Brain communications最新文献

{"title":"Pupil-linked arousal, cortical activity, and cognition in Alzheimer's disease.","authors":"Michael C B David, Emma-Jane Mallas, Lucia M Li, Magdalena A Kolanko, Ramin Nilforooshan, Man Lai Tsoi, Hanim Karakoc, Karen Hoang, Johanna Brandt, Charikleia Triantafyllou, Dragos C Gruia, Darije Custovic, Peter J Lally, Karl A Zimmerman, Paresh A Malhotra, Gregory Scott, David J Sharp","doi":"10.1093/braincomms/fcaf236","DOIUrl":"10.1093/braincomms/fcaf236","url":null,"abstract":"<p><p>Arousal dysfunction contributes to impairments seen in Alzheimer's disease. However, the nature and degree of this dysfunction have not been studied in detail. We investigated changes in tonic and phasic arousal using simultaneous pupillometry-EEG, relating these changes to locus coeruleus integrity, a key arousal nucleus. Forty Alzheimer's disease participants and 30 controls underwent neuropsychological testing using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), MRI designed to show contrast in the locus coeruleus as a measure of integrity and simultaneous pupillometry-EEG during 5 min of eyes-open resting-state. Pupillometry-EEG was then also applied during an oddball task which included a passive session and sessions in which responses to target stimuli were required, to test the effect of salience. Alzheimer's disease had lower locus coeruleus integrity (<i>b</i> = -0.26, <i>P</i> = 0.02) and lower peak alpha frequency (tonic arousal) (<i>b</i> = -1.09, <i>P</i> < 0.001). Both were related to ADAS-Cog. There was a very strong relationship between pupil size and both periodic and aperiodic EEG power. Cortical slowing in Alzheimer's disease affected this relationship, particularly at low frequencies. During the attentionally demanding oddball task, Alzheimer's disease participants' behavioural performance was impaired, with reduced accuracy and slower and more variable reaction times. They also had reduced pupil responses to salient stimuli (phasic arousal) (estimate = -0.19, <i>P</i> < 0.001). EEG and pupil measures of pre-stimulus tonic arousal were strongly correlated and predicted behavioural responses in both groups. Arousal fluctuations at rest and in response to stimuli are abnormal in Alzheimer's disease as measured by combined pupillometry and EEG. Salient stimuli that require a behavioural response are accompanied by a phasic increase in arousal, demonstrated by pupil dilation to oddball stimuli. This response is slower and of smaller magnitude in Alzheimer's disease patients. Cortical slowing (reduced peak alpha frequency) is seen in Alzheimer's disease, and this is modulated by arousal level and relates to overall cognition. Pupil-linked arousal responses and alpha EEG fluctuations are tightly coupled, but cortical slowing in Alzheimer's disease influences this coupling. The tools used here to measure neurophysiological arousal level have potential in understanding the nature of arousal system dysfunction in Alzheimer's disease at the group level. These tools may also be used as biomarkers at the individual level in order to target patients most likely to benefit from arousal-modulating medications.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 4","pages":"fcaf236"},"PeriodicalIF":4.1,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12280328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The lifetime accumulation of multimorbidity and its influence on dementia risk: a UK Biobank study.","authors":"Raihaan Patel, Grace Gillis, Clare E Mackay, Ludovica Griffanti, Congxiyu Wang, Klaus P Ebmeier, Sana Suri","doi":"10.1093/braincomms/fcaf222","DOIUrl":"10.1093/braincomms/fcaf222","url":null,"abstract":"<p><p>The number of people living with dementia worldwide is projected to reach 150 million by 2050, making prevention a crucial priority for health services. The co-occurrence of two or more chronic health conditions, termed multimorbidity, occurs in up to 80% of dementia patients, making multimorbidity an important risk factor for dementia. However, we lack an understanding of the specific health conditions, and their age of onset, that drive the link between multimorbidity and dementia. Using data from 282 712 participants of the UK Biobank, we defined the sequential patterns of accumulation of 46 chronic conditions over the life course. By grouping individuals based on their life history of chronic illness, we show here that the risk of incident dementia can be stratified by both the type and timing of their accumulated chronic conditions. We identified several distinct clusters of multimorbidity throughout the lifespan (cardiometabolic, mental health, neurovascular, peripheral vascular, eye diseases and low/no multimorbidity). We