Cognitive profile in multiple sclerosis and post-COVID condition: a comparative study using a unified taxonomy.

Post-COVID condition (PCC) and multiple sclerosis (MS) share some clinical and demographic features, including cognitive symptoms and fatigue. Some pathophysiological mechanisms well-known in MS, such as autoimmunity, neuroinflammation and myelin damage, have also been implicated in PCC. In this study, we aimed to compare the cognitive phenotypes of two large cohorts of patients with PCC and MS, and to evaluate the relationship between fatigue and cognitive performance. Cross-sectional study including 218 patients with PCC and 218 with MS matched by age, sex, and years of education. Patients were evaluated with a comprehensive neuropsychological protocol and were categorized according to the International Classification of Cognitive Disorders system. Fatigue and depression were also assessed. Cognitive profiles of PCC and MS largely overlapped, with a greater impairment in episodic memory in MS, but with small effect sizes. The most salient deficits in both disorders were in attention and processing speed. The severity of fatigue was greater in patients with PCC. Still, the correlations between fatigue severity and neuropsychological tests were more prominent in the case of MS. There were no differences in the severity of depression among groups. Our study found similar cognitive profiles in PCC and MS. Fatigue was more severe in PCC, but was more associated with cognitive performance in MS. Further comparative studies addressing the mechanisms related to cognitive dysfunction and fatigue may be of interest to advance the knowledge of these disorders and develop new therapies.

TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43.

TDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as "TDP-43 proteinopathies". Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of ∼50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usually associated with ALS, many clinical reports have linked these mutations to cognitive impairments and/or FTD, but also to other neurodegenerative disorders including Parkinsonism (PD) or progressive supranuclear palsy (PSP). TDP-43 is a ubiquitously expressed, highly conserved RNA-binding protein that is involved in many cellular processes, mainly RNA metabolism. To investigate systemic pathological mechanisms in TDP-43 proteinopathies, aiming to capture the pleiotropic effects of TDP-43 mutations, we have further characterised a mouse model carrying a point mutation (M323K) within the endogenous Tardbp gene. Homozygous mutant mice developed cognitive and behavioural deficits as early as 3 months of age. This was coupled with significant brain structural abnormalities, mainly in the cortex, hippocampus, and white matter fibres, together with progressive cortical interneuron degeneration and neuroinflammation. At the motor level, progressive phenotypes appeared around 6 months of age. Thus, cognitive phenotypes appeared to be of a developmental origin with a mild associated progressive neurodegeneration, while the motor and neuromuscular phenotypes seemed neurodegenerative, underlined by a progressive loss of upper and lower motor neurons as well as distal denervation. This is accompanied by progressive elevated TDP-43 protein and mRNA levels in cortex and spinal cord of homozygous mutant mice from 3 months of age, together with increased cytoplasmic TDP-43 mislocalisation in cortex, hippocampus, hypothalamus, and spinal cord at 12 months of age. In conclusion, we find that Tardbp M323K homozygous mutant mice model many aspects of human TDP-43 proteinopathies, evidencing a dual role for TDP-43 in brain morphogenesis as well as in the maintenance of the motor system, making them an ideal in vivo model system to study the complex biology of TDP-43.

Leptin haploinsufficiency exerts sex-dependent partial protection in SOD1G93A mice by reducing inflammatory pathways in the adipose tissue.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by significant metabolic disruptions, including weight loss and hypermetabolism in both patients and animal models. Leptin, an adipose-derived hormone, displays altered levels in ALS. Genetically reducing leptin levels (Lepob/+) to maintain body weight improved motor performance and extended survival in female SOD1G93A mice, although the exact molecular mechanisms behind these effects remain elusive. Here, we corroborated the sexual dimorphism in circulating leptin levels in ALS patients and in SOD1G93A mice. We reproduced a previous strategy to generate a genetically deficient leptin SOD1G93A mice (SOD1G93ALepob/+) and studied the transcriptomic profile in the subcutaneous adipose tissue and the spinal cord. We found that leptin deficiency reduced the inflammation pathways activated by the SOD1G93A mutation in the adipose tissue, but not in the spinal cord. These findings emphasize the importance of considering sex-specific approaches in metabolic therapies and highlight the role of leptin in the systemic modulation of ALS by regulating immune responses outside the central nervous system.

FDG-PET-based neural correlates of Addenbrooke's cognitive examination III scores in Alzheimer's disease and frontotemporal degeneration.

