Brain最新文献

Functional neurological disorder (FND) is continuing to gain increasing recognition globally as a valid and potentially treatable disorder. Iatrogenic harm towards patients with FND is significant, however, and has been around for centuries. Despite advances in our understanding around the aetiology, pathophysiology and treatment of FND, many aspects of such harm continue to persist. Avoidance of iatrogenic harm has been highlighted by clinicians as one of the most important therapeutic considerations in FND; however, the sources and range of potential harms, or indeed ways to mitigate them, have not previously been summarized. Using a combination of clinical and research experience and scoping review methodology, this review aims to describe the main sources of iatrogenic harm towards patients with FND, including harm from misdiagnosis, delayed diagnosis and treatment, direct harm from professional interactions, other stigma-related harms, harm related to diagnostic overshadowing and over-diagnosis of FND. We also describe some potential ways to address and prevent such harms, such as ways to reduce misdiagnosis with a focus on rule in signs, optimizing teaching and communication, ensuring parity of FND with other medical conditions and continued integration of patient and professional organizations.

Pain is a non-motor symptom that impairs quality of life in patients with Parkinson's disease. Pathological nociceptive hypersensitivity in patients could be due to changes in the processing of somatosensory information at the level of the basal ganglia, including the subthalamic nucleus (STN), but the underlying mechanisms are not yet defined. Here, we investigated the interaction between the STN and the dorsal horn of the spinal cord (DHSC), by first examining the nature of STN neurons that respond to peripheral nociceptive stimulation and the nature of their responses under normal and pathological conditions. Next, we studied the consequences of deep brain stimulation (DBS) of the STN on the electrical activity of DHSC neurons. Then, we investigated whether the therapeutic effect of STN-DBS would be mediated by the brainstem descending pathway involving the rostral ventromedial medulla. Finally, to better understand how the STN modulates allodynia, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) expressed in the STN. The study was carried out on the 6-OHDA rodent model of Parkinson's disease, obtained by stereotactic injection of the neurotoxin into the medial forebrain bundle of rats and mice. In these animals, we used motor and nociceptive behavioural tests, in vivo electrophysiology of STN and wide dynamic range (WDR) DHSC neurons in response to peripheral stimulation, deep brain stimulation of the STN and the selective DREADD approach. Vglut2-ires-cre mice were used to specifically target and inhibit STN glutamatergic neurons. STN neurons are able to detect nociceptive stimuli, encode their intensity and generate windup-like plasticity, like WDR neurons in the DHSC. These phenomena are impaired in dopamine-depleted animals, as the intensity response is altered in both spinal and subthalamic neurons. Furthermore, as with L-DOPA, STN-DBS in rats ameliorated 6-OHDA-induced allodynia, and this effect is mediated by descending brainstem projections leading to normalization of nociceptive integration in DHSC neurons. Furthermore, this therapeutic effect was reproduced by selective inhibition of STN glutamatergic neurons in Vglut2-ires-cre mice. Our study highlights the centrality of the STN in nociceptive circuits, its interaction with the DHSC and its key involvement in pain sensation in Parkinson's disease. Furthermore, our results provide for the first-time evidence that subthalamic DBS produces analgesia by normalizing the responses of spinal WDR neurons via descending brainstem pathways. These effects are due to direct inhibition, rather than activation of glutamatergic neurons in the STN or passage fibres, as shown in the DREADDs experiment.

