Shedding light on motor premanifest myotonic dystrophy type 1: A molecular, muscular and central nervous system follow-up study.

BACKGROUND AND PURPOSE: Myotonic dystrophy type 1 (DM1) is a hereditary and multisystemic disease that is characterized by heterogeneous manifestations. Although muscular impairment is central to DM1, a premanifest DM1 form has been proposed for those characterized by the absence of muscle signs in precursory phases. Nevertheless, subtle signs and/or symptoms related to other systems, such as the central nervous system (CNS), may emerge and progress gradually. This study aimed to validate the premanifest DM1 concept and to characterize and track affected individuals from a CNS centred perspective. METHODS: Retrospective data of 120 participants (23 premanifest DM1, 25 manifest DM1 and 72 healthy controls) were analysed transversally and longitudinally (over 11.17 years). Compiled data included clinical, neuropsychological and neuroradiological (brain volume and white matter lesion, WML) measures taken at two time points. RESULTS: Manifest DM1 showed significantly more molecular affectation, worse performance on neuropsychological domains, lower grey and white matter volumes and a different pattern of WMLs than premanifest DM1. The latter was slightly different from healthy controls regarding brain volume and WMLs. Additionally, daytime sleepiness and molecular expansion size explained 50% of the variance of the muscular deterioration at follow-up in premanifest individuals. CONCLUSIONS: Premanifest DM1 individuals showed subtle neuroradiological alterations, which suggests CNS involvement early in the disease. Based on follow-up data, a debate emerges around the existence of a 'non-muscular DM1' subtype and/or a premanifest phase, as a precursory stage to other DM1 manifestations.

White matter integrity changes and neurocognitive functioning in adult-late onset DM1: a follow-up DTI study.

Myotonic Dystrophy Type 1 (DM1) is a multisystemic disease that affects gray and white matter (WM) tissues. WM changes in DM1 include increased hyperintensities and altered tract integrity distributed in a widespread manner. However, the precise temporal and spatial progression of the changes are yet undetermined. MRI data were acquired from 8 adult- and late-onset DM1 patients and 10 healthy controls (HC) at two different timepoints over 9.06 years. Fractional anisotropy (FA) and mean diffusivity (MD) variations were assessed with Tract-Based Spatial Statistics. Transversal and longitudinal intra- and intergroup analyses were conducted, along with correlation analyses with clinical and neuropsychological data. At baseline, reduced FA and increased MD values were found in patients in the uncinate, anterior-thalamic, fronto-occipital, and longitudinal tracts. At follow-up, the WM disconnection was shown to have spread from the frontal part to the rest of the tracts in the brain. Furthermore, WM lesion burden was negatively correlated with FA values, while visuo-construction and intellectual functioning were positively correlated with global and regional FA values at follow-up. DM1 patients showed a pronounced WM integrity loss over time compared to HC, with a neurodegeneration pattern that suggests a progressive anterior-posterior disconnection. The visuo-construction domain stands out as the most sensitive neuropsychological measure for WM microstructural impairment.

Frailty is associated with mortality in brain tumor patients.

Frailty represents a state of vulnerability that increases the risk of adverse health outcomes. In the last years, frailty has emerged as a good indicator of patient's functional reserve and it seems to be a predictor of negative outcomes in oncological patients. In this work, we analyzed the clinical utility of frailty as preoperative risk assessment tool in a brain tumor cohort from Donostia University Hospital (Spain). For that, we used several frailty tools consisting of questionnaires based on frailty phenotype (FRAIL scale), evaluating functional performance (Gait Speed) and a self-report questionnaire that includes variables related to the physical, cognitive and psychosocial domains of frailty (Tilburg Frailty Indicator). We identified a higher percentage of patients in vulnerable situation prior to surgery when using frailty tools compared to routine scales such as Karnosfky score and Barthel Index. Remarkably, patients diagnosed with malignant tumors were frailer and presented significant less six-month survival than patients with benign tumors by all the frailty scales abovementioned. In line with this, the vast majority of patients that became pre-frail or frail after neurosurgery (by FRAIL scale) harbored a malignant tumor. Moreover, frailty status significantly correlated with patient's mortality and autonomy, but not with the presence of postoperative outcomes in our cohort. Taken together, our results show that frailty measurement, mainly by FRAIL scale, is a useful tool to evaluate preoperative risk in brain tumor patients as well as patient's prognosis after neurosurgery.

