Background and purpose
Friedreich's ataxia (FRDA) is the most common autosomal‐recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities and slowly progressive ataxia. All ...magnetic resonance imaging (MRI)‐based studies have focused on the evaluation of adult patients. Therefore, we designed a cross‐sectional multimodal MRI‐based study to investigate the anatomical substrates involved in the early stages of FRDA.
Methods
We enrolled 37 patients (12 children) and 38 controls. All subjects underwent MRI in a 3T device to assess gray and white matter. We used measures from FreeSurfer and CERES to evaluate the cerebral and cerebellar cortices. The T1 multiatlas assessed deep gray matter. The diffusion tensor imaging multiatlas was used to investigate microstructural abnormalities in brain white matter and SpineSeg was used to assess the cervical spinal cord. All analyses were corrected for multiple comparisons.
Results
Comparison with age‐matched controls showed that pediatric patients have spinal cord, inferior cerebellar peduncle and red nucleus damage. In contrast, adult patients showed more widespread white matter damage than pediatric patients. With regard to gray matter, we found cortical thinning at the left central sulcus and volumetric reduction in the thalami and hippocampi only in adult patients. Finally, values of fractional anisotropy in adult patients and radial diffusivity in pediatric patients from the inferior cerebellar peduncle correlated with disease duration and ataxia severity, respectively.
Conclusions
Structural damage in FRDA begins in the spinal cord and inferior cerebellar peduncle as well as the red nucleus, and progresses to cerebral areas in adulthood. These results shed some light on the early stages of FRDA and highlight potential neuroimaging markers for therapeutic trials.
Background and purpose
Machado−Joseph disease (MJD/SCA3) is the most frequent spinocerebellar ataxia, characterized by brainstem, basal ganglia and cerebellar damage. Few magnetic resonance imaging ...based studies have investigated damage in the cerebral cortex. The objective was to determine whether patients with MJD/SCA3 have cerebral cortex atrophy, to identify regions more susceptible to damage and to look for the clinical and neuropsychological correlates of such lesions.
Methods
Forty‐nine patients with MJD/SCA3 (mean age 47.7 ± 13.0 years, 27 men) and 49 matched healthy controls were enrolled. All subjects underwent magnetic resonance imaging scans in a 3 T device, and three‐dimensional T1 images were used for volumetric analyses. Measurement of cortical thickness and volume was performed using the FreeSurfer software. Groups were compared using ancova with age, gender and estimated intracranial volume as covariates, and a general linear model was used to assess correlations between atrophy and clinical variables.
Results
Mean CAG expansion, Scale for Assessment and Rating of Ataxia (SARA) score and age at onset were 72.1 ± 4.2, 14.7 ± 7.3 and 37.5 ± 12.5 years, respectively. The main findings were (i) bilateral paracentral cortex atrophy, as well as the caudal middle frontal gyrus, superior and transverse temporal gyri, and lateral occipital cortex in the left hemisphere and supramarginal gyrus in the right hemisphere; (ii) volumetric reduction of basal ganglia and hippocampi; (iii) a significant correlation between SARA and brainstem and precentral gyrus atrophy. Furthermore, some of the affected cortical regions showed significant correlations with neuropsychological data.
Conclusions
Patients with MJD/SCA3 have widespread cortical and subcortical atrophy. These structural findings correlate with clinical manifestations of the disease, which support the concept that cognitive/motor impairment and cerebral damage are related in disease.
Background and purpose
In Friedreich's ataxia (FRDA), frataxin deficiency results in iron redistribution in the dentate nuclei (DNC). Clusters of iron cause inhomogeneities in a magnetic field and ...result in a reduction in T2 relaxation time (T2).
Methods
T2 was prospectively evaluated in DNC, putamen, substantia nigra (SN), cerebellar white matter (CWM) and caudate and the correlation with clinical parameters was investigated. Thirty‐five patients (range 9–51 years) and 44 controls (12–49 years) underwent T2 multi‐echo sequence in a 3T scanner. Twenty‐three patients (12–50 years) and 19 controls (14–49 years) were reassessed after 1 year. T2 was evaluated using specialized software (Aftervoxel) and severity of disease was quantified with the Friedreich Ataxia Rating Scale (FARS).