observed that the odds of developing dementia varied based on when these comorbidities were diagnosed. Until midlife (age 55), the accumulation of cardiometabolic conditions, such as coronary heart disease, atrial fibrillation, and diabetes, was most strongly associated with dementia risk. However, from 55 to 70 years, the accumulation of mental health conditions, such as anxiety and depression, as well as neurovascular conditions, such as stroke and transient ischaemic attack, was associated with an over 2-fold increase in dementia risk compared with low multimorbidity. Importantly, individuals who continuously and sequentially accumulate cardiometabolic, mental health, and neurovascular conditions were at greatest risk. The age-dependent role of multimorbidity in predicting dementia risk could be used for early stratification of individuals into high- and low-risk groups and could inform targeted prevention strategies based on a person's prior history of chronic disease.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 4","pages":"fcaf222"},"PeriodicalIF":4.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"[¹⁸F]SynVest-1 PET imaging in people with Parkinson's disease.","authors":"Sarah L Martin, Carme Uribe, Kimberly L Desmond, Lucas Narciso, Bayla Dolman, Edgardo Torres-Carmona, Isabelle Boileau, Ariel Graff-Guerrero, Neil Vasdev, Antonio P Strafella","doi":"10.1093/braincomms/fcaf258","DOIUrl":"10.1093/braincomms/fcaf258","url":null,"abstract":"<p><p>The [¹⁸F]SynVest-1 radiotracer targets the synaptic vesicle glycoprotein 2A (SV2A) and is a proxy of presynaptic density. Parkinson's disease is associated with synaptic dysfunction. Here we investigated synaptic density via the [¹⁸F]SynVest-1 radiotracer in people with PD compared with healthy controls, with reference to how it compares to the previous SV2A radiotracer, [11C]UCB-J. Ten Parkinson's patients and 12 healthy subjects underwent a [¹⁸F]SynVest-1 PET scan. We compared non-displaceable binding potential via voxel-wise and volume of interest analysis to investigate group differences. Volume-of-interest-analyses reported lower non-displaceable binding potential in key a priori regions associated with Parkinson's disease, namely the substantia nigra and caudate nucleus (<i>P</i> < 0.05). Follow-up exploratory volume-of-interest-analyses reported widespread reduction in non-displaceable binding potential within all brain lobes, cerebellum, hippocampus, thalamus and insula; however, these findings did not survive correction for multiple comparisons (<i>P</i> < 0.004). In addition, voxel-wise analyses with family-wise error correction, highlighted significantly lower non-displaceable binding potential in the PD cohort within the putamen and cerebellum. We did not observe any relationships between clinical metrics and non-displaceable binding potential. The results are in line with differences observed using the [¹¹C]UCB-J radiotracer. The [¹⁸F]SynVest-1 radiotracer confirmed lower synaptic density in the Parkinson's disease cohort and adds to the growing evidence of synaptic dysfunction in Parkinson's disease pathology.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 4","pages":"fcaf258"},"PeriodicalIF":4.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory markers in the cerebrospinal fluid linked to mortality in tuberculous meningitis.","authors":"Sofiati Dian, Valerie A C M Koeken, Edwin Ardiansyah, Ahmad R Ganiem, Kirsten van Abeelen, Raúl Aguirre-Gamboa, Feby Purnama, Sofia Imaculata, Jessi Annisa, Lidya Chaidir, Rovina Ruslami, Leo A B Joosten, Mihai G Netea, Bachti Alisjahbana, Reinout van Crevel, Arjan van Laarhoven, Vinod Kumar","doi":"10.1093/braincomms/fcaf273","DOIUrl":"10.1093/braincomms/fcaf273","url":null,"abstract":"<p><p>This study examines the role of host inflammation in the high mortality of tuberculous meningitis (TBM) and identifies potential biomarkers associated with improved survival. We conducted a case-control study involving 131 patients in a discovery cohort, 81 TBM patients in a validation cohort, and 43 non-infected controls from a referral hospital in Indonesia. We measured 94 inflammation-related proteins in cerebrospinal fluid (CSF) and performed genome-wide quantitative trait loci (QTL) mapping. Sixty-seven proteins were found to be differentially expressed between TBM patients and controls, with 64 proteins elevated in patients. Five proteins, including vascular endothelial growth factor (VEGF) and matrix metalloproteinase-10 (MMP-10), were identified as predictors of 180-day mortality in TBM patients. The validation cohort confirmed that MMP-10, but not VEGF, was predictive of mortality. Genome-wide QTL mapping identified two genome-wide significant and four suggestive genetic loci associated with CSF MMP-10, which also predicted survival in an additional cohort of 218 patients. High CSF concentrations of MMP-10, along with specific genetic loci, may be associated with survival in TBM patients, suggesting a potential role for MMP-10 in disease pathogenesis and warranting further investigation into its utility in host-directed therapies.