Plasma lipids are associated with white matter microstructural changes and axonal degeneration.

Dislipidemia is a risk factor for cognitive impairment. We studied the association between interindividual variability of plasma lipids and white matter (WM) microstructure, using diffusion tensor imaging (DTI) in 273 healthy adults. Special focus was placed on 7 regions of interest (ROI) which are structural components of cognitive neurocircuitry. We also investigated the effect of plasma lipids on cerebrospinal fluid (CSF) neurofilament light chain (NfL), an axonal degeneration marker. Low density lipoprotein (LDL) and triglyceride (TG) levels showed a negative association with axial diffusivity (AxD) in multiple regions. High density lipoproteins (HDL) showed a positive correlation. The association was independent of Apolipoprotein E (APOE) genotype, blood pressure or use of statins. LDL moderated the relation between NfL and AxD in the body of the corpus callosum (p = 0.041), right cingulum gyrus (p = 0.041), right fornix/stria terminalis (p = 0.025) and right superior longitudinal fasciculus (p = 0.020) and TG in the right inferior longitudinal fasciculus (p = 0.004) and left fornix/stria terminalis (p = 0.001). We conclude that plasma lipids are associated to WM microstructural changes and axonal degeneration and might represent a risk factor in the transition from healthy aging to disease.

Methylation of MGMT promoter does not predict response to temozolomide in patients with glioblastoma in Donostia Hospital.

O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status has been considered a prognostic factor in newly diagnosed glioblastoma (GBM). In this study, we evaluated the prognostic and predictive value of MGMT promoter methylation in patients with glioblastoma in Donostia Hospital. Surprisingly, methylation of MGMT promoter did not predict response to temozolomide in patients with glioblastoma in Donostia Hospital. Specifically, overall survival (OS) and progression-free survival (PFS) did not differ significantly by MGMT methylation status in our cohort. In contrast, both were longer in patients who received treatment, received more TMZ cycles, had a better general status and perform at least a partial resection. No association was detected between methylation of MGMT promoter and molecular markers such as ATRX, IDH, p53 and Ki67. These results indicate that MGMT methylation did not influence in patient survival in our cohort.

Neurodegeneration trajectory in pediatric and adult/late DM1: A follow-up MRI study across a decade.

OBJECTIVE: To characterize the progression of brain structural abnormalities in adults with pediatric and adult/late onset DM1, as well as to examine the potential predictive markers of such progression. METHODS: 21 DM1 patients (pediatric onset: N = 9; adult/late onset: N = 12) and 18 healthy controls (HC) were assessed longitudinally over 9.17 years through brain MRI. Additionally, patients underwent neuropsychological, genetic, and muscular impairment assessment. Inter-group comparisons of total and voxel-level regional brain volume were conducted through Voxel Based Morphometry (VBM); cross-sectionally and longitudinally, analyzing the associations between brain changes and demographic, clinical, and cognitive outcomes. RESULTS: The percentage of GM loss did not significantly differ in any of the groups compared with HC and when assessed independently, adult/late DM1 patients and their HC group suffered a significant loss in WM volume. Regional VBM analyses revealed subcortical GM damage in both DM1 groups, evolving to frontal regions in the pediatric onset patients. Muscular impairment and the outcomes of certain neuropsychological tests were significantly associated with follow-up GM damage, while visuoconstruction, attention, and executive function tests showed sensitivity to WM degeneration over time. INTERPRETATION: Distinct patterns of brain atrophy and its progression over time in pediatric and adult/late onset DM1 patients are suggested. Results indicate a possible neurodevelopmental origin of the brain abnormalities in DM1, along with the possible existence of an additional neurodegenerative process. Fronto-subcortical networks appear to be involved in the disease progression at young adulthood in pediatric onset DM1 patients. The involvement of a multimodal integration network in DM1 is discussed.

