Brain communications最新文献

Although network neuropsychology is a promising approach to the study of clinical profiles, the link between Alzheimer's disease (AD) biomarkers and neuropsychological networks is still undetermined. We hypothesized that network differences would exist between biomarker-positive and biomarker-negative participants, and that these would be driven by network nodes corresponding to performance on tests of episodic memory, as this is the cognitive domain most distinctively affected by AD since the earliest clinical stages. In this case-control study, we investigated sub-cohorts of individuals who had been (i) enrolled in the National Alzheimer's Coordinating Center initiative and (ii) tested with Version 3 of the Uniform Data Set neuropsychological battery (i.e. consisting of 11 tests). These included 1263 'β-amyloid positive' (A+), 1594 'β-amyloid negative' (A-), 442 'β-amyloid and hyperphosphorylated tau positive' (A + T+) and 734 'β-amyloid and hyperphosphorylated tau negative' (A-T-) participants. We first calculated neuropsychological residuals by regressing out age, years of education, sex, Clinical Dementia Rating scores and timepoint distance between neuropsychological and biomarker assessment. Secondly, we used rank-based correlations to define conditional associations across all pairs of test scores (i.e. the nodes of the network). Thirdly, we imposed a penalty (i.e. via the Least Absolute Shrinkage and Selection Operator method) to control for network sparsity. We then tested for differences in global network metrics and node centrality between A+ and A- and between A+T+ and A-T- participants using permutation-based inferential models. Differences were found between biomarker-positive and biomarker-negative sub-cohorts in global network metrics but, contrarily to our hypothesis, no differences were found in relation to episodic memory nodes. A significant node difference, however, was instead found in relation to category fluency (i.e. a test of semantic memory), with increased centrality observed among A+ participants. A similar, yet non-significant trend was also observed between A+T+ and A-T- participants. Network neuropsychology can complement and expand the study of cognitive performance carried out via 'traditional' univariate approaches. While univariate analyses reveal episodic memory decline in people with AD, this is not accompanied by any abnormalities at a neuropsychological network level. Our findings, however, highlight the importance of semantic memory alterations in A+ individuals. The wide set of neural and cognitive resources that sustain semantic memory may play a supportive role in the presence of neuropathology.

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a microglial receptor, sensitive to Phospholipids and Sphingomyelins, associated with neurodegeneration. Hypomorphic variants in the TREM2 gene significantly increase the risk of developing Alzheimer's disease (AD). The aim of this study was to characterize networks of lipids in post-mortem brain tissue from AD and Control donors, and to identify lipids associated with AD and impacted by dysfunctional TREM2. We studied human post-mortem brain tissue from the hippocampus and Brodmann area 9 (BA9) from 102 brains. Brain tissue from BA9 was available from n = 55 donors (14 Ad donors with a non-synonymous TREM2 risk variant [AD(TREM2+)], 20 Ad donors with no TREM2 risk variants [Ad(TREM2-)] and 21 Control donors), and brain tissue from the Hippocampus was available for n = 47 brain donors (7 Ad[TREM2+], 20 Ad[TREM2-] and 20 Control donors). Mass Spectrometry was performed to obtain lipidomic signatures spanning 99 lipid species that included the following lipid classes: Ceramides, Sphingomyelins, Phosphatidic acids, Phosphatidyl-cholines, Phosphatidyl-ethanolamines, Phosphatidyl-glycerols, Phosphatidyl-inositols, Phosphatidyl-serines and Triglycerides. Weighted gene co-expression network analysis (WGCNA) was used to identify highly correlated lipid modules and hubs in each brain region. Generalized least squares and linear regression analyses, adjusted for age at death, biological sex, number of Apolipoprotein E (APOE) ε4 alleles, and post-mortem delay, were used to assess the associations of lipid modules and hubs with AD and TREM2, in combined analyses across regions and in each region separately. Four lipid modules were relatively well-preserved between the two brain regions, and three of these modules were altered in AD donors and/or in AD TREM2 carriers. Levels of the BA9 'turquoise' module ('blue' hippocampus module), enriched in Sphingolipids and Phospholipids, were elevated in AD donors and particularly in AD TREM2 carriers [AD(TREM2+)]. The hub lipid of the BA9 'turquoise'/hippocampus 'blue' module, Phosphatidyl-serine [PS(32:1)], was increased in AD versus Control donors (beta = 0.677, 95% CI 0.28-1.08, P = 1.14E-03), and in AD(TREM2+) versus Control donors (beta = 1.00, 95% CI 0.53-1.48, P = 5.57E-03), whereas the strongest association was observed with Ceramide [Cer(d38:1)] increased in AD versus Control donors (beta = 0.929, 95% CI 0.46-1.40, P = 1.67E-04) and in AD(TREM2+) versus Controls donors (beta = 1.31, 95% CI 0.78-1.84, P = 4.35E-06). The consistent increase in TREM2 ligands such as Ceramides and Phosphatidyl-serines in the brains of AD donors, particularly TREM2 risk variants carriers, could reflect the presence of AD-associated damage signals in the form of stressed or apoptotic cells and damaged myelin.

