A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies.

AIMS: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. METHODS: Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. RESULTS: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. CONCLUSIONS: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study.

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.

Spinal cord damage in Machado-Joseph disease.

Machado-Joseph disease (SCA3) is the most frequent spinocerebellar ataxia worldwide and characterized by remarkable phenotypic heterogeneity. MRI-based studies in SCA3 focused in the cerebellum and connections, but little is known about cord damage in the disease and its clinical relevance. To evaluate the spinal cord damage in SCA3 through quantitative analysis of MRI scans. A group of 48 patients with SCA3 and 48 age and gender-matched healthy controls underwent MRI on a 3T scanner. We used T1-weighted 3D images to estimate the cervical spinal cord area (CA) and eccentricity (CE) at three C2/C3 levels based on a semi-automatic image segmentation protocol. The scale for assessment and rating of ataxia (SARA) was employed to quantify disease severity. The two groups-SCA3 and controls-were significantly different regarding CA (49.5 ± 7.3 vs 67.2 ± 6.3 mm(2), p < 0.001) and CE values (0.79 ± 0.06 vs 0.75 ± 0.05, p = 0.005). In addition, CA presented a significant correlation with SARA scores in the patient group (p = 0.010). CE was not associated with SARA scores (p = 0.857). In the multiple variable regression, we found that disease duration was the only variable associated with CA (coefficient = -0.629, p = 0.025). SCA3 is characterized by cervical cord atrophy and antero-posterior flattening. In addition, the spinal cord areas did correlate with disease severity. This suggests that quantitative analyses of the spinal cord MRI might be a useful biomarker in SCA3.

A multimodal evaluation of microstructural white matter damage in spinocerebellar ataxia type 3.

Although white matter damage may play a major role in the pathogenesis of spinocerebellar ataxia 3 (SCA3), available data rely exclusively upon macrostructural analyses. In this setting we designed a study to investigate white matter integrity. We evaluated 38 genetically-confirmed SCA3 patients (mean age, 52.76 ± 12.70 years; 21 males) with clinical scales and brain magnetic resonance imaging (MRI) and 38 healthy subjects as a control group (mean age, 48.86 ± 12.07 years, 20 male). All individuals underwent the same protocol for high-resolution T1 and T2 images and diffusion tensor imaging acquisition (32 directions) in a 3-T scanner. We used Tract-Based Spatial Statistics (FSL 4.1.4) to analyze diffusion data and SPM8/DARTEL for voxel-based morphometry of infratentorial structures. T2-relaxometry of cerebellum was performed with in-house-developed software Aftervoxel and Interactive Volume Segmentation (IVS). Patients' mean age at onset was 40.02 ± 11.48 years and mean duration of disease was 9.3 ± 2.7 years. Mean International Cooperative Ataxia Rating Scale (ICARS) and Scale for Assessment and Rating of Ataxia (SARA) scores were 32.08 ± 4.01 and 14.65 ± 7.33, respectively. Voxel-based morphometry demonstrated a volumetric reduction of gray and white matter in cerebellum and brainstem (P <.001). We found reduced fractional anisotropy (P <.05) in the cerebellum and brainstem. There were also areas of increased radial diffusivity (P <.05) in the cerebellum, brainstem, thalamus, frontal lobes, and temporal lobes. In addition, we found decreased T2-relaxation values in the white matter of the right cerebellar hemisphere. Microstructural white matter dysfunction, not previously reported, occurs in the cerebellum and brainstem of SCA3 patients.

Spinal cord atrophy correlates with disability in Friedreich's ataxia.

Although Friedreich's ataxia is characterized by spinal cord atrophy, it remains to be investigated the possible correlation of such atrophy with clinical disability and genetic parameters. Thirty-three patients with Friedreich's ataxia and 30 healthy controls underwent MRI on a 3 T scanner. We used T1-weighted 3D images to estimate spinal cord area and eccentricity at C2/C3 level based on a semi-automatic image segmentation protocol. We quantified severity of ataxia with the Friedreich ataxia rating scale (FARS). Mean cord area in Friedreich's ataxia was smaller than in controls (38 vs 67.9 mm(2), p < 0.001). In contrast, mean cord eccentricity was significantly higher in Friedreich's ataxia when compared to the controls (0.82 vs 0.76, p < 0.001). There was a significant correlation between cord areas and the FARS scores (r = -0.53, p = 0.002). Cord damage in Friedreich's ataxia results in atrophy combined with flattening. Cord area is associated to clinical disability and might be useful as a biomarker in the disease.

Amygdala enlargement occurs in patients with mesial temporal lobe epilepsy and hippocampal sclerosis with early epilepsy onset.

Mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS) is considered an electroclinical syndrome, and there is a debate whether it is a unique disease or an entity with distinct subtypes. Together with other mesial temporal structures, the amygdala is important in the epileptogenic network of patients with MTLE with HS. During automatic volumetric analysis of mesial structures in a group of 102 patients with MTLE with MRI signs of HS, we observed significant amygdala enlargement in 14 (14%) individuals compared to a group of 79 healthy subjects. The increased amygdala volume was contralateral to the epileptogenic zone and MRI signs of HS in 93% of these patients. Patients with MTLE with HS and enlarged amygdala had significantly earlier epilepsy onset than those without an increase of amygdala volumes. Mesial temporal lobe epilepsy with HS and enlarged amygdala may be a part of the spectrum of this condition.

Cortical correlates of affective syndrome in dementia due to Alzheimer's disease.

Neuropsychiatric symptoms in Alzheimer's disease (AD) are prevalent, however their relationship with patterns of cortical atrophy is not fully known. Objectives To compare cortical atrophy's patterns between AD patients and healthy controls; to verify correlations between neuropsychiatric syndromes and cortical atrophy. Method 33 AD patients were examined by Neuropsychiatric Inventory (NPI). Patients and 29 controls underwent a 3T MRI scanning. We considered four NPI syndromes: affective, apathy, hyperactivity and psychosis. Correlations between structural imaging and neuropsychiatric scores were performed by Freesurfer. Results were significant with a p-value < 0.05, corrected for multiple comparisons. Results Patients exhibited atrophy in entorhinal cortices, left inferior and middle temporal gyri, and precuneus bilaterally. There was correlation between affective syndrome and cortical thickness in right frontal structures, insula and temporal pole. Conclusion Cortical thickness measures revealed atrophy in mild AD. Depression and anxiety symptoms were associated with atrophy of right frontal, temporal and insular cortices.

Patterns of seizure control in patients with mesial temporal lobe epilepsy with and without hippocampus sclerosis.

OBJECTIVE: Patients with mesial temporal lobe epilepsy (MTLE) may present unstable pattern of seizures. We aimed to evaluate the occurrence of relapse-remitting seizures in MTLE with (MTLE-HS) and without (MTLE-NL) hippocampal sclerosis. METHOD: We evaluated 172 patients with MTLE-HS (122) or MTLE-NL (50). Relapse-remitting pattern was defined as periods longer than two years of seizure-freedom intercalated with seizure recurrence. "Infrequent seizures" was considered as up to three seizures per year and "frequent seizures" as any period of seizures higher than that. RESULTS: Thirty-seven (30%) MTLE-HS and 18 (36%) MTLE-NL patients had relapse-remitting pattern (X2, p = 0.470). This was more common in those with infrequent seizures (X2, p < 0.001). Twelve MTLE-HS and one MTLE-NL patients had prolonged seizure remission between the first and second decade of life (X2, p = 0.06). CONCLUSION: Similar proportion of MTLE-HS or MTLE-NL patients present relapse-remitting seizures and this occurs more often in those with infrequent seizures.

Interactive volume segmentation with differential image foresting transforms.

The absence of object information very often asks for considerable human assistance in medical image segmentation. Many interactive two-dimensional and three-dimensional (3-D) segmentation methods have been proposed, but their response time to user's actions should be considerably reduced to make them viable from the practical point of view. We circumvent this problem in the framework of the image foresting transform (IFT)--a general tool for the design of image operators based on connectivity--by introducing a new algorithm (DIFT) to compute sequences of IFTs in a differential way. We instantiate the DIFT algorithm for watershed-based and fuzzy-connected segmentations under two paradigms (single-object and multiple-object) and evaluate the efficiency gains of both approaches with respect to their linear-time implementation based on the nondifferential IFT. We show that the DIFT algorithm provides efficiency gains from 10 to 17, reducing the user's waiting time for segmentation with 3-D visualization on a common PC from 19-36 s to 2-3 s. We also show that the multiple-object approach is more efficient than the single-object paradigm for both segmentation methods.

Spinal cord atrophy correlates with disease duration and severity in amyotrophic lateral sclerosis.

Our objective was to investigate spinal cord (SC) atrophy in amyotrophic lateral sclerosis (ALS) patients, and to determine whether it correlates with clinical parameters. Forty-three patients with ALS (25 males) and 43 age- and gender-matched healthy controls underwent MRI on a 3T scanner. We used T1-weighted 3D images covering the whole brain and the cervical SC to estimate cervical SC area and eccentricity at C2/C3 level using validated software (SpineSeg). Disease severity was quantified with the ALSFRS-R and ALS Severity scores. SC areas of patients and controls were compared with a Mann-Whitney test. We used linear regression to investigate association between SC area and clinical parameters. Results showed that mean age of patients and disease duration were 53.1 ± 12.2 years and 34.0 ± 29.8 months, respectively. The two groups were significantly different regarding SC areas (67.8 ± 6.8 mm² vs. 59.5 ± 8.4 mm², p < 0.001). Eccentricity values were similar in both groups (p = 0.394). SC areas correlated with disease duration (r = - 0.585, p < 0.001), ALSFRS-R score (r = 0.309, p = 0.044) and ALS Severity scale (r = 0.347, p = 0.022). In conclusion, patients with ALS have SC atrophy, but no flattening. In addition, SC areas correlated with disease duration and functional status. These data suggest that quantitative MRI of the SC may be a useful biomarker in the disease.

