Brain communications最新文献

Late-onset epilepsy has been linked with accelerated cognitive decline and a higher risk of dementia. In this study, we sought to characterize the cognitive profile of participants with late-onset unexplained epilepsy and compare their MRI findings to healthy controls, to better understand underlying disease mechanisms. We recruited participants with at least one new-onset unexplained seizure at age 55 or later, without cortical lesions on MRI, within 5 years of the first seizure. We administered a neuropsychological battery to generate Preclinical Alzheimer Cognitive Composite and composite scores for delayed verbal recall, processing speed and executive function. We held a consensus meeting to determine whether the participants fulfilled criteria for mild cognitive impairment. An MRI volumetric analysis of hippocampal, amygdalae, and white matter hyperintensity volume was performed and compared to 353 healthy controls from the Harvard Aging Brain Study. On late-onset unexplained epilepsy participants, we also obtained 24-h EEG recording. Seventy participants were recruited, mean age 71.0 ± 7.0 years, 49% female, 15.6 ± 3.0 years of education. Impaired cognition (z-score ≤ -1.5) for late-onset unexplained epilepsy included the following: 15.9% for Preclinical Alzheimer Cognitive Composite -5, 23.2% for delayed verbal recall, 15.6% for processing speed and 7.5% for executive function. Seventeen percent were found to have mild cognitive impairment. Late-onset unexplained epilepsy participants who were drug resistant were more likely to have cognitive impairment (50% vs. 9%). When controlling for age, sex and race, late-onset unexplained epilepsy group had lower left AV (%; β = -0.003, P = 0.0016), right AV (%) (β = -0.003, P = 0.01), and log-transformed WMV (mm³; β = -0.21, P = 0.03) compared with Harvard Aging Brain Study (HABS); there were no differences in left or right HV between groups. EEG captured epileptiform abnormalities in 49% late-onset unexplained epilepsy participants, with a left temporal predominance (54%). In this single-site study of prospectively enrolled participants with late-onset unexplained epilepsy, we show that individuals with late-onset unexplained epilepsy exhibit cognitive impairments, mostly in verbal memory, and temporal dysfunction with left-sided predominance. Neuroimaging, when compared with healthy controls, shows lower amygdalae and white matter hyperintensity but not hippocampal volumes suggesting that the amygdalae is one of the earliest sites involved in the disease. The results also highlight the importance of seizure control given the association between mild cognitive impairment and drug-resistant epilepsy. Future studies extending these findings to Alzheimer's disease biomarkers and longitudinal follow-up will inform predictors of cognitive decline.

For over half a century, the cingulum has been the subject of neuroanatomical and therapeutic investigations owing to its wide range of functions and involvement in various neurological and psychiatric diseases. Recent clinical studies investigating neurosurgical techniques targeting the cingulum, like deep brain stimulation of the anterior cingulate cortex and cingulotomy, have further boosted interests in this central 'hub' as a target for chronic intractable pain. Proper targeting within the cingulum is essential to achieve sufficient pain relief. Despite the cingulum being the centre of research for over a century, its structural and functional organization remains a subject to debate, consequently complicating neurosurgical targeting of this area. This study aims to review anatomical and connectivity data of the cingulum from a clinical perspective in order to improve understanding of its role in pain. For the current study, a systematic literature search was performed to assess the anatomy and functional and structural connectivity of the cingulate bundle and cortex. These outcomes focus on MRI and PET data. Articles were searched within the PubMed database, and additional articles were found manually through reviews or references cited within the articles. After exclusion, 70 articles remained included in this analysis, with 50, 29 and 10 studies describing human, monkey and rat subjects, respectively. Outcomes of this analysis show the presence of various anatomical models, each describing other subdivisions within the cingulum. Moreover, connectivity data suggest that the cingulate bundle consists of three distinct fibre projections, including the thalamocortical, cingulate gyrus and anterior frontal and posterior parietal projections. Further, the cingulum is responsible for a variety of functions involved in chronic pain, like sensory processing, memory, spatial functioning, reward, cognition, emotion, visceromotor and endocrine control. Based on the current outcomes, it can be concluded that the cingulum is a central 'hub' for pain processing, because it is a melting pot for memory, cognition and affect that are involved in the complex phenomenon of pain experience, memory, spatial functioning, reward, cognition, emotion, visceromotor and endocrine control. Variability in anatomical and connectivity models complicate proper and standardized neurosurgical targeting, consequently leading to clinicians often being reluctant on stimulation and/or lesioning of the cingulum. Hence, future research should be dedicated to the standardization of these models, to allow for optimal targeting and management of patients with chronic intractable pain.

