TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy.

TMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone T185S coding variant contributes to protection, and if the presence of TMEM106B is helpful or harmful in the context of disease. Here, we address both questions while expanding the scope of TMEM106B study from TDP-43 to models of tauopathy. We generated knockout mice with constitutive deletion of TMEM106B, alongside knock-in mice encoding the T186S knock-in mutation (equivalent to the human T185S variant), and crossed both with a P301S transgenic tau model to study how these manipulations impacted disease phenotypes. We found that TMEM106B deletion accelerated cognitive decline, hind limb paralysis, tau pathology, and neurodegeneration. TMEM106B deletion also increased transcriptional correlation with human AD and the functional pathways enriched in KO:tau mice aligned with those of AD. In contrast, the coding variant protected against tau-associated cognitive decline, synaptic impairment, neurodegeneration, and paralysis without affecting tau pathology. Our findings reveal that TMEM106B is a critical safeguard against tau aggregation, and that loss of this protein has a profound effect on sequelae of tauopathy. Our study further demonstrates that the coding variant is functionally relevant and contributes to neuroprotection downstream of tau pathology to preserve cognitive function.

TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy.

TMEM106B is a risk modifier for a growing list of age-associated dementias including Alzheimer’s and frontotemporal dementia, yet its function remains elusive. Two key questions that emerge from past work are whether the conservative T185S coding variant found in the minor haplotype contributes to protection, and whether the presence of TMEM106B is helpful or harmful in the context of disease. Here we address both issues while extending the testbed for study of TMEM106B from models of TDP to tauopathy. We show that TMEM106B deletion accelerates cognitive decline, hindlimb paralysis, neuropathology, and neurodegeneration. TMEM106B deletion also increases transcriptional overlap with human AD, making it a better model of disease than tau alone. In contrast, the coding variant protects against tau-associated cognitive decline, neurodegeneration, and paralysis without affecting tau pathology. Our findings show that the coding variant contributes to neuroprotection and suggest that TMEM106B is a critical safeguard against tau aggregation.

Longitudinal Assessment of Tau-Associated Pathology by 18F-THK5351 PET Imaging: A Histological, Biochemical, and Behavioral Study.

Several common and debilitating neurodegenerative disorders are characterized by the intracellular accumulation of neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein. In Alzheimer's disease (AD), NFTs are accompanied by extracellular amyloid-beta (Aß), but primary tauopathy disorders are marked by the accumulation of tau protein alone, including forms of frontotemporal dementia (FTD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), among others. 18F-THK5351 has been reported to bind pathological tau as well as associated reactive astrogliosis. The goal of this study was to validate the ability of the PET tracer 18F-THK5351 to detect early changes in tau-related pathology and its relation to other pathological hallmarks. We demonstrated elevated in vivo 18F-THK5351 PET signaling over time in transgenic P301S tau mice from 8 months that had a positive correlation with histological and biochemical tau changes, as well as motor, memory, and learning impairment. This study indicates that 18F-THK5351 may help fill a critical need to develop PET imaging tracers that detect aberrant tau aggregation and related neuropathology in order to diagnose the onset of tauopathies, gain insights into their underlying pathophysiologies, and to have a reliable biomarker to follow during treatment trials.

What Do Confessions Reveal About Abusive Head Trauma? A Systematic Review.

Although confessions related to abusive head trauma (AHT) are reported, no detailed analysis exists. Therefore, we systematically reviewed studies of AHT confessions and examined the details, including country of origin, mechanisms and perpetrators' characteristics [PUBLISHER - THE PRECEDING UNDERLINED TEXT IS FOR THE MARGIN]. Employing 36 search terms across three search engines, we searched Medline and CINAHL from 1963 to 2018. All relevant studies underwent two independent reviews and data extraction. Descriptive statistics were used to characterise the sample; chi square and Fisher's exact tests were used to assess differences in demographic and clinical characteristics. Of 6759 identified studies, 157 full texts were reviewed and 55 articles from 15 countries spanning four continents were included. Included articles contained 434 confessions. The mechanisms of abuse included shaking alone (64.1%), impact alone (17.1%), shaking plus impact (18.0%) and other (0.9%). There was no statistically significant difference in the percentage of confessions reporting shaking alone when comparing continents: North America (64.0%), Europe (64.2%) and Oceania (60.0%; P=.92), or when comparing circumstances in which the confession was obtained: medical evaluation (74.6%) vs police or judicial investigations (63.4%; P=.11). Of 119 cases with identified perpetrators, 67.2 per cent were cases with males alone. Confessions reveal striking similarities in the mechanism of AHT (predominantly shaking) and occur across the globe.

Major complications associated with fork-based and screw-based tibial tuberosity advancement implants: 438 cases.

This study reports major complications in a large cohort of dogs following tibial tuberosity advancement using either a fork-based or a screw-based implant system. Four hundred thirty-eight stifles were included in the study and major complications occurred in 51 stifles. Explanatory variables evaluated included implant type and body weight. No variables evaluated were associated with major complications.

Complications majeures associées à des implants à base de fourche et de vis lors de chirurgie d'avancement de la tubérosité tibiale antérieure : 438 cas. Cette étude présente un rapport sur les complications majeures dans une grande cohorte de chiens après une chirurgie d'avancement de la tubérosité tibiale à l'aide d'un système d'implant à base de fourche ou de vis. Quatre cent trente-huit grassets ont été inclus dans l'étude et des complications majeures se sont produites dans 51 grassets. Les variables explicatives comprenaient le type d'implant et le poids corporel. Aucune variable évaluée n'a été associée à des complications majeures.(Traduit par Isabelle Vallières).

Mimics of child abuse: Can choking explain abusive head trauma?

Choking is one of the alternative explanations of abusive head trauma in children that have been offered in courtroom testimony and in the media. Most of these explanations - including choking - are not scientifically supported. This article highlights four points. (1) The origins of choking as an explanation for intracranial and retinal hemorrhages are speculative. (2) Choking has been used in high profile court testimony as an explanation for the death of a child thought to have been abused. (3) A case report that proposes choking as an alternative explanation for the death of a child diagnosed with abusive head trauma includes omissions and misrepresentations of facts. (4) There was a decision by the editor of the journal that published the case report that it was not necessary to include all the facts of the case; moreover, the editor indicated that facts are not required when presenting an alternative explanation. The use of scientifically unsupported alternative explanations for abusive head trauma based on inaccurate and biased information constitutes further victimization of the abused child and represents a travesty of justice.

Use of a TTA plate for correction of severe patella baja in a Chihuahua.

A 7 yr old spayed female Chihuahua presented for right hind limb lameness and reduced stifle range of motion. Radiographs showed a marked patella baja of the right stifle and evidence of a previous surgery to correct a medial patellar luxation. A tibial tuberosity osteotomy was performed to allow proximal translation of the tibial tuberosity, which was stabilized with a tibial tuberosity advancement plate. Four weeks postoperatively, lameness and articular range of motion were improved, and the use of anti-inflammatory and analgesic medications was discontinued. The dog was still ambulating well and had no lameness 12 mo postsurgically.