Evaluation of the cognitive outcome after out-of-hospital cardiac arrest: The role of thalamus.

Cardiac arrest survivors develop a variety of neuropsychological impairments and neuroanatomical lesions. The goal of this study is to evaluate if brain voxel-based morphometry and lesional Magnetic Resonance Imaging (MRI) analyses performed in the acute phase of an Out-of-Hospital Cardiac Arrest (OHCA) can be sensitive enough to predict the persistence of neuropsychological disorders beyond 3 months. Survivors underwent a prospective brain MRI during the first month after an OHCA and performed neuropsychological assessments at 1 and 3 months. According to the second neuropsychological assessment, survivors were separated into two subgroups, a deficit subgroup with persistent memory, executive functions, attention and/or praxis disorders (n = 11) and a preserved subgroup, disorders free (n = 14). Brain vascular lesion images were investigated, and volumetric changes were compared with healthy controls. Correlations were discussed between brain MRI results, OHCA data and the second neuropsychological assessment. Analyses of acute ischemic lesions did not reveal significant differences between the two subgroups (p = .35), and correlations with cognitive impairments could not be assessed. voxel-based morphometry analyses revealed a global cerebral volume reduction for the two subgroups and a clear decrease of the right thalamic volume for the deficit subgroup. It was associated with a cognitive dysexecutive syndrome represented by four executive indexes according to the 'Groupe de Réflexion pour l'Evaluation des Fonctions EXécutives' criteria. The right thalamus atrophy seems to be more predictive than the vascular lesions and more specific than a global cerebral volume reduction of post-OHCA neuropsychological executive disorders.

Haploinsufficiency of the Primary Familial Brain Calcification Gene SLC20A2 Mediated by Disruption of a Regulatory Element.

OBJECTIVE: Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with diverse neuropsychiatric expression. Five genes were reported as PFBC causative when carrying pathogenic variants. Haploinsufficiency of SLC20A2, which encodes an inorganic phosphate importer, is a major cause of autosomal-dominant PFBC. However, PFBC remains genetically unexplained in a proportion of patients, suggesting the existence of additional genes or cryptic mutations. We analyzed exome sequencing data of 71 unrelated, genetically unexplained PFBC patients with the aim to detect copy number variations that may disrupt the expression of core PFBC-causing genes. METHODS: After the identification of a deletion upstream of SLC20A2, we assessed its consequences on gene function by reverse transcriptase droplet digital polymerase chain reaction (RT-ddPCR), an ex vivo inorganic phosphate uptake assay, and introduced the deletion of a putative SLC20A2 enhancer mapping to this region in human embryonic kidney 293 (HEK293) cells by clustered regularly interspaced short palindromic repeats (CRISPR) - CRISPR-associated protein 9 (Cas9). RESULTS: The 8p11.21 deletion, segregating with PFBC in a family, mapped 35 kb upstream of SLC20A2. The deletion carriers/normal controls ratio of relative SLC20A2 mRNA levels was 60.2% (P < 0.001). This was comparable with that of patients carrying an SLC20A2 premature stop codon (63.4%; P < 0.001). The proband exhibited a 39.3% decrease of inorganic phosphate uptake in blood (P = 0.015). In HEK293 cells, we observed a 39.8% decrease in relative SLC20A2 mRNA levels after normalization on DNA copy number (P < 0.001). DISCUSSION: We identified a deletion of an enhancer of SLC20A2 expression, with carriers showing haploinsufficiency in similar ranges to loss-of-function alleles, and we observed reduced mRNA levels after deleting this element in a cellular model. We propose a 3-step strategy to identify and easily assess the effect of such events. © 2020 International Parkinson and Movement Disorder Society.

Acute loss of psychic self-activation after cardiac arrest and delayed bilateral pallidal lesions on brain MRI.

The delay between cardiac arrest and brain MRI is usually extremely different in the few cerebral imaging studies assessing the affected brain areas. We report an unusual case of loss of psychic self-activation appeared immediately after a cardiac arrest in a middle age patient. The first brain MRI, one month after the vascular event, did not show the classical lesions typically reported, such as lesion of the caudate nucleus or the globus pallidus. Two years later, although the cognitive performances of our patient were improved, a second brain MRI demonstrated bilateral pallidal lesions, suggesting a possible mechanism with delayed hypoxic lesions.

Contribution of DNA methylation profiling to the reclassification of a variant of uncertain significance in the KDM5C gene.

KDM5C encodes a demethylase of the histone H3 lysine 4 residue, involved in chromatin regulation and gene expression. Hemizygous KDM5C pathogenic variants cause X-linked intellectual disability of Claes-Jensen type. Because of its mode of inheritance and the low specificity of the clinical phenotype, interpretation of variants can be difficult, hence the need for functional studies and biomarkers specific to this disorder. We present the case of a male patient with intellectual disability, behavioral abnormalities and subtle dysmorphic features, in which genetic investigation identified a hemizygous novel missense KDM5C variant of uncertain significance (VUS), inherited from his asymptomatic mother and present in his paucisymptomatic sister. We assessed the global genomic DNA methylation status from a whole blood sample of the proband. Global DNA methylation profiling specifically identified the recently discovered epi-signature of Claes-Jensen syndrome. This result served as a biomarker which independently highlighted KDM5C as the cause of the disorder in this patient. Because of the X-linked mode of inheritance, variant reclassification had a high impact on genetic counseling in this family. This example highlights the value of global methylome profiling in situations of variants of uncertain significance in genes with a known specific epi-signature.