Ring finger protein 213 (RNF213) p.Arg4810Lys (c.14429G > A) is associated with intracranial artery stenosis; however, its association with extracranial artery stenosis remains unknown. We aimed to elucidate the clinical significance and association of RNF213 p.Arg4810Lys with stroke subtypes, extracranial artery stenosis, and maximum intima-media thickness. A cohort of 600 patients with stroke prospectively collected over 1 year was assessed for the presence of RNF213 p.Arg4810Lys. A total of 1202 patients served as controls. The association of RNF213 p.Arg4810Lys with various stroke subtypes was studied. In sub-analyses, the association of RNF213 p.Arg4810Lys with intracranial artery stenosis/extracranial artery stenosis and maximum intima-media thickness were assessed. RNF213 p.Arg4810Lys was more common in patients with stroke (3.3%) than in those without stroke (1.1%). RNF213 p.Arg4810Lys was significantly associated with stroke. Among various stroke subtypes, large-artery atherosclerosis, both due to intracranial artery stenosis and extracranial artery stenosis, was most significantly associated with RNF213 p.Arg4810Lys. In the sub-analysis, intracranial artery stenosis-only, extracranial artery stenosis-only, and concurrent intracranial artery stenosis and extracranial artery stenosis groups were significantly associated with RNF213 p.Arg4810Lys, regardless of stroke type (adjusted odds ratio, 3.72; 95% confidence interval, 1.30-10.60; P = 0.014, adjusted odds ratio, 7.04; 95% confidence interval, 1.51-32.77; P= 0.013, adjusted odds ratio, 11.68; 95% confidence interval, 4.25-32.07; P 0.001, respectively). RNF213 p.Arg4810Lys was associated with increased maximum intima-media thickness, measured using carotid artery ultrasonography (multiple regression analysis β = 0.165; P = 0.004). These results were replicated in an independent validation cohort. In conclusion, RNF213 p.Arg4810Lys increases the risk of stroke. In addition to intracranial artery stenosis, RNF213 p.Arg4810Lys is associated with extracranial artery stenosis and maximum intima-media thickness. Evaluating RNF213 p.Arg4810Lys may help predict the incidence and type of stroke.

We assessed the association between leisure time physical activity patterns across 30 years of adulthood with a range of in vivo Alzheimer's disease-related neurodegenerative markers and cognition, and their interplay, at age 70. Participants from the 1946 British birth cohort study prospectively reported leisure time physical activity five times between ages 36 and 69 and were dichotomized into (i) not active (no participation/month) and (ii) active (participated once or more/month) and further derived into: (0) never active (not active); (1) active before 50's only (≤43 years); (2) active from 50's onwards only (≥53 years); (3) always active (active throughout). Participants underwent 18F-florbetapir Aβ and magnetic resonance imaging at age 70. Regression analyses were conducted to assess the direct and the moderating relationship between leisure time physical activity metrics, Alzheimer's disease-related neurodegeneration markers (including Aβ status, hippocampal and whole-brain volume, and cortical thickness in Alzheimer's disease signature regions) and cognition. All models were adjusted for childhood cognition, education and childhood socioeconomic position, and examined by sex. Findings drawn from 468 participants (49% female) demonstrated a direct association between being active before 50 years old (≤43 years) and throughout life (up to age 69 years), with larger hippocampal volume at age 70 (P < 0.05). There was little evidence that leisure time physical activity had direct effects on other brain health measures (all P > 0.05). However, leisure time physical activity patterns modified and attenuated the association between poorer cognitive functioning at age 70 and a range of Alzheimer's disease-related neurodegenerative markers (Aβ status; hippocampal and whole-brain volume; cortical thickness in Alzheimer's disease regions) (all P < 0.05). We found suggestive evidence that women with early markers of Alzheimer's disease-related neurodegeneration were most sensitive to leisure time physical activity patterns: a lifetime of inactivity in women exacerbated the manifestation of early Alzheimer's disease markers (Aβ and cortical thickness-related cognition), yet, if women were active across life or early in life, it mostly buffered these negative relationships. Engagement in leisure time physical activity in the life course is associated with better cognitive functioning at age 70, even in those with early markers of Alzheimer's disease. If causal, this is likely via multiple pathways, potentially through the preservation of hippocampal volume, as well as via cognitive resilience pathways delaying cognitive manifestations of early markers of Alzheimer's disease, particularly in women. Our findings warrant further research to shed light on the mechanisms of physical activity as a potential disease-modifying intervention of brain health and cognitive resilience.

