SARS-CoV-2's brain impact: revealing cortical and cerebellar differences via cluster analysis in COVID-19 recovered patients.

BACKGROUND: COVID-19 is a disease known for its neurological involvement. SARS-CoV-2 infection triggers neuroinflammation, which could significantly contribute to the development of long-term neurological symptoms and structural alterations in the gray matter. However, the existence of a consistent pattern of cerebral atrophy remains uncertain. OBJECTIVE: Our study aimed to identify patterns of brain involvement in recovered COVID-19 patients and explore potential relationships with clinical variables during hospitalization. METHODOLOGY: In this study, we included 39 recovered patients and 39 controls from a pre-pandemic database to ensure their non-exposure to the virus. We obtained clinical data of the patients during hospitalization, and 3 months later; in addition we obtained T1-weighted magnetic resonance images and performed standard screening cognitive tests. RESULTS: We identified two groups of recovered patients based on a cluster analysis of the significant cortical thickness differences between patients and controls. Group 1 displayed significant cortical thickness differences in specific cerebral regions, while Group 2 exhibited significant differences in the cerebellum, though neither group showed cognitive deterioration at the group level. Notably, Group 1 showed a tendency of higher D-dimer values during hospitalization compared to Group 2, prior to p-value correction. CONCLUSION: This data-driven division into two groups based on the brain structural differences, and the possible link to D-dimer values may provide insights into the underlying mechanisms of SARS-COV-2 neurological disruption and its impact on the brain during and after recovery from the disease.

Frontostriatal Circuits Alterations Associated with Cognitive Flexibility Deterioration in Huntington's Disease.

BACKGROUND: Recent resting-state functional magnetic resonance imaging studies have reported abnormal functional connectivity (FC) in the prefrontal cortex (PFC)-striatum circuit in patients with premanifest Huntington's disease (HD). However, there is a lack of evidence showing persistence of abnormal frontostriatal FC and its relation to cognitive flexibility performance in patients with clinically manifest HD. OBJECTIVE: The aim of this study was to evaluate the resting-state FC integrity of the frontostriatal circuit and its relation to cognitive flexibility in HD patients and healthy controls (HCs). METHOD: Eighteen patients with early clinical HD manifestation and 18 HCs matched for age, sex, and education participated in this study. Both groups performed the Cambridge Neuropsychological Test Automated Battery (CANTAB) Intra-Extra Dimensional (IED) set-shift task, which measures cognitive flexibility. Resting-state functional magnetic resonance images were also acquired to examine the FC in specific frontostriatal circuits. Eight regions of interest were preselected based on regions previously associated with extradimensional (ED) shifting in patients with premanifest HD. RESULTS: Significant negative correlations between the number of attentional set-shifting errors and the ventral striatum-ventrolateral PFC FC were found in the HD group. This group also showed negative FC correlations between the total errors and the FC between right ventral striatum-right ventrolateral PFC, left ventral striatum-left ventrolateral PFC, and right ventral striatum-left ventrolateral PFC. Negative correlations between the ED errors and left ventral striatum-left ventrolateral PFC and right ventral striatum-right ventrolateral PFC FC were also found. Finally, a positive correlation between the number of stages completed and left ventral striatum-left ventrolateral PFC FC was found. CONCLUSIONS: Manifest HD patients show significant cognitive flexibility deficits in attentional set-shifting that are associated with FC alterations in the frontostriatal circuit. These results show that FC abnormalities found in the prodromal stage of the disease can also be associated with cognitive flexibility deficits at a later clinical stage, making them good candidates to be explored in longitudinal studies.

ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by an expanded pentanucleotide repeat in the ATXN10 gene. This repeat expansion, when fully penetrant, has a size of 850-4,500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., seizures. Here, we describe a Mexican kindred in which we identified both pure (ATTCT)n and mixed (ATTCT)n-(ATTCC)n expansions in the same family. We used amplification-free targeted sequencing and optical genome mapping to decipher the composition of these repeat expansions. We found a considerable degree of mosaicism of the repeat expansion. This mosaicism was confirmed in skin fibroblasts from individuals with ATXN10 expansions with RNAScope in situ hybridization. All affected family members with the mixed ATXN10 repeat expansion showed typical clinical signs of spinocerebellar ataxia and epilepsy. In contrast, individuals with the pure ATXN10 expansion present with Parkinson's disease or are unaffected, even in individuals more than 20 years older than the average age at onset for SCA10. Our findings suggest that the pure (ATTCT)n expansion is non-pathogenic, while repeat interruptions, e.g., (ATTCC)n, are necessary to cause SCA10. This mechanism has been recently described for several other repeat expansions including SCA31 (BEAN1), SCA37 (DAB1), and three loci for benign adult familial myoclonic epilepsy BAFME (SAMD12, TNRC6A, RAPGEF2). Therefore, long-read sequencing and optical genome mapping of the entire genomic structure of repeat expansions are critical for clinical practice and genetic counseling, as variations in the repeat can affect disease penetrance, symptoms, and disease trajectory.

Critical role of acute hypoxemia on the cognitive impairment after severe COVID-19 pneumonia: a multivariate causality model analysis.