The regulation of appetite by pharmaceuticals has gained significant interest for the treatment of obesity and cachexia. The melanocortin 4 receptor (MC4R) and the ghrelin receptor (GhrR) are known to play a crucial role in the regulation of energy homeostasis. Thus, peptide ligands, which modulate these receptors, have become attractive therapeutic lead structures. A key challenge is the efficient delivery of such peptides to the targeted receptors, which are expressed in the hypothalamus. Therefore, direct nose-to-brain delivery is a compelling strategy. Here, we report on food intake that is modulated by using intranasal applied peptides. We synthesized fluorescently labelled variants of the MC4R agonist setmelanotide, the GhrR agonist ghrelin (Ghr) and the GhrR inverse agonist KbFwLL-NH₂ [β-(3-benzothienyl)-D-alanine (b)] and assessed their receptor activity. Further, we measured the permeability and stability of these peptides on Calu-3 cells as a model system for the nasal mucosa. Next, the uptake of peptides after intranasal application was analysed in vivo by quantification of fluorescent signals in the olfactory bulb, cortex and hypothalamus. In addition, we monitored the effects of the two most promising peptides on food intake in vivo. Although no significant changes in body weight were observed, we detected differences in the daily change in food intake: this parameter was reduced for mice treated with setmelanotide variants and increased for mice treated with GhrR agonists compared to a control group. Taken together, our findings clearly underline the high potential of intranasal peptide administration for modulating food intake.

Brain age is a promising neuroimaging biomarker, reflecting biological aging, but long-term trajectories and predictive value for cognitive outcomes post-stroke remains unclear. This study aimed to characterize brain aging trajectories over 8 years following a first-ever stroke and to evaluate the predictive value of brain age estimates for long-term cognitive outcomes. We analysed data from working-age (<65 years) ischaemic stroke patients with small- and medium-sized strokes (lesion volumes <70 ml), using two longitudinal stroke cohorts. T1-weighted MRI was acquired in the acute phase and at multiple time points up to 8 years post-stroke. Montreal cognitive assessment (MoCA) was assessed at follow-up sessions. Brain age was estimated using a state-of-the-art deep learning model. Brain-predicted age difference (Brain-PAD) was calculated as estimated brain age minus chronological age and corrected by regressing on age, age² and sex. Linear mixed-effects models examined Brain-PAD over multiple time points (whole-brain, ipsilesional and contralesional). Normalized brain volume was derived from FreeSurfer and included in the whole-brain analysis. Linear regression models evaluated whether brain age was associated with cognitive performance (MoCA) at long-term follow-up. We included 120 patients [n = 50 (42%) female, mean ± SD age at discharge was 54.9 ± 9 and National Institutes of Health Stroke Scale was 3.7 ± 6.4], with a mean follow-up of 3.4 ± 2.5 years. The mean MoCA score at follow-up was 24.7 ± 3.7. Brain-PAD increased significantly over time in the whole-brain analysis (β = 0.6/year, P < 0.01), indicating 60% acceleration in brain aging after stroke, with the association remaining significant after adjusting for normalized brain volume (β = 0.5/year, P < 0.01). Accelerated brain aging was observed in the ipsilesional hemisphere (β = 0.7/year, P < 0.01), but not the contralesional hemisphere (β = 0.3/year, P = 0.12). Higher brain age in the acute phase of stroke predicted lower MoCA scores at follow-up (β = -0.12, P < 0.05), whereas chronological age was not a significant predictor (P = 0.12). The association between brain age estimations and cognitive performance remained significant after adjusting for age, sex and education (β = -0.42, P < 0.01). In this longitudinal study, we found accelerated brain aging following stroke. Furthermore, brain age was associated with cognitive outcomes several years later, highlighting its potential as an early biomarker for long-term cognitive prognosis.

