High-resolution CT phenotypes in pulmonary sarcoidosis: a multinational Delphi consensus study

One view of sarcoidosis is that the term covers many different diseases. However, no classification framework exists for the future exploration of pathogenetic pathways, genetic or trigger predilections, patterns of lung function impairment, or treatment separations, or for the development of diagnostic algorithms or relevant outcome measures. We aimed to establish agreement on high-resolution CT (HRCT) phenotypic separations in sarcoidosis to anchor future CT research through a multinational two-round Delphi consensus process. Delphi participants included members of the Fleischner Society and the World Association of Sarcoidosis and other Granulomatous Disorders, as well as members' nominees. 146 individuals (98 chest physicians, 48 thoracic radiologists) from 28 countries took part, 144 of whom completed both Delphi rounds. After rating of 35 Delphi statements on a five-point Likert scale, consensus was achieved for 22 (63%) statements. There was 97% agreement on the existence of distinct HRCT phenotypes, with seven HRCT phenotypes that were categorised by participants as non-fibrotic or likely to be fibrotic. The international consensus reached in this Delphi exercise justifies the formulation of a CT classification as a basis for the possible definition of separate diseases. Further refinement of phenotypes with rapidly achievable CT studies is now needed to underpin the development of a formal classification of sarcoidosis

Soluble brain homogenates from diverse human and mouse sources preferentially seed diffuse Aβ plaque pathology when injected into newborn mouse hosts

Background: Seeding of pathology related to Alzheimer’s disease (AD) and Lewy body disease (LBD) by tissue homogenates or purified protein aggregates in various model systems has revealed prion-like properties of these disorders. Typically, these homogenates are injected into adult mice stereotaxically. Injection of brain lysates into newborn mice represents an alternative approach of delivering seeds that could direct the evolution of amyloid-β (Aβ) pathology co-mixed with either tau or α-synuclein (αSyn) pathology in susceptible mouse models. Methods: Homogenates of human pre-frontal cortex were injected into the lateral ventricles of newborn (P0) mice expressing a mutant humanized amyloid precursor protein (APP), human P301L tau, human wild type αSyn, or combinations thereof. The homogenates were prepared from AD and AD/LBD cases displaying variable degrees of Aβ pathology and co-existing tau and αSyn deposits. Behavioral assessments of APP transgenic mice injected with AD brain lysates were conducted. For comparison, homogenates of aged APP transgenic mice that preferentially exhibit diffuse or cored deposits were similarly injected into the brains of newborn APP mice. Results: We observed that lysates from the brains with AD (Aβ+, tau+), AD/LBD (Aβ+, tau+, αSyn+), or Pathological Aging (Aβ+, tau-, αSyn-) efficiently seeded diffuse Aβ deposits. Moderate seeding of cerebral amyloid angiopathy (CAA) was also observed. No animal of any genotype developed discernable tau or αSyn pathology. Performance in fear-conditioning cognitive tasks was not significantly altered in APP transgenic animals injected with AD brain lysates compared to nontransgenic controls. Homogenates prepared from aged APP transgenic mice with diffuse Aβ deposits induced similar deposits in APP host mice; whereas homogenates from APP mice with cored deposits induced similar cored deposits, albeit at a lower level. Conclusions: These findings are consistent with the idea that diffuse Aβ pathology, which is a common feature of human AD, AD/LBD, and PA brains, may arise from a distinct strain of misfolded Aβ that is highly transmissible to newborn transgenic APP mice. Seeding of tau or αSyn comorbidities was inefficient in the models we used, indicating that additional methodological refinement will be needed to efficiently seed AD or AD/LBD mixed pathologies by injecting newborn mice

Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder

Developmental delay and intellectual disability (DD and ID) are heterogeneous phenotypes that arise in many rare monogenic disorders. Because of this rarity, developing cohorts with enough individuals to robustly identify disease-associated genes is challenging. Social-media platforms that facilitate data sharing among sequencing labs can help to address this challenge. Through one such tool, GeneMatcher, we identified nine DD- and/or ID-affected probands with a rare, heterozygous variant in the gene encoding the serine/threonine-protein kinase BRSK2. All probands have a speech delay, and most present with intellectual disability, motor delay, behavioral issues, and autism. Six of the nine variants are predicted to result in loss of function, and computational modeling predicts that the remaining three missense variants are damaging to BRSK2 structure and function. All nine variants are absent from large variant databases, and BRSK2 is, in general, relatively intolerant to protein-altering variation among humans. In all six probands for whom parents were available, the mutations were found to have arisen de novo. Five of these de novo variants were from cohorts with at least 400 sequenced probands; collectively, the cohorts span 3,429 probands, and the observed rate of de novo variation in these cohorts is significantly higher than the estimated background-mutation rate (p = 2.46 × 10$^{-6}$). We also find that exome sequencing provides lower coverage and appears less sensitive to rare variation in BRSK2 than does genome sequencing; this fact most likely reduces BRSK2's visibility in many clinical and research sequencing efforts. Altogether, our results implicate damaging variation in BRSK2 as a source of neurodevelopmental disease

Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder

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