes in patients with IBP, and predictors of progression to SpA, in a population‐based cohort.MethodsWe conducted a retrospective, longitudinal study using the Rochester Epidemiology Project, a longstanding population‐based cohort of residents of Olmsted County, MN. Patients ages 16–35 years with clinical visits for back pain from 1999 to 2003 were identified, and we screened these patients for the presence of new‐onset IBP and performed medical record reviews to collect data on clinical, laboratory, and imaging features of SpA. Outcomes in these patients were followed up until July 2016. We used survival analysis for competing risks to examine progression to either SpA, a non‐SpA diagnosis, or resolution of back pain. Recursive partitioning was used to identify predictors of progression to SpA.ResultsAmong 5,304 patients with back pain, we identified 124 patients with new‐onset IBP. After a median follow‐up of 13.2 years, IBP had progressed to SpA in 39 patients, 15 patients developed a non‐SpA diagnosis, and 58 patients had resolution of IBP. At 10 years, the probability of having SpA was 30%, while the probability of resolution of IBP was 43%. The most important predictors for progression to SpA were uveitis, male sex, and family history of SpA.ConclusionIn a minority of patients, new‐onset IBP progresses to SpA, while IBP resolves in many. That IBP often resolves may explain the difference between the prevalence of IBP (3–6%) and the prevalence of SpA (0.4–1.3%).

ObjectiveThe long‐term outcome of patients with nonradiographic axial spondyloarthritis (SpA) is unclear, particularly whether few or most progress to ankylosing spondylitis (AS). Our objective was to examine the progression to AS in a population‐based inception cohort of patients with nonradiographic axial SpA.MethodsThe Rochester Epidemiology Project (REP) is a longstanding population‐based study of health in the residents of Olmsted County, Minnesota. We searched the REP from 1985 to 2010 using diagnostic and procedural codes for back pain, HLA–B27, and magnetic resonance imaging of the pelvis, and we performed detailed chart reviews to identify subjects who fulfilled the Assessment of SpondyloArthritis international Society classification criteria for axial SpA but did not have AS. We followed these subjects from disease onset to March 15, 2015, and used survival analysis to measure the time to progression to AS.ResultsAfter screening 2,151 patients, we identified 83 subjects with new‐onset nonradiographic axial SpA. Over a mean follow‐up of 10.6 years, progression to AS occurred in 16 patients. The probability that the condition would remain as nonradiographic axial SpA at 5, 10, and 15 years was 93.6%, 82.7%, and 73.6%, respectively. There was more frequent and more rapid progression among subjects in the imaging arm (n = 18) than among those in the clinical arm (n = 65) (28% versus 17%; hazard ratio 3.50 [95% confidence interval 1.15–10.6], P = 0.02).ConclusionProgression to AS occurred in a minority (26%) of patients with nonradiographic axial SpA over as long as 15 years of follow‐up. This suggests that the classification criteria for nonradiographic axial SpA identifies many patients in whom the condition is unlikely to progress to AS or that nonradiographic axial SpA represents a prolonged prodromal state that takes longer to evolve to AS and thus requires longer follow‐up.

Objective: To report a case in which a young woman receiving medroxyprogesterone acetate injections developed deep vein thrombosis (DVT) after prolonged travel. Case Summary: An obese 27-year-old African American woman who had been receiving medroxyprogesterone acetate injections 150 mg intramuscularly every 3 months for 6 years experienced DVT after a 56-hour car ride. The patient's known risk factors for DVT included immobility, obesity (140 kg), and medroxyprogesterone acetate therapy. Family and personal history for thrombotic events were denied. Tests were performed after detection of the DVT to assess the patient for anticoagulation defects; results revealed an unidentified underlying protein S deficiency. All other test results were within normal limits. Discussion: Based on the Naranjo probability scale, it is possible that the DVT experienced by our patient was due to medroxyprogesterone acetate. Although she did have other risk factors for DVT, her underlying protein S deficiency was diagnosed after the thrombosis. Literature describing the relationship between the injectable form of contraception and thrombosis is limited. Therefore, this report reviews protein S deficiency, the relationship between oral contraceptives (OCs) and thrombosis, the influence of immobility on thrombosis development, and the clinical implications of evaluating patients for underlying inherited clotting abnormalities before initiating OCs. Conclusions: When considering whether to prescribe contraceptives, clinicians should assess the patient's risk factors for thrombosis, such as family or personal history. Although generally not recommended, prescreening tests may be considered if there is a positive family or personal history.

Background and Purpose— Telemedicine techniques can be used to address the rural–metropolitan disparity in acute stroke care. The Stroke Team Remote Evaluation Using a Digital Observation Camera (STRokE DOC) trial reported more accurate decision making for telemedicine consultations compared with telephone-only and that the California-based research network facilitated a high rate of thrombolysis use, improved data collection, low risk of complications, low technical complications, and favorable assessment times. The main objective of the STRokE DOC Arizona TIME (The Initial Mayo Clinic Experience) trial was to determine the feasibility of establishing, de novo, a single-hub, multirural spoke hospital telestroke research network across a large geographical area in Arizona by replicating the STRokE DOC protocol. Methods— Methods included prospective, single-hub, 2-spoke, randomized, blinded, controlled trial of a 2-way, site-independent, audiovisual telemedicine system designed for remote examination of adult patients with acute stroke versus telephone consultation to assess eligibility for treatment with intravenous thrombolysis. The primary outcome measure was whether the decision to give thrombolysis was correct. Secondary outcomes were rate of thrombolytic use, 90-day functional outcomes, incidence of intracerebral hemorrhages, and technical observations. Results— From December 2007 to October 2008, 54 patients were assessed, 27 of whom were randomized to each arm. Mean National Institutes of Health Stroke Scale score at presentation was 7.3 (SD 6.2) points. No consultations were aborted; however, technical problems (74%) were prevalent in the telemedicine arm. Overall, the correct treatment decision was established in 87% of the consultations. Both modalities, telephone (89% correct) and telemedicine (85% correct), performed well. Intravenous thrombolytic treatment was used in 30% of the telemedicine and telephone consultations. Good functional outcomes at 90 days were not significantly different. There were no statistically significant differences in mortality (4% in telemedicine and 11% in telephone) or rates of intracerebral hemorrhage (4% in telemedicine and 0% in telephone). Conclusions— It is feasible to extend the original STRokE DOC trial protocol to a new state and establish an operational single-hub, multispoke rural hospital telestroke research network in Arizona. The trial was not designed to have sufficient power to detect a difference between the 2 consultative modes: telemedicine and telephone-only. Whether by telemedicine or telephone consultative modalities, there were appropriate treatment decisions, high rates of thrombolysis use, improved data collection, low rates of intracerebral hemorrhage, and equally favorable time requirements. The learning curve was steep for the hub and spoke personnel of the new telestroke network, as reflected by frequent technical problems. Overall, the results support the effectiveness of highly organized and structured stroke telemedicine networks for extending expert stroke care into rural remote communities lacking sufficient neurological expertise.