Myotonic dystrophy type 1 is a dominantly inherited disorder, affecting musculoskeletal and central nervous systems and mainly characterized by progressive muscular atrophy and multisystemic damages including cardiac, respiratory and sleep dysfunctions. Neuroimaging studies conducted in myotonic dystrophy type 1 patients have documented widespread cerebral alterations encompassing structural, microstructural, functional and metabolic aspects of the brain, while comparatively few studies have investigated the role of iron concentration in the pathophysiology of central nervous system impairment. We report here the use of quantitative susceptibility (χ) mapping to explore iron content of both cortical and subcortical structures in myotonic dystrophy type 1 patients and to assess its possible clinical relevance, combining imaging and clinical data. Thirty-four myotonic dystrophy type 1 participants (20 females, 46.8 ± 12.0 years old) and 35 age- and sex- matched healthy controls (20 females, 50.5 ± 17.3 years old) were included in the study. All participants underwent MRI examinations in the same 3-Tesla scanner. The MRI protocol included 3D morphological T₁-weighted magnetization prepared rapid gradient echo and T₂*weighted multi-echo gradient echo for quantitative susceptibility mapping reconstruction. Cortical and subcortical structures were automatically segmented, and a volume of interest-based analysis was performed; χ distributions were compared between the two groups and myotonic dystrophy type 1 χ values were correlated with clinical and laboratory data. In the myotonic dystrophy type 1 group, a significant increase of χ was found in almost all cortical gyri, as a non-specific sign of neurodegeneration. Among subcortical structures, χ was significantly higher in myotonic dystrophy type 1 group in both thalamus (ventral and pulvinar nuclei) and brainstem (pons and medulla), compared to healthy controls. Additionally, correlation analysis showed some links between χ in subcortical structures and clinical signs, suggesting greater iron concentration with deterioration of clinical conditions. Thalamic χ values were associated with cardiological parameters and disability scores and, as with brainstem χ, they were also positively correlated with the number of central apnoeas; finally, thalamic and brainstem χ were negatively correlated with the age of onset. This study showed a correlation between autonomic dysfunction related to certain subcortical structures and their χ; higher values of χ correlated with greater functional impairment, suggesting iron accumulation detected by the quantitative susceptibility mapping technique is a possible biomarker of disease progression.

Alcohol use disorder (AUD) is a complex condition including affective, cognitive and motivational dimensions. Although AUD is known to induce diffuse brain damage, including grey matter shrinkage and ventricular enlargement, the microstructural changes it induces in white matter remain incompletely understood. This study leverages multi-shell diffusion MRI and multi-fixel models to (i) undertake whole-brain and tract-specific analyses to investigate the microstructure of white matter (WM) tracts affected by AUD, (ii) evaluate whether these differences persist in early abstinence, and (iii) correlate these results with clinical measures evaluated by validated psychological questionnaires. We recruited a final cohort of 37 AUD patients, admitted for alcohol withdrawal and selected for their ongoing alcohol consumption at the time of admission, and a demographically matched control group of 19 healthy subjects. Both groups underwent MRI scans at baseline and 18 days later, with assessments of depression, obsession-compulsion, and anxiety conducted in both sessions for the AUD patients and once for the control group. The imaging results confirmed the presence in AUD participants of clusters microstructural alterations in the fornix, corpus callosum, cingulum, uncinate fasciculus and anterior thalamic radiations. These white matter tracts presented global and localized microstructural changes in axial diffusivity and fractional anisotropy, which are linked to axonal damage and inflammation. There was no significant improvement in the diffusion metrics after almost three weeks of abstinence, although clinical measures did improve significantly. Depression scores were significantly elevated in the patients at admission and decreased with time. Depression scores before withdrawal showed correlations with microstructural metrics across the right anterior thalamic radiations, the isthmus of the corpus callosum, and the right uncinate fasciculus. Lower fractional anisotropy and higher radial diffusivity were predictive of higher depression scores. Overall, these findings highlight the long-term vulnerability of WM tracts affected by AUD and the link between tract microstructure, brain function and behaviour.

The relationship between functional language lateralization and diffusion MRI-based white matter metrics remains a subject of considerable interest and complexity. This systematic review aims to synthesize existing diffusion MRI studies examining white matter correlates of functional language dominance. Twenty-five studies were identified through searches of Web of Science, Scopus and Ovid MEDLINE (search period: inception to 16th May 2023), involving adults with epilepsy, tumours or healthy controls. The results suggest that while the arcuate fasciculus and corpus callosum are commonly associated with language lateralization in clinical populations, the findings in healthy individuals are more variable, often influenced by factors such as handedness. Other white matter tracts, such as uncinate fasciculus, showed less consistent associations with language dominance across studies. Interestingly, temporal lobe regions, especially those involved in semantic processing, exhibited stronger correlations with diffusion measures compared to frontal areas associated with phonological tasks. Methodological inconsistencies, such as variability in sample selection, task design and analytical techniques, were identified as significant challenges in comparing findings across studies. Future research should aim for larger, more diverse sample sizes, whole-brain approaches and a wider range of functional MRI tasks to better elucidate the role of white matter in language lateralization. If regions of interest-based studies are utilized, a more standardized approach to tract segmentation should be adopted to ensure consistency and improve comparability across studies.