Results
T2 of both DNC was significantly shorter in the FRDA group at baseline (right, 58.6 ± 8.3 ms vs. 63.7 ± 8.1 ms, P = 0.013; left, 56.7 ± 7.7 ms vs. 62.6 ± 6.8 ms, P = 0.001). No significant difference was found between groups regarding the SN, putamen, CWM and caudate T2. DNC T2 values correlated with age, FARS total score and FARS III subscore on both sides. Prospectively, there was a significant reduction of T2 in FRDA patients in right and left DNC (P = 0.001 and 0.009) but not in other structures. Amongst controls, none of the regions significantly changed after 1 year. DNC T2 change over time correlated with GAA expansions and clinical deterioration (expressed by a change in FARS scores).
Conclusions
DNC T2 values are abnormal in FRDA, progress over time and correlate with ataxia severity. These results strongly suggest that DNC relaxometry can be a useful neuroimaging marker in FRDA.
Neurological diseases are responsible for approximately 6.8 million deaths every year. They affect up to 1 billion people worldwide and cause significant disability and reduced quality of life. In ...most neurological disorders, the diagnosis can be challenging; it frequently requires long-term investigation. Thus, the discovery of better diagnostic methods to help in the accurate and fast diagnosis of neurological disorders is crucial. Circulating nucleic acids (CNAs) are defined as any type of DNA or RNA that is present in body biofluids. They can be found within extracellular vesicles or as cell-free DNA and RNA. Currently, CNAs are being explored as potential biomarkers for diseases because they can be obtained using non-invasive methods and may reflect unique characteristics of the biological processes involved in several diseases. CNAs can be especially useful as biomarkers for conditions that involve organs or structures that are difficult to assess, such as the central nervous system. This review presents a critical assessment of the most current literature about the use of plasma and serum CNAs as biomarkers for several aspects of neurological disorders: defining a diagnosis, establishing a prognosis, and monitoring the disease progression and response to therapy. We explored the biological origin, types, and general mechanisms involved in the generation of CNAs in physiological and pathological processes, with specific attention to neurological disorders. In addition, we present some of the future applications of CNAs as non-invasive biomarkers for these diseases. Key words: Circulating nucleic acids; Neurological disorders; Cell-free DNA; Cell-free RNA; Biomarker; CNAs
Protein coding sequences represent only 2% of the human genome. Recent advances have demonstrated that a significant portion of the genome is actively transcribed as non-coding RNA molecules. These ...non-coding RNAs are emerging as key players in the regulation of biological processes, and act as "fine-tuners" of gene expression. Neurological disorders are caused by a wide range of genetic mutations, epigenetic and environmental factors, and the exact pathophysiology of many of these conditions is still unknown. It is currently recognized that dysregulations in the expression of non-coding RNAs are present in many neurological disorders and may be relevant in the mechanisms leading to disease. In addition, circulating non-coding RNAs are emerging as potential biomarkers with great potential impact in clinical practice. In this review, we discuss mainly the role of microRNAs and long non-coding RNAs in several neurological disorders, such as epilepsy, Huntington disease, fragile X-associated ataxia, spinocerebellar ataxias, amyotrophic lateral sclerosis (ALS), and pain. In addition, we give information about the conditions where microRNAs have demonstrated to be potential biomarkers such as in epilepsy, pain, and ALS.
The mechanisms guiding the progression of neuronal damage in patients with Huntington disease (HD) are not completely understood. It is unclear whether the genotype--that is, the length of the ...expanded CAG repeat--guides the location and speed of grey matter decline once HD is clinically manifested. Moreover, the relationship between cortical and subcortical grey matter atrophy and the severity of motor symptoms of HD is controversial.
In this article, we longitudinally studied, over the period of 1 year, a cohort of 49 patients with HD. We investigated: first, the clinical relevance of regional progressive grey matter atrophy; and second, the relationship between the ratio of atrophy progression and genotype.
The length of the expanded CAG repeat was quantified for all patients and the United Huntington's Disease Rating Scale (UHDRS) was used to rate the severity of clinical symptoms. Grey matter atrophy was determined using voxel-based morphometry (VBM) of brain MRI. Progression of atrophy was quantified in 37 patients who were submitted to two different MRI scans, the second scan 1 year later than the first.
Overall, patients exhibited progressive atrophy involving the caudate, pallidum, putamen, insula, cingulate cortex, cerebellum, orbitofrontal cortex, medial temporal lobes and middle frontal gyri. Patients with a larger UHDRS score exhibited selective atrophy of the caudate, thalamus, midbrain, insula and frontal lobes. Patients with longer, expanded CAG repeat sequences showed faster rates and more widespread atrophy, particularly those patients with more than 55 expanded CAG repeats.