Considering the growing age of the world population, the incidence of epilepsy in older adults is expected to increase significantly. It has been suggested that late-onset temporal lobe epilepsy (LO-TLE) may be neurodegenerative in origin and overlap with Alzheimer's disease (AD). Herein, we aimed to characterize the pattern of cortical atrophy and CSF biomarkers of AD (total and phosphorylated tau and amyloid-β) in a selected population of LO-TLE of unknown origin. We prospectively enrolled individuals with temporal lobe epilepsy onset after the age of 50 and no cognitive impairment. They underwent a structural MRI scan and CSF biomarkers measurement. Imaging and biomarkers data were compared to three retrospectively collected groups: (i) age-sex-matched healthy controls; (ii) patients with mild cognitive impairment (MCI) and abnormal CSF AD biomarkers (MCI-AD); and (iii) patients with MCI and normal CSF AD biomarkers (MCI-noAD). From a pool of 52 patients, 20 consecutive eligible LO-TLE patients with a mean disease duration of 1.8 years were recruited. As control populations, 25 patients with MCI-AD, 25 patients with MCI-noAD and 25 healthy controls were enrolled. CSF biomarkers returned normal values in LO-TLE, significantly different from patients with MCI due to AD. There were no differences in cortico-subcortical atrophy between epilepsy patients and healthy controls, while patients with MCI demonstrated widespread injuries of cortico-subcortical structures. Individuals with LO-TLE, characterized by short disease duration and normal CSF amyloid-β and tau protein levels, showed patterns of cortical thickness and subcortical volumes not significantly different from healthy controls, but highly different from patients with MCI, either due to AD or not.

Obese adults are often reported to have smaller brain volumes than their non-obese peers. Whether this represents evidence of accelerations in obesity-driven atrophy or is instead a legacy of developmental differences established earlier in the lifespan remains unclear. This study investigated whether early-life differences in adiposity explain differences in numerous adult brain traits commonly attributed to mid-life obesity. We used a two-sample life course Mendelian randomization study in 37 501 adults recruited to UK Biobank (UKB) imaging centres from 2014, with secondary analyses in 6996 children assessed in the Adolescent Brain Cognitive Development Study (ABCD) recruited from 2018. Exposures were genetic variants for childhood (266 variants) and adult (470 variants) adiposity derived from a genome-wide association study (GWAS) of 407 741 UKB participants. Primary outcomes were: adult total brain volume; grey matter volume, thickness and surface area; white matter volume and hyperintensities; and hippocampus, amygdala and thalamus volumes at mean age 55 in the UKB. Secondary outcomes were equivalent childhood measures collected at mean age 10 in ABCD. In the UKB, individuals who were genetically predicted to have had higher levels of adiposity in childhood were found to have multiple smaller adult brain volumes relative to intracranial volume [e.g. z-score difference in normalized brain volume per category increase in adiposity-95% confidence interval (CI) = -0.20 (-0.28, -0.12); P = 4 × 10-6]. These effect sizes remained essentially unchanged after accounting for birthweight or current adult obesity in multivariable models, whereas most observed adult effects attenuated towards null [e.g. adult z-score (95% CI) for total volume = 0.06 (-0.05, 0.17); P = 0.3]. Observational analyses in ABCD showed a similar pattern of changes already present in those with a high body mass index by age 10 [z-score (95% CI) = -0.10 (-0.13, -0.07); P = 8 × 10-13], with follow-up genetic risk score analyses providing some evidence for a causal effect already at this early age. Sensitivity analyses revealed that many of these effects were likely due to the persistence of larger head sizes established in those who gained excess weight in childhood [childhood z-score (95% CI) for intracranial volume = 0.14 (0.05, 0.23); P = 0.002], rather than smaller brain sizes per se. Our data suggest that the persistence of early-life developmental differences across the life course may underlie numerous neuroimaging traits commonly attributed to obesity-related atrophy in later life.

Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models. As small molecule TRPV4 antagonists have proven safe in trials for other disease indications, channel inhibition is a promising therapeutic strategy for TRPV4 patients. However, the current knowledge of the clinical features and natural history of TRPV4-related neuromuscular disease is insufficient to enable rational clinical trial design. To address these issues, we developed a TRPV4 patient database and administered a TRPV4-specific patient questionnaire. Here, we report demographic and clinical information, including CMT Examination Scores (CMTES), from 68 patients with known pathogenic TRPV4 variants, 40 of whom also completed the TRPV4 patient questionnaire. TRPV4 patients showed a bimodal age of onset, with the largest peak occurring in the first 2 years of life. Compared to CMT type 1A (CMT1A) patients, TRPV4 patients showed distinct symptoms and signs, manifesting more ambulatory difficulties and more frequent involvement of proximal arm and leg muscles. Although patients reported fewer sensory symptoms, sensory dysfunction was often detected clinically. Many patients were affected by vocal fold weakness (55%) and shortness of breath (55%), and 11% required ventilatory support. Skeletal abnormalities were common, including scoliosis (64%), arthrogryposis (33%) and foot deformities. Strikingly, patients with infantile onset of disease showed less sensory involvement and less progression of symptoms. These results highlight distinctive clinical features in TRPV4 patients, including motor-predominant disease, proximal arm and leg weakness, severe ambulatory difficulties, vocal fold weakness, respiratory dysfunction and skeletal involvement. In addition, patients with infantile onset of disease appeared to have a distinct phenotype with less apparent disease progression based on CMTES. These collective observations indicate that clinical trial design for TRPV4-related neuromuscular disease should include outcome measures that reliably capture non-length dependent motor dysfunction, vocal fold weakness and respiratory disease.

The microtubule-associated protein Tau is a driver of neuronal dysfunction in Alzheimer's disease and other tauopathies. In this process, Tau initially undergoes subtle changes to its abundance, subcellular localization and a vast array of post-translational modifications including phosphorylation that progressively result in the protein's somatodendritic accumulation and dysregulation of multiple Tau-dependent cellular processes. Given the various loss- and gain-of-functions of Tau in disease and the brain-wide changes in the proteome that characterize tauopathies, we asked whether targeting Tau would restore the alterations in proteostasis observed in disease. Therefore, by phage display, we generated a novel pan-Tau antibody, RNJ1, that preferentially binds human Tau and neutralizes proteopathic seeding activity in multiple cell lines and benchmarked it against a clinically tested pan-Tau antibody, HJ8.5 (murine version of tilavonemab). We then evaluated both antibodies, alone and in combination, in the K3 tauopathy mouse model, showing reduced Tau pathology and improvements in neuronal function following 14 weekly treatments, without obtaining synergy for the combination. These effects were more pronounced in female mice. To investigate the molecular mechanisms contributing to improvements in neuronal function, we employed quantitative proteomics, phosphoproteomics and kinase prediction analysis to first establish alterations in K3 mice relative to wild-type controls at the proteome level. In female K3 mice, we found 342 differentially abundant proteins, which are predominantly involved in metabolic and microtubule-associated processes, strengthening previously reported findings of defects in several functional domains in multiple tauopathy models. We next asked whether antibody-mediated Tau target engagement indirectly affects levels of deregulated proteins in the K3 model. Importantly, both immunotherapies, in particular RNJ1, induced abundance shifts towards a restoration to wild-type levels (proteostasis). A total of 257 of 342 (∼75%) proteins altered in K3 were closer in abundance to wild-type levels after RNJ1 treatment, and 73% after HJ8.5 treatment. However, the magnitude of these changes was less pronounced than that observed with RNJ1. Furthermore, analysis of the phosphoproteome showed an even stronger restoration effect with RNJ1, with ∼82% of altered phosphopeptides in K3 showing a shift to wild-type levels, and 75% with HJ8.5. Gene set over-representation analysis further confirmed that proteins undergoing restoration are involved in biological pathways affected in K3 mice. Together, our study suggests that a Tau immunotherapy-induced restoration of proteostasis links target engagement and treatment efficacy.