There is a pressing unmet clinical and health economic need for effective drugs to treat cognitive impairment that occurs in neurodegenerative diseases. JAK4D is a first-in-class thyrotropin releasing hormone (TRH) analogue that overcomes the pharmacological limitations of thyrotropin releasing hormone and enables delivery of the long-recognized multifactorial neurotherapeutic actions of thyrotropin releasing hormone without inducing endocrine side effects. JAK4D is demonstrated to be neuroprotective and significantly reduce excitotoxic-induced hippocampal-dependent memory deficits in rat. In the present study, we used the scopolamine challenge test coupled with the novel object recognition test to evaluate the effect of JAK4D on scopolamine-induced recognition memory deficits in the male, Lister-Hooded rat. Scopolamine administration has been shown by others to mimic cholinergic and brain network disruption in neurodegenerative diseases. Although the scopolamine challenge test does not fully replicate the pathophysiology of neurodegenerative disease, such as Alzheimer's disease, it is a well-recognized acute pharmacological model for assessing the ability of pharmacological interventions to counteract memory deficits relevant to neurodegenerative diseases. In this model of cholinergic dysfunction, we also assessed the effects of thyrotropin releasing hormone, taltirelin (a degradation-stabilized thyrotropin releasing hormone analogue) and the acetylcholinesterase inhibitor, donepezil, as a positive reference compound. The discrimination (d2) index was used as the primary measure to assess the effect of treatment on scopolamine-induced performance deficit in the novel object recognition test. d2 is a standard well-recognized measure of discrimination between a novel and familiar object in the novel object recognition test, which advantageously takes into account individual differences in exploration levels. Across all investigations, JAK4D (1 mg/kg i.p.) significantly reversed scopolamine-induced recognition memory impairment (P = 0.0274, P = 0.0002, P < 0.0001). The degree of reversal of scopolamine-induced memory deficits by JAK4D (1 mg/kg i.p.) was indistinguishable from that observed for donepezil (0.1 mg/kg p.o.) (P = 0.026). Subcutaneously administered JAK4D (0.3-10.0 mg/kg) also significantly reversed this deficit (P = 0.0432-0.0021). Furthermore, similar pro-cognitive effects were exerted by thyrotropin releasing hormone (5 mg/kg i.p., P = 0.0055) and taltirelin (10 mg/kg p.o., P = 0.0002). Together, these results underscore the relevance of the central thyrotropin releasing hormone signalling system for the treatment of memory impairment. Data from the current study provide further evidence in support of the potential of JAK4D as a novel therapeutic for cognitive deficits in neurodegenerative diseases.

Imagining a movement without executing it has measurable effects on physical performance, learning, and rehabilitation. However, these effects rely on our ability to imagine performing actions, a complex, covert skill that is difficult to quantify. While movement imagery ability can be assessed by behavioural methods or measuring its neural correlates, the relationship between these measures is uncertain. This Registered Report will determine the association between three key behavioural processes during movement imagery - generation, maintenance and manipulation - and well-established neurophysiological measures of corticospinal excitability and intracortical inhibition during imagery, obtained via Transcranial Magnetic Stimulation. A behavioural battery including a questionnaire, a 'mental chronometry' task, and a hand rotation task will be collected alongside the amplitude of Motor Evoked Potentials and the change in Short Interval Cortical Inhibition during imagery. Bayesian correlations will assess the association between these measures to provide a comprehensive evaluation of the neuro-behavioural correlates of movement imagery.

Alzheimer's disease (AD) is a significant global health issue, impacting 50 million individuals with dementia worldwide, a number projected to triple by 2050. Although research has been conducted for decades, there is no effective prevention, treatment, or early diagnostic method for AD. Research on AD in Latin America (LatAm) faces unique challenges compared to developed countries due to socioeconomic, cultural, and infrastructural factors. While the prevalence of dementia is rapidly increasing in LatAm due to demographic shifts, the region is underrepresented in research, diagnostics and care. The informed consent process, a critical aspect of research, becomes particularly complex with individuals who have cognitive impairments. It requires a balance between protecting vulnerable individuals and advancing research for their benefit. By developing and implementing best practices, ethical research can be conducted with this population, ensuring they receive appropriate care. This review provides an update on informed consent for AD research in Chile.