Biology subjects

Sampaio, C.

Publications and source records attributed to Sampaio, C..

6 recordsLinked to original sources

bioRxiv2025

Disruption of Striatal Intrinsic Ignition in Huntington's Disease: an In-Silico Perturbational Approach to Emulate Disease Progression and Recovery

Huntingtons disease (HD) is a neurodegenerative disorder caused by a single gene that severely affects motor, cognitive, and behavioral functions and is ultimately fatal. While disruptions in the structural integrity of the striatum are well documented, less is known about how the underlying functional impairments relate to the disease. We developed a large-scale modeling framework based on intrinsic ignition to uncover functional anomalies during HD progression. We first measured how much a spontaneous event in one brain region influences the rest of the brain, then systematically perturbed the activity of the striatum to predict the empirical changes in functional connectivity (FC) by re-optimizing the model parameters and conducting in-silico experiments. Results showed that disruption of the activity dynamics in the caudate, and to some extent the putamen, are the key factors that explain a substantial amount of the variance in FC alterations during HD progression. We then assessed the ability to recover whole-brain functional activity by driving the caudate and putamen activity towards a healthy-like regime and found that, by tuning the local bifurcation parameter of caudate and putamen, it is possible to recover whole-brain healthy functional activity, albeit moderately. Surprisingly, although the functional disruptions in the caudate better explained the alterations in FC, the recovery of the dynamics was more effective in the putamen. Overall, our results suggest that the disruptions of the dynamics in the striatum can explain the gross functional connectivity changes in HD. Our study demonstrates that computational modeling is an important tool to reveal the underlying patterns behind the observed data and provides an opportunity to test interventional mechanisms in silico.

neuroscience↗

bioRxiv2025

Large Scale Functional and Effective Connectivity Alterations cross the Huntington's Disease Integrated Staging System

Huntingtons disease (HD) is a progressive neurodegenerative disease with severe motor, cognitive and behavioral symptoms. There is a recent impetus to develop treatments that slow progression before clinical signs emerge. Such early interventions require biomarkers sensitive to the very earliest HD progression. Here we applied cutting-edge fMRI analysis on data collected in the Track-On HD study to evaluate whether functional and effective connectivity obtained from model-free and model-based approaches can produce useful biomarkers of HD progression. We analyzed data from 231 participants with up to three annual visits each and created five groups comprising normative controls and four HD groups according to the Huntingtons Disease Integrated Staging System (HD-ISS). We found significant differences across the HD-ISS stages but not in their longitudinal change. Specifically, we found attenuated functional and effective connectivity in the caudate nucleus in HD-ISS-2, and this effect extended to other corticostriatal connections in HD-ISS-3. Overall, most of the alterations were only evident in advanced HD stages, and we did not observe widespread alterations in cortical connectivity and graph topography. Although HD-ISS groups did not differ in the amount of in-scanner motion, we did find measures of functional and effective connectivity to be sensitive to motion. We conclude that fMRI can indeed capture attenuation of cortico-striatal functional and effective connectivity across HD progression. This is the first study to investigate fMRI alterations across the recently created HD-ISS stages within a novel framework of signal flow across the whole brain.

neuroscience↗

bioRxiv2024

Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease reveal shared and tissue-specific effects

Huntingtons disease (HD), due to expansion of a CAG repeat in HTT, is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing. Differential capture of non-DNA-repair gene modifiers by multiple measures of cognitive and motor dysfunction argues additionally for cell-type specificity of pathogenic processes. Beyond trans modifiers, differential effects are also illustrated at HTT by a 5-UTR variant that promotes somatic expansion in blood without influencing clinical HD, while, even after correcting for uninterrupted CAG length, a synonymous sequence change at the end of the CAG repeat dramatically hastens onset of motor signs without increasing somatic expansion. Our findings are directly relevant to therapeutic suppression of somatic expansion in HD and related disorders and provide a route to define the individual neuronal cell types that contribute to different HD clinical phenotypes.

genetics↗

bioRxiv2019

Genetic overlap between psychiatric disorders and neuropsychiatric symptoms in HD

Huntingtons disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized exam of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown. We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders, and of intelligence, and testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n=5160) of HD patients. Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence. In general, polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.

genetics↗

bioRxiv2019

Huntington's disease onset is determined by length of uninterrupted CAG, not encoded polyglutamine, and is modified by DNA maintenance mechanisms

The effects of variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from huntingtins polyglutamine segment, dictates the rate at which HD develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally-occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question a fundamental premise of the "polyglutamine disorders".

genetics↗

bioRxiv2018

Uromonitor(R) as a novel sensitive and specific urine-based test for recurrence surveillance of patients with non-muscle invasive bladder cancer

Bladder cancer is the most frequent malignancy of the urinary system and is ranked the seventh most diagnosed cancer in men worldwide. About 70-75% of all newly diagnosed patients with bladder cancer will present disease confined to the mucosa or submucosa, the non-muscle invasive bladder cancer (NMIBC) subtype. Of those, approximately 70% will recur after transurethral resection (TUR). Due to this high rate of recurrence, patients are submitted to an intensive follow-up program that should be maintained throughout many years, or even throughout life, resulting in an expensive follow-up, with cystoscopy being the most cost-effective procedure for NMIBC screening. Currently, the gold standard procedure for detection and follow-up of NMIBC is based on the association of cystoscopy and urine cytology. As cystoscopy is a very invasive approach, over the years, many different non-invasive (both in serum and urine samples) assays have been developed in order to search genetic and protein alterations related to the development, progression and recurrence of bladder cancer. TERT promoter mutations and FGFR3 hotspot mutations are the most frequent somatic alterations in bladder cancer and constitute the most reliable biomarkers for bladder cancer. Based on these findings, an ultra-sensitive assay called Uromonitor(R) was developed that corresponds to a urine-based assay capable of detecting trace amounts of the two most common alterations in NMIBC, TERT promoter and FGFR3 mutation, in urine samples. The Uromonitor(R) test was performed in a cohort of 72 patients, firstly diagnosed with bladder cancer and under surveillance for NMIBC, to access its sensitivity and specificity in the detection of NMIBC recurrence. Uromonitor(R) was shown to be highly sensitive and specific in detecting recurrence of bladder cancer in patients under surveillance of non-muscle invasive bladder cancer.

cancer biology↗