Cortical correlates of affective syndrome in dementia due to Alzheimer’s disease / Correlatos corticais da síndrome afetiva na demência da doença de Alzheimer

Neuropsychiatric symptoms in Alzheimer’s disease (AD) are prevalent, however their relationship with patterns of cortical atrophy is not fully known. Objectives To compare cortical atrophy’s patterns between AD patients and healthy controls; to verify correlations between neuropsychiatric syndromes and cortical atrophy. Method 33 AD patients were examined by Neuropsychiatric Inventory (NPI). Patients and 29 controls underwent a 3T MRI scanning. We considered four NPI syndromes: affective, apathy, hyperactivity and psychosis. Correlations between structural imaging and neuropsychiatric scores were performed by Freesurfer. Results were significant with a p-value < 0.05, corrected for multiple comparisons. Results Patients exhibited atrophy in entorhinal cortices, left inferior and middle temporal gyri, and precuneus bilaterally. There was correlation between affective syndrome and cortical thickness in right frontal structures, insula and temporal pole. Conclusion Cortical thickness measures revealed atrophy in mild AD. Depression and anxiety symptoms were associated with atrophy of right frontal, temporal and insular cortices. .

Os sintomas neuropsiquiátricos na doença de Alzheimer (DA) são prevalentes, porém suas relações com padrões de atrofia cortical não são totalmente compreendidas. Objetivos Comparar padrões de atrofia cortical entre DA e controles; verificar se há correlações entre sintomas neuropsiquiátricos e atrofia cortical. Método 33 pacientes com DA foram examinados pelo Inventário Neuropsiquiátrico. Os pacientes e 29 controles foram submetidos à RNM. Consideramos quatro síndromes: afetiva, apatia, hiperatividade e psicose. Correlações entre imagens estruturais e os scores foram feitas pelo Freesurfer. Os resultados foram significantes com um valor de p < 0,05, corrigido para múltiplas comparações. Resultados Pacientes exibiram atrofia nos córtices entorrinais, giros temporal médio e inferior esquerdos, e precuneo bilateralmente. Houve correlação entre síndrome afetiva e espessura cortical em estruturais frontais direitas, ínsula e polo temporal. Conclusão Medidas de espessura cortical revelaram atrofia na DA. Sintomas de depressão e ansiedade foram associados à atrofia dos córtices frontal direito, temporal e ínsula. .

Patterns of seizure control in patients with mesial temporal lobe epilepsy with and without hippocampus sclerosis / Padrões de controle de crises em pacientes com epilepsia de lobo temporal com ou sem esclerose hipocampal

Objective Patients with mesial temporal lobe epilepsy (MTLE) may present unstable pattern of seizures. We aimed to evaluate the occurrence of relapse-remitting seizures in MTLE with (MTLE-HS) and without (MTLE-NL) hippocampal sclerosis. Method We evaluated 172 patients with MTLE-HS (122) or MTLE-NL (50). Relapse-remitting pattern was defined as periods longer than two years of seizure-freedom intercalated with seizure recurrence. “Infrequent seizures” was considered as up to three seizures per year and “frequent seizures” as any period of seizures higher than that. Results Thirty-seven (30%) MTLE-HS and 18 (36%) MTLE-NL patients had relapse-remitting pattern (X2, p = 0.470). This was more common in those with infrequent seizures (X2, p < 0.001). Twelve MTLE-HS and one MTLE-NL patients had prolonged seizure remission between the first and second decade of life (X2, p = 0.06). Conclusion Similar proportion of MTLE-HS or MTLE-NL patients present relapse-remitting seizures and this occurs more often in those with infrequent seizures. .

Objetivo Pacientes com epilepsia do lobo temporal mesial (ELTM) podem apresentar padrão instável de crises epilépticas. Nosso objetivo foi avaliar ocorrência de crises remitente-recorrentes em ELTM com (ELTM-EH) e sem (ELTM-NL) esclerose hipocampal. Método Avaliamos 172 pacientes com ELTM-EH (122) ou ELTM-NL (50). Padrão remitente-recorrente foi definido como períodos superiores a dois anos de remissão intercalados com recorrência de crises. Até três crises por ano foram consideradas como "infrequentes" e qualquer período com frequência maior como "frequentes". Resultados Trinta e sete (30%) pacientes com ELTM-EH e 18 (36%) com ELTM-NL apresentaram crises remitente-recorrentes (X2, p = 0,470), mais comum naqueles com crises infrequentes (X2, p < 0,001). Doze pacientes com ELTM-EH e um ELTM-NL apresentaram remissão prolongada de crises entre a primeira e a segunda década de vida (X2, p = 0,06). Conclusão Proporção semelhante de pacientes com ELTM-EH e ELTM-NL apresentam crises remitente-recorrentes e isso ocorre com maior frequência em pacientes com crises esporádicas. .