Charcot-Marie-Tooth (CMT) neuropathies represent a broad and very heterogeneous group of disorders for which no therapies are yet available. Due to the huge genetic heterogeneity, therapeutical approaches that can benefit several forms independently of the unique pathogenetic mechanism have been sought. Niacin, nicotinic acid, is a vitamin used for many decades as anti-dyslipidaemic and anti-cholesterol drug product under the commercial name of Niaspan^®, the extended-release formulation of niacin. Of note, niacin can have other effects depending on the dose, formulation and physiology and it has been used to reduce inflammation, to promote angiogenesis and to protect neurons, muscle and axons by boosting nicotinamide adenine dinucleotide (NAD⁺) levels. Niacin also activates TNF-alpha convertase enzyme (TACE) secretase, which negatively regulates Neuregulin type I-mediated signalling in the peripheral nervous system and myelination. We previously postulated that niacin-mediated TACE activation can be effective in reducing aberrant excessive myelin associated with different CMT forms. Here, we explored efficacy of this strategy by performing a long-term preclinical trial and we provided evidence that a novel niacin-based long-lasting formulation ameliorates neurophysiology and reduces fibre degeneration in a model of Charcot-Marie-Tooth type 4B1 (CMT4B1) neuropathy, characterized by aberrant myelin. We also sought to determine whether this strategy might interfere with nerve regeneration, which is dependent on Neuregulin type I signalling. Surprisingly, we found that the Mtmr2 knockout mice, a model of CMT4B1, have a defect in nerve regeneration and that niacin-based treatment is not detrimental to nerve regeneration.

One of the most pressing questions after a stroke is whether an individual patient will recover in the long term. Previous studies demonstrated that spatial neglect-a common cognitive deficit after right hemispheric stroke-is a strong predictor for poor performance on a wide range of everyday tasks and for resistance to rehabilitation. The possibility of predicting long-term prognosis of spatial neglect is therefore of great relevance. The aim of the present study was to test the prognostic value of different imaging and non-imaging features from right hemispheric stroke patients: individual demographics (age, sex), initial neglect severity and acute lesion information (size, location). Patients' behaviour was tested twice in the acute and the chronic phases of stroke and prediction models were built using machine learning-based algorithms with repeated nested cross-validation and feature selection. Model performances indicate that demographic information seemed less beneficial. The best variable combination comprised individual neglect severity in the acute phase of stroke, together with lesion location and size. The latter were based on individual lesion overlaps with a previously proposed chronic neglect region of interest that covers anterior parts of the superior and middle temporal gyri and the basal ganglia. These variables achieved a remarkably high level of accuracy by explaining 66% of the total variance of neglect patients, making them promising features in the prediction of individual outcome prognosis. An online tool is provided with which our algorithm can be used for individual outcome predictions (https://niivue.github.io/niivue-neglect/).

Episodic migraine is reflected by cyclic changes in behavior and cortical processing. We aimed to identify how functional connectivity changes over the entire migraine cycle. By using longitudinal neuroimaging and a whole-brain connectivity analysis approach, we tested 12 episodic migraine patients across 82 functional MRI recordings during spontaneous migraine headaches with follow-up measurements over the pain-free interval without any external stimulation. We found that the functional connectivity linearly increased over the interictal interval. In the prodromal phase, we observed the strongest connections between the anterior agranular insula and the posterior orbitofrontal cortex with sensory, motor and cingulate areas. The strength of the connections dropped during the headache. Peak connectivity during the prodromal phase and its collapse during the headache can be regarded as a mechanism of normalizing cortical processing. We speculate about a malfunction at the molecular level in agranular frontal and insular regions, which needs to be addressed in subsequent studies.