Cerebrospinal Fluid 7-Ketocholesterol Level is Associated with Amyloid-ß42 and White Matter Microstructure in Cognitively Healthy Adults.

BACKGROUND: Abnormal cholesterol metabolism changes the neuronal membrane and may promote amyloidogenesis. Oxysterols in cerebrospinal fluid (CSF) are related to Alzheimer's disease (AD) biomarkers in mild cognitive impairment and dementia. Cholesterol turnover is important for axonal and white matter (WM) microstructure maintenance. OBJECTIVE: We aim to demonstrate that the association of oxysterols, AD biomarkers, and WM microstructure occurs early in asymptomatic individuals. METHODS: We studied the association of inter-individual variability of CSF 24-hydroxycholesterol (24-OHC), 27-hydroxycholesterol (27-OHC), 7-ketocholesterol (7-KC), 7ß-hydroxycholesterol (7ß-OHC), amyloid-ß42 (Aß42), total-tau (t-tau), phosphorylated-tau (p-tau), neurofilament (NfL), and WM microstructure using diffusion tensor imaging, generalized linear models and moderation/mediation analyses in 153 healthy adults. RESULTS: Higher 7-KC levels were related to lower Aß42, indicative of greater AD pathology (p = 0.041) .  Higher 7-KC levels were related to lower fractional anisotropy (FA) and higher mean (MD), axial (AxD), and radial (RD) diffusivity. 7-KC modulated the association between AxD and NfL in the corpus callosum splenium (B = 39.39, p = 0.017), genu (B = 68.64, p = 0.000), and fornix (B = 10.97, p = 0.000). Lower Aß42 levels were associated to lower FA and higher MD, AxD, and RD in the fornix, corpus callosum, inferior longitudinal fasciculus, and hippocampus. The association between AxD and Aß42 was moderated by 7K-C (p = 0.048). CONCLUSION: This study adds clinical evidence to support the role of 7K-C on axonal integrity and the involvement of cholesterol metabolism in the Aß42 generation process.

Liquid Biopsy in Glioblastoma: Opportunities, Applications and Challenges.

Liquid biopsy represents a minimally invasive procedure that can provide similar information from body fluids to what is usually obtained from a tissue biopsy sample. Its implementation in the clinical setting might significantly renew the field of medical oncology, facilitating the introduction of the concepts of precision medicine and patient-tailored therapies. These advances may be useful in the diagnosis of brain tumors that currently require surgery for tissue collection, or to perform genetic tumor profiling for disease classification and guidance of therapy. In this review, we will summarize the most recent advances and putative applications of liquid biopsy in glioblastoma, the most common and malignant adult brain tumor. Moreover, we will discuss the remaining challenges and hurdles in terms of technology and biology for its clinical application.

Encefalomielitis extensa por Borrelia: una forma atípica de neuroborreliosis / Extensive encephalomyelitis due to Borrelia: an atypical form of neuroborreliosis

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PR-LncRNA signature regulates glioma cell activity through expression of SOX factors.

Long non-coding RNAs (LncRNAs) have emerged as a relevant class of genome regulators involved in a broad range of biological processes and with important roles in tumor initiation and malignant progression. We have previously identified a p53-regulated tumor suppressor signature of LncRNAs (PR-LncRNAs) in colorectal cancer. Our aim was to identify the expression and function of this signature in gliomas. We found that the expression of the four PR-LncRNAs tested was high in human low-grade glioma samples and diminished with increasing grade of disease, being the lowest in glioblastoma samples. Functional assays demonstrated that PR-LncRNA silencing increased glioma cell proliferation and oncosphere formation. Mechanistically, we found an inverse correlation between PR-LncRNA expression and SOX1, SOX2 and SOX9 stem cell factors in human glioma biopsies and in glioma cells in vitro. Moreover, knock-down of SOX activity abolished the effect of PR-LncRNA silencing in glioma cell activity. In conclusion, our results demonstrate that the expression and function of PR-LncRNAs are significantly altered in gliomagenesis and that their activity is mediated by SOX factors. These results may provide important insights into the mechanisms responsible for glioblastoma pathogenesis.