Retrograde amnesia with transposition in the past: A neuropsychological and PET study of a case.

OBJECTIVE: Retrograde amnesia (RA) with a "transposition in the past" phenomenon has been rarely reported. Patients presenting disproportionate RA for all events over a defined period of time offer an opportunity to investigate the unclear relationship between autobiographical memory and the self, through the well-known self-memory system (SMS). METHOD: We report the case of a 31-year-old right-handed woman who presented to the emergency department of our tertiary care center with an ongoing episode of RA. After resolution of the episode, she had a second transient episode of RA. An extensive neuropsychological battery was performed to assess her autobiographical and nonautobiographical memory during and after the 2 episodes of RA. She also had an 18F-Fluorodeoxyglucose Positron Emission Tomography (FDG PET) scan during the second RA episode. RESULTS: During the 2 RA episodes, results showed lacunar amnesia for autobiographical as well as nonautobiographical memories of the time period between the present and the past 15 years, with preserved anterograde memory. Moreover, her memories before this lost period were more accurate than those after the 2 RA episodes. During the 2 RA episodes, our patient experienced a "transposition in the past" phenomenon. Statistical analysis of the PET scan demonstrated a significant hypometabolism within the right hippocampus. CONCLUSION: The "transposition in the past" phenomenon illustrates the relationship between both episodic and autobiographical memories and the functioning of self, according to the SMS model. Moreover, this case suggests the involvement of the hippocampus in this phenomenon. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Mirrored and rotated stimuli are not the same: A neuropsychological and lesion mapping study.

Agnosia for mirrored stimuli is a rare clinical deficit. Only eight patients have been reported in the literature so far and little is known about the neural substrates of this agnosia. Using a previously developed experimental test designed to assess this agnosia, namely the Mirror and Orientation Agnosia Test (MOAT), as well as voxel-lesion symptom mapping (VLSM), we tested the hypothesis that focal brain-injured patients with right parietal damage would be impaired in the discrimination between the canonical view of a visual object and its mirrored and rotated images. Thirty-four consecutively recruited patients with a stroke involving the right or left parietal lobe have been included: twenty patients (59%) had a deficit on at least one of the six conditions of the MOAT, fourteen patients (41%) had a deficit on the mirror condition, twelve patients (35%) had a deficit on at least one the four rotated conditions and one had a truly selective agnosia for mirrored stimuli. A lesion analysis showed that discrimination of mirrored stimuli was correlated to the mesial part of the posterior superior temporal gyrus and the lateral part of the inferior parietal lobule, while discrimination of rotated stimuli was correlated to the lateral part of the posterior superior temporal gyrus and the mesial part of the inferior parietal lobule, with only a small overlap between the two. These data suggest that the right visual 'dorsal' pathway is essential for accurate perception of mirrored and rotated stimuli, with a selective cognitive process and anatomical network underlying our ability to discriminate between mirrored images, different from the process of discriminating between rotated images.

Impaired functional differentiation for categories of objects in the ventral visual stream: A case of developmental visual impairment.

We report the case of a 14-year-old girl suffering from severe developmental visual impairment along with delayed language and cognitive development, and featuring a clear-cut dissociation between spared dorsal and impaired ventral visual pathways. Visual recognition of objects, including faces and printed words, was affected. In contrast, movement perception and visually guided motor control were preserved. Structural MRI was normal on inspection, but Voxel Based Morphometry (VBM) revealed reduced grey matter density in the mesial occipital and ventral occipito-temporal cortex. Functional MRI during the perception of line drawings uncovered impaired differentiation which is normally observed at even younger ages: no local category preferences could be identified within the occipito-temporal cortex for faces, houses, words or tools. In contrast, movement-related activations appeared to be normal. Finally, those abnormalities evolved on the background of chronic bilateral occipital epileptic activity, including continuous spike-wave discharges during sleep, which may be considered as the primary cause of non-specific intellectual disability and visual impairment.

Visual agnosia and posterior cerebral artery infarcts: an anatomical-clinical study.

BACKGROUND: To evaluate systematically the cognitive deficits following posterior cerebral artery (PCA) strokes, especially agnosic visual disorders, and to study anatomical-clinical correlations. METHODS AND FINDINGS: We investigated 31 patients at the chronic stage (mean duration of 29.1 months post infarct) with standardized cognitive tests. New experimental tests were used to assess visual impairments for words, faces, houses, and objects. Forty-one healthy subjects participated as controls. Brain lesions were normalized, combined, and related to occipitotemporal areas responsive to specific visual categories, including words (VWFA), faces (FFA and OFA), houses (PPA) and common objects (LOC). Lesions were located in the left hemisphere in 15 patients, in the right in 13, and bilaterally in 3. Visual field defects were found in 23 patients. Twenty patients had a visual disorder in at least one of the experimental tests (9 with faces, 10 with houses, 7 with phones, 3 with words). Six patients had a deficit just for a single category of stimulus. The regions of maximum overlap of brain lesions associated with a deficit for a given category of stimuli were contiguous to the peaks of the corresponding functional areas as identified in normal subjects. However, the strength of anatomical-clinical correlations was greater for words than for faces or houses, probably due to the stronger lateralization of the VWFA, as compared to the FFA or the PPA. CONCLUSIONS: Agnosic visual disorders following PCA infarcts are more frequent than previously reported. Dedicated batteries of tests, such as those developed here, are required to identify such deficits, which may escape clinical notice. The spatial relationships of lesions and of regions activated in normal subjects predict the nature of the deficits, although individual variability and bilaterally represented systems may blur those correlations.