Spatial navigation deficits — overlooked cognitive marker for preclinical Alzheimer disease?

Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities

Predictors of Access to Rehabilitation in the Year Following Traumatic Brain Injury : A European Prospective and Multicenter Study

Background Although rehabilitation is beneficial for individuals with traumatic brain injury (TBI), a significant proportion of them do not receive adequate rehabilitation after acute care. Objective Therefore, the goal of this prospective and multicenter study was to investigate predictors of access to rehabilitation in the year following injury in patients with TBI. Methods Data from a large European study (CENTER-TBI), including TBIs of all severities between December 2014 and December 2017 were used (N = 4498 patients). Participants were dichotomized into those who had and those who did not have access to rehabilitation in the year following TBI. Potential predictors included sociodemographic factors, psychoactive substance use, preinjury medical history, injury-related factors, and factors related to medical care, complications, and discharge. Results In the year following traumatic injury, 31.4% of patients received rehabilitation services. Access to rehabilitation was positively and significantly predicted by female sex (odds ratio [OR] = 1.50), increased number of years of education completed (OR = 1.05), living in Northern (OR = 1.62; reference: Western Europe) or Southern Europe (OR = 1.74), lower prehospital Glasgow Coma Scale score (OR = 1.03), higher Injury Severity Score (OR = 1.01), intracranial (OR = 1.33) and extracranial (OR = 1.99) surgery, and extracranial complication (OR = 1.75). On contrast, significant negative predictors were lack of preinjury employment (OR = 0.80), living in Central and Eastern Europe (OR = 0.42), and admission to hospital ward (OR = 0.47; reference: admission to intensive care unit) or direct discharge from emergency room (OR = 0.24). Conclusions Based on these findings, there is an urgent need to implement national and international guidelines and strategies for access to rehabilitation after TBI.Peer reviewe

Evolution of the Mongol-Okhotsk ocean as constrained by new palaeomagnetic data from the Mongol-Okhotsk suture zone, Siberia

This paper presents new data from palaeomagnetic investigations on the Upper Palaeozoic and Mesozoic geological units from the Siberian platform and the Mongol-Okhotsk suture zone. Within the southern portion of the Mongol-Okhotsk suture we collected palaeomagnetic samples from the Late Permian Belektuy formation (Borzya region; 50.7°N, 116.9°E) and the Middle-Late Jurassic Shadaron formation (Unda-Daya; 51.5°N, 117.5°E). We sampled the Late Permian Alentuy formation (Khilok region; 50.8°N, 107.2°E), the Early to Middle Jurassic Irkutsk sedimentary basin (ISB; 52.0°N, 104.0°E), the Late Jurassic Badin formation (Mogzon region; 51.8°N, 112.0°E), and the Early Cretaceous Gusinoozesk formation (Gusinoc Lake region; 51.2°N, 106.5°E) additionally in the northern region of the Mongol-Okhotsk suture. Apart from the results of the ISB and Gusinoozersk formations, which show very large ellipses of confidence and might be the present-day geomagnetic field overprint, our results allow us to constrain the evolution of the Mongol-Okhotsk Ocean palaeomagnetically from the Late Permian to the Middle-Late Jurassic. They confirm that this large Permian ocean closed during the Jurassic, ending up in the late Jurassic or the beginning of the Cretaceous in the eastern end of the suture zone, as suspected on geological grounds. However, although geological data suggest a Middle Jurassic closure of the Mongol-Okhotsk Ocean in the west Trans-Baikal region, our data show evidence of a still large palaeolatitude difference between the Amuria and Siberia blocks. This is interpreted as a result of the quite fast closure of the ocean after the Middle Jurassic. Finally, our new palaeomagnetic results exhibit very large tectonic rotations around local vertical axes, which we interpret as probably arising both from collision processes and from a left-lateral shear movement along the suture zone, due to the eastward extrusion of Mongolia under the effect of the collision of India into Asia

Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3' regulatory region.

International audienceB-cell malignancies, such as human Burkitt's lymphoma, often contain translocations that link c-myc or other proto-oncogenes to the immunoglobulin heavy chain locus (IgH, encoded by Igh). The nature of elements that activate oncogenes within such translocations has been a long-standing question. Translocations within Igh involve DNA double-strand breaks initiated either by the RAG1/2 endonuclease during variable, diversity and joining gene segment (V(D)J) recombination, or by activation-induced cytidine deaminase (AID, also known as AICDA) during class switch recombination (CSR). V(D)J recombination in progenitor B (pro-B) cells assembles Igh variable region exons upstream of mu constant region (Cmu) exons, which are the first of several sets of C(H) exons ('C(H) genes') within a C(H) locus that span several hundred kilobases (kb). In mature B cells, CSR deletes Cmu and replaces it with a downstream C(H) gene. An intronic enhancer (iEmu) between the variable region exons and Cmu promotes V(D)J recombination in developing B cells. Furthermore, the Igh 3' regulatory region (Igh3'RR) lies downstream of the C(H) locus and modulates CSR by long-range transcriptional enhancement of C(H) genes. Transgenic mice bearing iEmu or Igh3'RR sequences fused to c-myc are predisposed to B lymphomas, demonstrating that such elements can confer oncogenic c-myc expression. However, in many B-cell lymphomas, Igh-c-myc translocations delete iEmu and place c-myc up to 200 kb upstream of the Igh3'RR. Here we address the oncogenic role of the Igh3'RR by inactivating it in two distinct mouse models for B-cell lymphoma with Igh-c-myc translocations. We show that the Igh3'RR is dispensable for pro-B-cell lymphomas with V(D)J recombination-initiated translocations, but is required for peripheral B-cell lymphomas with CSR-associated translocations. As the Igh3'RR is not required for CSR-associated Igh breaks or Igh-c-myc translocations in peripheral B-cell lymphoma progenitors, we conclude that this regulatory region confers oncogenic activity by long-range and developmental stage-specific activation of translocated c-myc genes

The Changing Face of the Earth Throughout the Ages

International audienc