Functional brain network centrality is related to APOE genotype in cognitively normal elderly.

INTRODUCTION: Amyloid plaque deposition in the brain is an early pathological change in Alzheimer's disease (AD), causing disrupted synaptic connections. Brain network disruptions in AD have been demonstrated with eigenvector centrality (EC), a measure that identifies central regions within networks. Carrying an apolipoprotein (APOE)-ε4 allele is a genetic risk for AD, associated with increased amyloid deposition. We studied whether APOE-ε4 carriership is associated with EC disruptions in cognitively normal individuals. METHODS: A total of 261 healthy middle-aged to older adults (mean age 56.6 years) were divided into high-risk (APOE-ε4 carriers) and low-risk (noncarriers) groups. EC was computed from resting-state functional MRI data. Clusters of between-group differences were assessed with a permutation-based method. Correlations between cluster mean EC with brain volume, CSF biomarkers, and psychological test scores were assessed. RESULTS: Decreased EC in the visual cortex was associated with APOE-ε4 carriership, a genetic risk factor for AD. EC differences were correlated with age, CSF amyloid levels, and scores on the trail-making and 15-object recognition tests. CONCLUSION: Our findings suggest that the APOE-ε4 genotype affects brain connectivity in regions previously found to be abnormal in AD as a sign of very early disease-related pathology. These differences were too subtle in healthy elderly to use EC for single-subject prediction of APOE genotype.

Increased CAIDE dementia risk, cognition, CSF biomarkers, and vascular burden in healthy adults.

OBJECTIVE: To investigate the cognitive profile of healthy individuals with increased Cardiovascular Risk Factors, Aging and Dementia (CAIDE) dementia risk score and to explore whether this association is related to vascular burden and CSF biomarkers of amyloidosis and neurodegeneration. METHOD: Cognitively normal participants (mean age 57.6 years) from the Gipuzkoa Alzheimer Project study were classified as having high risk (HR; n = 82) or low risk (LR; n = 293) for dementia according to a CAIDE score cutoff of 9. Cognitive composites were compared between groups. We explored using generalized linear models the role of APOE genotype, MRI white matter hyperintensities (WMH), and CSF (n = 218) levels of ß-amyloid1-42 (Aß1-42), total tau (t-tau), and phosphorylated tau (p-tau) in the association between CAIDE score and cognition. RESULTS: HR participants obtained lower scores on executive function (EF) (p = 0.001) and visual perception and construction (VPC) (p < 0.001) composites. EF composite was associated with CAIDE score × p-tau (p = 0.001), CAIDE score × t-tau (p = 0.001), and WMH (p = 0.003). VPC composite was associated with APOE (p = 0.001), Aß1-42 (p = 0.004), the interaction APOE × Aß1-42 (p = 0.003), and WMH (p = 0.004). Performance on global memory was associated with Aß1-42 (p = 0.006), APOE (p = 0.008), and their interaction (p = 0.006). Analyses were adjusted for age, education, sex, premorbid intelligence, and stress. CONCLUSION: Healthy participants at increased dementia risk based on CAIDE scores show lower performance in EF and VPC. This difference is related to APOE, WMH, and Alzheimer biomarkers.

Cortical microstructural changes along the Alzheimer's disease continuum.