These results confirm that brain atrophy progresses after the clinical onset of HD and that regional atrophy is related to symptom severity. Moreover, our results also indicate that intensity and rate of progression of brain atrophy are more pronounced in patients with larger, expanded CAG repeat sequences.
The pilocarpine-induced (PILO) model has helped elucidate the electrophysiological and molecular aspects related to mesial temporal lobe epilepsy. It has been suggested that the extensive cell death ...and edema observed in the brains of these animals could be induced by increased inflammatory responses, such as the rapid release of the inflammatory cytokine interleukin 1 beta (Il1b). In this study, we investigate the role of endogenous Il1b in the acute phase of the PILO model. Our aim is twofold. First, we want to determine whether it is feasible to silence Il1b in the central nervous system using a non-invasive procedure. Second, we aim to investigate the effect of silencing endogenous Il1b and its antagonist, Il1rn.We used RNA interference applied non-invasively to knockdown
Il1b
and its endogenous antagonist
Il1rn.
We found that knocking down
Il1b
prior to pilocarpine injection increased the mortality rate of treated animals. Furthermore, we observed that, when exposing the animals to more Il1b by silencing its endogenous antagonist
Il1rn
, there was a better response to
status epilepticus
with decreased animal mortality in the acute phase of the PILO model. Thus, we show the feasibility of using a novel, less invasive approach to study genes involved in the inflammatory response in the central nervous system. Furthermore, our results provide suggestive evidence that modulating endogenous Il1b improves animal survival in the acute phase of the PILO model and may have effects that extend into the chronic phase.
To investigate the relationship between brain MRI and clinical characteristics and patterns of antiepileptic drug (AED) response in patients with mesial temporal lobe epilepsy (MTLE).
A total of 165 ...MTLE patients were divided into seizure-free with AED (AED responders, n = 50), pharmacoresistant (n = 87), and remitting-relapsing seizure control group (n = 28). All groups were evaluated regarding age, frequency of seizures, and age at epilepsy onset, duration of epilepsy, febrile seizures, presence and side of hippocampal atrophy (HA), and initial precipitating injuries. For gray matter (GM) MRI voxel-based morphometry (VBM) we selected only patients with unilateral HA on visual MRI analysis (n = 100). Comparisons were made between all groups and 75 healthy controls.
Age at epilepsy onset was lower (p = 0.005) and initial frequency of seizures was higher in the pharmacoresistant compared with the other 2 groups (p = 0.018). All groups showed GM atrophy compared to controls in ipsilateral hippocampus, bilateral parahippocampal gyri, frontal, occipital, parietal, and cerebellar areas. In the AED responders group, such findings were more restricted to areas ipsilateral to the epileptic focus and more widespread in the pharmacoresistant and remitting-relapsing groups. VBM pairwise comparisons showed areas with GM volume reduction in the pharmacoresistant and remitting-relapsing groups compared with AED responders in bilateral periorbital frontal (p < 0.01), cingulum (p < 0.05), and temporal lobe contralateral to the epileptic focus (p < 0.05).
Pharmacoresistant and remitting-relapsing groups presented a similar pattern of GM atrophy, which was more widespread compared with AED responders. Conversely, age at epilepsy onset was lower and initial seizure frequency was higher in pharmacoresistant patients.
Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by expansion of the polyglutamine domain of the ataxin-3 (ATX3) ...protein. MJD/SCA3 is the most frequent autosomal dominant ataxia in many countries. The mechanism underlying MJD/SCA3 is thought to be mainly related to protein misfolding and aggregation leading to neuronal dysfunction followed by cell death. Currently, there are no effective treatments for patients with MJD/SCA3. Here, we report on the potential use of lithium carbonate and coenzyme Q10 to reduce cell death caused by the expanded ATX3 in cell culture. Cell viability and apoptosis were evaluated by MTT assay and by flow cytometry after staining with annexin V-FITC/propidium iodide. Treatment with lithium carbonate and coenzyme Q10 led to a significant increase in viability of cells expressing expanded ATX3 (Q84). In addition, we found that the increase in cell viability resulted from a significant reduction in the proportion of apoptotic cells. Furthermore, there was a significant change in the expanded ATX3 monomer/aggregate ratio after lithium carbonate and coenzyme Q10 treatment, with an increase in the monomer fraction and decrease in aggregates. The safety and tolerance of both drugs are well established; thus, our results indicate that lithium carbonate and coenzyme Q10 are good candidates for further in vivo therapeutic trials.
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