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 4","pages":"fcaf273"},"PeriodicalIF":4.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12284393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperuricaemia is associated with smaller volumes in the caudate nucleus head and putamen.","authors":"Naoki Omori, Manabu Ishida, Masahiro Takamura, Satoshi Abe, Atsushi Nagai","doi":"10.1093/braincomms/fcaf263","DOIUrl":"10.1093/braincomms/fcaf263","url":null,"abstract":"<p><p>Hyperuricaemia is a risk factor for gout, kidney diseases, and cerebrovascular diseases. Uric acid (UA) is also known as an antioxidant and has been suggested to inhibit the progression of neurodegenerative diseases, such as Parkinson's disease. However, only a few studies have focused on the potential effects of UA on the basal ganglia. This study aimed to measure UA levels and basal ganglia volumes in community-dwelling adults and to evaluate the association thereof. Blood UA levels and brain MRI data were collected from individuals who underwent brain health checkups between January 2015 and March 2022 at Shimane Institute of Health Science. Participants were classified into three groups based on their UA levels: normal-low UA (< 5.0 mg/dL), normal-high UA (5.0-7.0 mg/dL), and hyperuricaemia (> 7.0 mg/dL). MRI was used to assess the presence of asymptomatic infarcts, microbleeds, and the severity of enlarged perivascular spaces in the basal ganglia. The volumes of the caudate nucleus, globus pallidus, putamen, substantia nigra, and subthalamic nucleus were calculated using voxel-based morphometry (VBM) as <i>Z</i>-scores adjusted for participant age, sex, and total intracranial volume. Analysis of covariance and smooth-curve fitting models were used to examine the association between UA levels and basal ganglia volumes. In total, 981 participants were included in the analysis. Analysis of covariance revealed that the hyperuricaemia group had significantly higher <i>Z</i>-scores (indicating smaller volumes) in the bilateral caudate nucleus head and putamen than those of the normal-high UA group. The smooth-curve model showed U-shaped associations with smaller volumes for both high and low UA levels, whereas piecewise linear regression analysis confirmed significant regression lines only in the group with higher UA levels. Although UA is thought to have a neuroprotective effect in adults, our findings indicate that hyperuricaemia may contribute to smaller volumes in the caudate nucleus head and putamen. This suggests that excessive UA levels could negatively affect basal ganglia structure and neurological health.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 4","pages":"fcaf263"},"PeriodicalIF":4.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12260223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beta burst-driven adaptive deep brain stimulation for gait impairment and freezing of gait in Parkinson's disease.","authors":"Kevin B Wilkins, Matthew N Petrucci, Emilia F Lambert, Jillian A Melbourne, Aryaman S Gala, Pranav Akella, Laura Parisi, Chuyi Cui, Yasmine M Kehnemouyi, Shannon L Hoffman, Sudeep Aditham, Cameron Diep, Hannah J Dorris, Jordan E Parker, Jeffrey A Herron, Helen M Bronte-Stewart","doi":"10.1093/braincomms/fcaf266","DOIUrl":"10.1093/braincomms/fcaf266","url":null,"abstract":"<p><p>Freezing of gait is a debilitating symptom of Parkinson's disease that is often refractory to medication. Prolonged beta bursts within the subthalamic nucleus are associated with worse impairment and freezing, which are improved with deep brain stimulation. The goal of the study was to investigate the feasibility, safety and tolerability of beta burst-driven adaptive deep brain stimulation for gait impairment and freezing of gait in Parkinson's disease. Seven individuals with Parkinson's disease were implanted with the investigational Summit™ RC + S deep brain stimulation system (Medtronic, PLC, Dublin, Ireland). A PC-in-the-loop architecture adjusted stimulation in real-time based on beta burst durations in the subthalamic nucleus. A rigorous calibration procedure was employed to find participant-specific adaptive deep brain stimulation parameters. In a double-blind design, participants performed a harnessed stepping-in-place task, a free walking turning and barrier course, instrumented measures of bradykinesia and clinical motor