Davson's equation relates the state of stable intracranial pressure (ICP) to the production rate of CSF (I_F) and resistance to CSF outflow (R_OUT). Both parameters are assumed to be independent of ICP, but results are conflicting. The objective is to define the relationship between ICP, I_F and R_OUT using a systematic literature review. Medline and Embase were searched from inception up to 12 February 2024. Experimental studies exploring the association between ICP, I_F, and R_OUT were included. Individual measurements of ICP, I_F and/or R_OUT were extracted from tables or graphs, alongside descriptive parameters (population, ICP measurement site, disease, and computational method). Linear regression and mixed effects models were applied. From 1304 references, 25 articles were included in our meta-analysis. I_F is approximately constant across all pathologies independent of the ICP level, population, disease, ICP measurement site and the measurement/estimation method. Conversely, ICP was positively correlated with R_OUT. The intercorrelation, however, differed by population, disease, ICP measurement site and estimation method. Additionally, I_F derived from Davson's Equation compared with the measured I_F were similar for patients with hydrocephalus but differed for patients with acute brain injury. Davson's Equation describes the various components of cerebrospinal fluid dynamics. The results underline important caveats for its use in patients with acute brain injury wherein the estimated values differ from the measured ones. Overall, additional metrics describing the cerebrovascular system or the underlying disease have to be taken into account for more accurate estimations.

Congenital myasthenic syndromes are a group of inherited disorders characterized by defective neuromuscular transmission and fatigable muscle weakness. Causative mutations have been identified in over 30 genes, including DOK7, a gene encoding a post-synaptic protein crucial in the formation and stabilization of the neuromuscular junction. Mutations in this gene are one of the leading three most prevalent causes of congenital myasthenia in diverse populations across the globe. The majority of DOK7 congenital myasthenic patients experience varying degrees of disability despite receiving optimized treatment (usually salbutamol), necessitating the development of improved therapeutic approaches. Here, we executed a dose escalation pre-clinical trial using a DOK7 congenital myasthenic syndrome mouse model to assess the efficacy of AMP-101, an innovative recombinant adeno-associated viral gene replacement therapy. This mouse model harbours a duplication in the Dok7 gene that corresponds to the mutation most commonly found in DOK7 congenital myasthenia patients, c.1124-1127dupTGCC. The model has a much more severe phenotype than patients, and lives for only a few days. AMP-101 is based on AAVrh74 and contains human DOK7 cDNA under the control of a muscle-restricted promoter. Three doses of AMP-101 (2 × 10¹³ vg/kg, 6 × 10¹³ vg/kg or 1 × 10¹⁴ vg/kg) were administered intraperitoneally at 4 days of age. We show that the two higher doses of 6 × 10¹³ vg/kg and 1 × 10¹⁴ vg/kg generated enlarged neuromuscular junctions and rescued the very severe phenotype of the model. Treated mice became at least as strong as wild-type littermates, as demonstrated by using an inverted screen hang test, a rotarod test and a grip strength test. EMG showed that the treated model mice had decrement of compound muscle action potential on repetitive nerve stimulation, which indicates defective signalling at the neuromuscular junction. However, male models treated with 1 × 10¹⁴ vg/kg showed the least decrement that was not statistically different from wild-type littermates. Western blot analysis demonstrated robust expression of DOK7 in the diaphragm and tibialis anterior muscles. These data show that AMP-101 is an effective treatment in a mouse model for DOK7 congenital myasthenia, and suggests that AMP-101 is a promising candidate to move forward to clinic trials as a gene therapy for patients.

This scientific commentary refers to 'Quantitative susceptibility mapping is more sensitive and specific than phase imaging in detecting chronic active multiple sclerosis lesion rims: pathological validation', by Gillen et al. (https://doi.org/10.1093/braincomms/fcaf011).