BACKGROUND: A high proportion of coronavirus disease 2019 (COVID-19) survivors may develop long-term cognitive impairment. We aimed to develop a multivariate causal model exposing the links between COVID-19-associated biomarkers, illness-related variables, and their effects on cognitive performance. METHODS: In this prospective study, we assess the potential drivers for the development of cognitive impairment in patients with severe COVID-19 pneumonia aged ≥ 18 years at 6-month follow-up after hospital discharge, using the Montreal Cognitive Assessment (MoCA). Patients with pre-existing cognitive impairment were excluded. Laboratory results at hospital admission were clustered by principal component analysis (PCA) and included in a path analysis model evaluating the causal relationship between age, comorbidities, hypoxemia, invasive mechanical ventilation (IMV) requirement, in-hospital delirium, and cognitive performance. RESULTS: We studied 92 patients: 54 (58.7%) men and 38 (41.3%) women, with median age of 50 years (interquartile range 42-55), among whom 50 (54.4%) tested positive for cognitive impairment at 6-month follow-up. Path analysis revealed a direct link between the thrombo-inflammatory component of PCA (C-reactive protein, fibrinogen, and neutrophils) and hypoxemia severity at hospital admission. Our model showed that low PaO2/FiO2 ratio values, unlike the thrombo-inflammatory component, had a direct effect on cognitive performance, independent from age, in-hospital delirium, and invasive mechanical ventilation. CONCLUSION: In this study, biomarkers of thrombo-inflammation in COVID-19 and low PaO2/FiO2 had a negative effect on cognitive performance 6 months after hospital discharge. These results highlight the critical role of hypoxemia as a driver for impaired cognition in the mid-term.

Mapping the Cerebellar Cognitive Affective Syndrome in Patients with Chronic Cerebellar Strokes.

The cerebellar cognitive affective syndrome (CCAS) has been consistently described in patients with acute/subacute cerebellar injuries. However, studies with chronic patients have had controversial findings that have not been explored with new cerebellar-target tests, such as the CCAS scale (CCAS-S). The objective of this research is to prove and contrast the usefulness of the CCAS-S and the Montreal Cognitive Assessment (MoCA) test to evaluate cognitive/affective impairments in patients with chronic acquired cerebellar lesions, and to map the cerebellar areas whose lesions correlated with dysfunctions in these tests. CCAS-S and MoCA were administrated to 22 patients with isolated chronic cerebellar strokes and a matched comparison group. The neural bases underpinning both tests were explored with multivariate lesion-symptom mapping (LSM) methods. MoCA and CCAS-S had an adequate test performance with efficient discrimination between patients and healthy volunteers. However, only impairments determined by the CCAS-S resulted in significant regional localization within the cerebellum. Specifically, patients with chronic cerebellar lesions in right-lateralized posterolateral regions manifested cognitive impairments inherent to CCAS. These findings concurred with the anterior-sensorimotor/posterior-cognitive dichotomy in the human cerebellum and revealed clinically intra- and cross-lobular significant regions (portions of right lobule VI, VII, Crus I-II) for verbal tasks that overlap with the "language" functional boundaries in the cerebellum. Our findings prove the usefulness of MoCA and CCAS-S to reveal cognitive impairments in patients with chronic acquired cerebellar lesions. This study extends the understanding of long-term CCAS and introduces multivariate LSM methods to identify clinically intra- and cross-lobular significant regions underpinning chronic CCAS.

Cognitive Impairments in Spinocerebellar Ataxia Type 10 and Their Relation to Cortical Thickness.

BACKGROUND: Spinocerebellar ataxia type 10 is a neurodegenerative disorder caused by the expansion of an ATTCT pentanucleotide repeat. Its clinical features include ataxia and, in some cases, epileptic seizures. There is, however, a dearth of information about its cognitive deficits and the neural bases underpinning them. OBJECTIVES: The objectives of this study were to characterize the performance of spinocerebellar ataxia type 10 patients in 2 cognitive domains typically affected in spinocerebellar ataxias, memory and executive function, and to correlate the identified cognitive impairments with ataxia severity and cerebral/cerebellar cortical thickness, as quantified by MRI. METHODS: Memory and executive function tests were administered to 17 genetically confirmed Mexican spinocerebellar ataxia type 10 patients, and their results were compared with 17 healthy matched volunteers. MRI was performed in 16 patients. RESULTS: Patients showed deficits in visual and visuospatial short-term memory, reduced storage capacity for verbal memory, and impaired monitoring, planning, and cognitive flexibility, which were ataxia independent. Patients with seizures (n = 9) and without seizures (n = 8) did not differ significantly in cognitive performance. There were significant correlations between short-term visuospatial memory impairment and posterior cerebellar lobe cortical thickness (bilateral lobule VI, IX, and right X). Cognitive flexibility deficiencies correlated with cerebral cortical thickness in the left middle frontal, cingulate, opercular, and temporal gyri. Cerebellar cortical thickness in several bilateral regions was correlated with motor impairment. CONCLUSIONS: Patients with spinocerebellar ataxia type 10 show significant memory and executive dysfunction that can be correlated with deterioration in the posterior lobe of the cerebellum and prefrontal, cingulate, and middle temporal cortices. © 2021 International Parkinson and Movement Disorder Society.