INTRODUCTION: Cortical mean diffusivity (MD) and free water fraction (FW) changes are proposed biomarkers for Alzheimer's disease (AD). METHODS: We included healthy control subjects (N = 254), mild cognitive impairment (N = 41), and AD dementia (N = 31) patients. Participants underwent a lumbar puncture and a 3 T magnetic resonance imaging. Healthy control subjects were classified following National Institute on Aging-Alzheimer's Association stages (stage 0, N = 220; stage 1, N = 25; and stage 2/3, N = 9). We assessed the cortical MD, cortical FW, and cortical thickness (CTh) changes along the AD continuum. RESULTS: Microstructural and macrostructural changes show a biphasic trajectory. Stage 1 subjects showed increased CTh and decreased MD and FW with respect the stage 0 subjects. Stage 2/3 subjects showed decreased CTh and increased cortical MD and FW, changes that were more widespread in symptomatic stages. DISCUSSION: These results support a biphasic model of changes in AD, which could affect the selection of patients for clinical trials and the use of magnetic resonance imaging as a surrogate marker of disease modification.

Cerebrospinal fluid mitochondrial DNA in the Alzheimer's disease continuum.

Low levels of cell-free mitochondrial DNA (mtDNA) in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients have been identified and proposed as a novel biomarker for the disease. The lack of validation studies of previous results prompted us to replicate this finding in a comprehensive series of patients and controls. We applied droplet digital polymerase chain reaction in CSF specimens from 124 patients representing the AD spectrum and 140 neurologically healthy controls. The following preanalytical and analytical parameters were evaluated: the effect of freeze-thaw cycles on mtDNA, the linearity of mtDNA load across serial dilutions, and the mtDNA levels in the diagnostic groups. We found a wide range of mtDNA copies, which resulted in a high degree of overlap between groups. Although the AD group presented significantly higher mtDNA counts, the receiver-operating characteristic analysis disclosed an area under the curve of 0.715 to distinguish AD patients from controls. MtDNA was highly stable with low analytical variability. In conclusion, mtDNA levels in CSF show a high interindividual variability, with great overlap within phenotypes and presents low sensitivity for AD.

Beneficial effect of bilingualism on Alzheimer's disease CSF biomarkers and cognition.

Bilingualism as a component of cognitive reserve has been claimed to delay the onset of Alzheimer's disease (AD). However, its effect on cerebrospinal fluid (CSF) AD-biomarkers has not been investigated. We assessed cognitive performance and CSF AD-biomarkers, and potential moderation effect of bilingualism on the association between age, CSF AD-biomarkers, and cognition. Cognitively healthy middle-aged participants classified as monolinguals (n = 100, nCSF = 59), early (n = 81, nCSF = 55) and late bilinguals (n = 97, nCSF = 52) were evaluated. Models adjusted for confounders showed that bilinguals performed better than monolinguals on digits backwards (early-bilinguals p = 0.003), Judgment of Line Orientation (JLO) (early-bilinguals p = 0.018; late-bilinguals p = 0.004), and Trail Making Test-B (late-bilinguals p = 0.047). Early bilingualism was associated with lower CSF total-tau (p = 0.019) and lower prevalence of preclinical AD (NIA-AA classification) (p = 0.02). Bilingualism showed a moderation effect on the relationship between age and CSF AD-biomarkers and the relationship between age and executive function. We conclude that bilingualism contributes to cognitive reserve enhancing executive and visual-spatial functions. For the first time, this study reveals that early bilingualism is associated with more favorable CSF AD-biomarker profile.

Targeting SOX2 as a Therapeutic Strategy in Glioblastoma.

Glioblastoma is the most common and malignant brain cancer in adults. Current therapy consisting of surgery followed by radiation and temozolomide has a moderate success rate and the tumor reappears. Among the features that a cancer cell must have to survive the therapeutic treatment and reconstitute the tumor is the ability of self-renewal. Therefore, it is vital to identify the molecular mechanisms that regulate this activity. Sex-determining region Y (SRY)-box 2 (SOX2) is a transcription factor whose activity has been associated with the maintenance of the undifferentiated state of cancer stem cells in several tissues, including the brain. Several groups have detected increased SOX2 levels in biopsies of glioblastoma patients, with the highest levels associated with poor outcome. Therefore, SOX2 silencing might be a novel therapeutic approach to combat cancer and particularly brain tumors. In this review, we will summarize the current knowledge about SOX2 in glioblastoma and recapitulate several strategies that have recently been described targeting SOX2 in this malignancy.