Introduction: The Addenbrooke's Cognitive Examination III (ACE-III) is a brief test useful for neuropsychological assessment. Several studies have validated the test for the diagnosis of Alzheimer's disease (AD) and frontotemporal dementia (FTD). In this study, we aimed to examine the metabolic correlates associated with the performance of ACE-III in AD and behavioral variant FTD. Methods: We enrolled 300 participants in a cross-sectional study, including 180 patients with AD, 60 with behavioral FTD (bvFTD), and 60 controls. An 18F-Fluorodeoxyglucose positron emission tomography study was performed in all cases. Correlation between the ACE-III and its domains (attention, memory, fluency, language, and visuospatial) with the brain metabolism was estimated. Results: The ACE-III showed distinct neural correlates in bvFTD and AD, effectively capturing the most relevant regions involved in these disorders. Neural correlates differed for each domain, especially in the case of bvFTD. Lower ACE-III scores were associated with more advanced stages in both disorders. The ACE-III exhibited high discrimination between bvFTD vs. HC, and between AD vs. HC. Additionally, it was sensitive to detect hypometabolism in brain regions associated with bvFTD and AD. Conclusion: Our study contributes to the knowledge of the brain regions associated with ACE-III, thereby facilitating its interpretation, and highlighting its suitability for screening and monitoring. This study provides further validation of ACE-III in the context of AD and FTD.

Validation of the European Cross-Cultural Neuropsychological Test Battery (CNTB) for the assessment of mild cognitive impairment due to Alzheimer's disease and Parkinson's disease.

Background: The Cross-Cultural Neuropsychological Test Battery (CNTB) is a novel test battery specifically designed to reduce the impact of multiculturality in cognitive assessment. Objective: We aimed to validate the CNTB in Spaniards in patients with Alzheimer's disease (AD), including patients at mild cognitive impairment (MCI) and mild dementia stages, and Parkinson's disease with MCI (PD-MCI). Methods: Thirty patients with AD-MCI, 30 with AD-dementia (AD-D), and 30 with PD-MCI were recruited. Each clinical group was compared against a healthy control group (HC) with no differences in sex, age, or years of education. Intergroup comparisons, ROC analysis, and cut-off scores were calculated. Results: AD-MCI scored lower than HC in those subtests associated with episodic memory and verbal fluency. AD-D also showed lower scores in executive functions and visuospatial tests. Effect sizes for all the subtests were large. PD-MCI showed lower performance than HC in memory and executive functions, particularly on error scores, with large effect sizes. Comparing AD-MCI and PD-MCI, AD-MCI had lower memory scores, while PD-MCI showed the worst performance in executive functions. CNTB showed appropriate convergent validity with standardized neuropsychological tests measuring the same cognitive domains. We obtained similar cut-off scores to previous studies performed in other populations. Conclusions: The CNTB showed appropriate diagnostic properties in AD and PD, including those stages with mild cognitive impairment. This supports the utility of the CNTB for the early detection of cognitive impairment in AD and PD.

Lipid Metabolic Alterations in the ALS-FTD Spectrum of Disorders.

There is an increasing interest in the study of the relation between alterations in systemic lipid metabolism and neurodegenerative disorders, in particular in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). In ALS these alterations are well described and evident not only with the progression of the disease but also years before diagnosis. Still, there are some discrepancies in findings relating to the causal nature of lipid metabolic alterations, partly due to the great clinical heterogeneity in ALS. ALS presentation is within a disorder spectrum with Frontotemporal Dementia (FTD), and many patients present mixed forms of ALS and FTD, thus increasing the variability. Lipid metabolic and other systemic metabolic alterations have not been well studied in FTD, or in ALS-FTD mixed forms, as has been in pure ALS. With the recent development in lipidomics and the integration with other -omics platforms, there is now emerging data that not only facilitates the identification of biomarkers but also enables understanding of the underlying pathological mechanisms. Here, we reviewed the recent literature to compile lipid metabolic alterations in ALS, FTD, and intermediate mixed forms, with a view to appraising key commonalities or differences within the spectrum.

The Integration of Cell Therapy and Biomaterials as Treatment Strategies for Remyelination.

Multiple sclerosis (MS) is a chronic degenerative autoimmune disease of the central nervous system that causes inflammation, demyelinating lesions, and axonal damage and is associated with a high rate of early-onset disability. Disease-modifying therapies are used to mitigate the inflammatory process in MS but do not promote regeneration or remyelination; cell therapy may play an important role in these processes, modulating inflammation and promoting the repopulation of oligodendrocytes, which are responsible for myelin repair. The development of genetic engineering has led to the emergence of stable, biocompatible biomaterials that may promote a favorable environment for exogenous cells. This review summarizes the available evidence about the effects of transplantation of different types of stem cells reported in studies with several animal models of MS and clinical trials in human patients. We also address the advantages of combining cell therapy with biomaterials.