Lewy body dementia and Alzheimer's disease (AD) are leading causes of cognitive impairment, characterized by distinct but overlapping neuropathological hallmarks. Lewy body disease (LBD) is characterized by α-synuclein aggregates in the form of Lewy bodies as well as the deposition of extracellular amyloid plaques, with many cases also exhibiting neurofibrillary tangle (NFT) pathology. In contrast, AD is characterized by amyloid plaques and neurofibrillary tangles. Both conditions often co-occur with additional neuropathological changes, such as vascular disease and TDP-43 pathology. To elucidate shared and distinct molecular signatures underlying these mixed neuropathologies, we extensively analysed transcriptional changes in the anterior cingulate cortex, a brain region critically involved in cognitive processes. We performed bulk tissue RNA sequencing from the anterior cingulate cortex and determined differentially expressed genes (q-value <0.05) in control (n = 81), LBD (n = 436), AD (n = 53) and pathological amyloid cases consisting of amyloid pathology with minimal or no tau pathology (n = 39). We used gene set enrichment and weighted gene correlation network analysis to understand the pathways associated with each neuropathologically defined group. LBD cases had strong upregulation of inflammatory pathways and downregulation of metabolic pathways. The LBD cases were further subdivided into either high Thal amyloid, Braak NFT, or low pathological burden cohorts. Compared to the control cases, the LBD cohorts consistently showed upregulation for genes involved in protein folding and cytokine immune response, as well as downregulation of fatty acid metabolism. Surprisingly, concomitant tau pathology within the LBD cases resulted in no additional changes. Some core inflammatory pathways were shared between AD and LBD but with numerous disease-specific changes. Direct comparison of LBD cohorts versus AD cases revealed strong enrichment of synaptic signalling, behaviour and neuronal system pathways. Females had a stronger response overall in both LBD and AD, with several sex-specific changes. Overall, the results identify genes commonly and uniquely dysregulated in neuropathologically defined LBD and AD cases, shedding light on shared and distinct molecular pathways. Additionally, the study underscores the importance of considering sex-specific changes in understanding the complex transcriptional landscape of these neurodegenerative diseases.

Brain inflammation, with an increased density of microglia and macrophages, is an important component of Alzheimer's disease and a potential therapeutic target. However, it is incompletely characterized, particularly in patients whose disease begins before the age of 65 years and, thus, have few co-pathologies. Inflammation has been usefully imaged with translocator protein (TSPO) PET, but most inflammation PET tracers cannot image subjects with a low-binder TSPO rs6971 genotype. In an important development, participants with any TSPO genotype can be imaged with a novel tracer, 11C-ER176, that has a high binding potential and a more favourable metabolite profile than other TSPO tracers currently available. We applied 11C-ER176 to detect brain inflammation in mild cognitive impairment (MCI) caused by early-onset Alzheimer's disease. Furthermore, we sought to correlate the brain localization of inflammation, volume loss, elevated amyloid-β (Aβ)and tau. We studied brain inflammation in 25 patients with early-onset amnestic MCI (average age 59 ± 4.5 years, 10 female) and 23 healthy controls (average age 65 ± 6.0 years, 12 female), both groups with a similar proportion of all three TSPO-binding affinities. 11C-ER176 total distribution volume (VT), obtained with an arterial input function, was compared across patients and controls using voxel-wise and region-wise analyses. In addition to inflammation PET, most MCI patients had Aβ (n = 23) and tau PET (n = 21). For Aβ and tau tracers, standard uptake value ratios were calculated using cerebellar grey matter as region of reference. Regional correlations among the three tracers were determined. Data were corrected for partial volume effect. Cognitive performance was studied with standard neuropsychological tools. In MCI caused by early-onset Alzheimer's disease, there was inflammation in the default network, reaching statistical significance in precuneus and lateral temporal and parietal association cortex bilaterally, and in the right amygdala. Topographically, inflammation co-localized most strongly with tau (r = 0.63 ± 0.24). This correlation was higher than the co-localization of Aβ with tau (r = 0.55 ± 0.25) and of inflammation with Aβ (0.43 ± 0.22). Inflammation co-localized least with atrophy (-0.29 ± 0.26). These regional correlations could be detected in participants with any of the three rs6971 TSPO polymorphisms. Inflammation in Alzheimer's disease-related regions correlated with impaired cognitive scores. Our data highlight the importance of inflammation, a potential therapeutic target, in the Alzheimer's disease process. Furthermore, they support the notion that, as shown in experimental tissue and animal models, the propagation of tau in humans is associated with brain inflammation.