Impact of APOE-ɛ4 and family history of dementia on gray matter atrophy in cognitively healthy middle-aged adults.

The apolipoprotein E ε4 allele (APOE4) and family history of dementia (FH) are well-known risk factors for the development of sporadic Alzheimer's disease. We assessed the effects of these risk factors on gray matter (GM) volume in 295 cognitively healthy middle-aged community-dwelling subjects. Voxel-based morphometry was used to study GM volume differences between high- and low-risk subjects, based on APOE4 carriership (n = 74), first-degree FH (n = 228), or both (n = 62). No significant results were found using a corrected p value. Using a more lenient threshold (p < 0.001 and minimum cluster size of 100 voxels), APOE4 carriers had reduced GM in the striatum compared to noncarriers. Subjects with FH had reduced GM in right precuneus compared to subjects without FH. Maternal and paternal FH provided similar atrophy patterns. APOE4 carriers with FH had GM reductions in bilateral insula compared to subjects with neither APOE4 nor FH. We conclude that a family history of dementia and APOE4 carriership are both associated with regional GM decreases in cognitively healthy middle-aged subjects, with differential effects on brain regions typically affected in Alzheimer's disease.

mTOR inhibition decreases SOX2-SOX9 mediated glioma stem cell activity and temozolomide resistance.

BACKGROUND: SOX2 and SOX9 are commonly overexpressed in glioblastoma, and regulate the activity of glioma stem cells (GSCs). Their specific and overlapping roles in GSCs and glioma treatment remain unclear. METHODS: SOX2 and SOX9 levels were examined in human biopsies. Gain and loss of function determined the impact of altering SOX2 and SOX9 on cell proliferation, senescence, stem cell activity, tumorigenesis and chemoresistance. RESULTS: SOX2 and SOX9 expression correlates positively in glioma cells and glioblastoma biopsies. High levels of SOX2 bypass cellular senescence and promote resistance to temozolomide. Mechanistic investigations revealed that SOX2 acts upstream of SOX9. mTOR genetic and pharmacologic (rapamycin) inhibition decreased SOX2 and SOX9 expression, and reversed chemoresistance. CONCLUSIONS: Our findings reveal SOX2-SOX9 as an oncogenic axis that regulates stem cell properties and chemoresistance. We identify that rapamycin abrogate SOX protein expression and provide evidence that a combination of rapamycin and temozolomide inhibits tumor growth in cells with high SOX2/SOX9.

Gray matter network disruptions and amyloid beta in cognitively normal adults.

Gray matter networks are disrupted in Alzheimer's disease (AD). It is unclear when these disruptions start during the development of AD. Amyloid beta 1-42 (Aß42) is among the earliest changes in AD. We studied, in cognitively healthy adults, the relationship between Aß42 levels in cerebrospinal fluid (CSF) and single-subject cortical gray matter network measures. Single-subject gray matter networks were extracted from structural magnetic resonance imaging scans in a sample of cognitively healthy adults (N = 185; age range 39-79, mini-mental state examination >25, N = 12 showed abnormal Aß42 < 550 pg/mL). Degree, clustering coefficient, and path length were computed at whole brain level and for 90 anatomical areas. Associations between continuous Aß42 CSF levels and single-subject cortical gray matter network measures were tested. Smoothing splines were used to determine whether a linear or nonlinear relationship gave a better fit to the data. Lower Aß42 CSF levels were linearly associated at whole brain level with lower connectivity density, and nonlinearly with lower clustering values and higher path length values, which is indicative of a less-efficient network organization. These relationships were specific to medial temporal areas, precuneus, and the middle frontal gyrus (all p < 0.05). These results suggest that mostly within the normal spectrum of amyloid, lower Aß42 levels can be related to gray matter networks disruptions.