assessments in four conditions: OFF stimulation, on adaptive, continuous or randomly adapting deep brain stimulation. Adaptive deep brain stimulation was successfully implemented and deemed safe and tolerable in all participants. Gait metrics such as overall percent time freezing and mean peak shank angular velocity improved on adaptive deep brain stimulation compared to OFF and showed similar efficacy as continuous deep brain stimulation. Similar improvements were also seen for overall clinical motor impairment, including tremor and quantitative metrics of bradykinesia. The current pilot study demonstrated initial safety, tolerability, and feasibility of adaptive deep brain stimulation for freezing of gait in Parkinson's disease in the acute laboratory setting, supporting the future investigation of its longer-term efficacy in the at-home setting.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 4","pages":"fcaf266"},"PeriodicalIF":4.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12268161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vasomotor fluctuations are increased in primary central nervous system lymphoma: a case-control study with fast functional MRI.","authors":"Valter Poltojainen, Matti Järvelä, Janette Kemppainen, Nina Keinänen, Michaela Bode, Juha-Matti Isokangas, Hanne Kuitunen, Juha Nikkinen, Eila Sonkajärvi, Vesa Korhonen, Timo Tuovinen, Niko Huotari, Lauri Raitamaa, Janne Kananen, Heta Helakari, Tommi-Kalevi Korhonen, Sami Tetri, Outi Kuittinen, Vesa Kiviniemi","doi":"10.1093/braincomms/fcaf262","DOIUrl":"10.1093/braincomms/fcaf262","url":null,"abstract":"<p><p>Primary CNS lymphoma is an aggressive brain tumour. An accumulation of malignant cells around cerebral blood vessels may potentially impair the convection of cerebrospinal fluid within perivascular spaces. Recent evidence links an increased variation of the blood oxygen level-dependent signal, a marker for haemodynamic changes, to risk of mortality in lymphoma. In this study, we aimed to characterize the physiological source(s) of increased blood oxygen level-dependent signal variation in lymphoma and characterize the link between altered physiological pulsations and mortality. Thirty lymphoma patients (median age 66 years; 9 females) and 40 healthy age-matched controls (median age 62 years; 29 females) were scanned using an ultrafast functional MRI sequence. We extracted physiological brain pulsation frequency bands from functional MRI data: full band (0.008-5 Hz), very low frequency (0.008-0.1 Hz), respiratory (0.1-0.5 Hz) and cardiac (0.7-2 Hz). We compared the respective pulsation amplitudes between groups using non-parametric covariate-adjusted permutation tests and studied the link between region-specific pulsation amplitudes and mortality in receiver-operating characteristic (ROC) and survival analyses. The lymphoma group showed higher amplitudes in all brain pulsation bands (<i>P</i> ≤ 0.05), with a global increase in the very-low-frequency band. Additionally, we detected increased fluctuation amplitudes in regions extending beyond the macroscopically visible tumour areas. The very-low-frequency and respiratory bands showed a link to mortality in the lymphoma patients, very-low-frequency band being independent of other predictive markers. Increased very-low-frequency amplitude, reflecting propagating vasomotor waves, was the main source for the increased blood oxygen level-dependent signal variation in lymphoma. The patients dying during follow-up showed higher very-low-frequency and respiratory amplitudes compared with the surviving patients, implicating them as a potential prognostic marker.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 4","pages":"fcaf262"},"PeriodicalIF":4.1,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12268500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Morphometric characteristics of tibial nerve and their relationship with age.","authors":"Shahram Oveisgharan, Armand Collin, Jingyun Yang, Sue E Leurgans, Veronique VanderHorst, David A Bennett, Julien Cohen-Adad, Osvaldo Delbono, Aron S Buchman","doi":"10.1093/braincomms/fcaf267","DOIUrl":"10.1093/braincomms/fcaf267","url":null,"abstract":"<p><p>Peripheral nerve comprises a crucial component of the distributed motor/sensory system. However, there is a paucity of data on peripheral nerve morphology derived from large numbers of older adults. This study aimed to quantify the morphometric characteristics of myelinated nerve fibres of the tibial nerve obtained from deceased community-dwelling older adults and examine their association with age. The tibial nerves were obtained from consecutive autopsies of older adults without a history of diabetes who were participants of the Rush Memory and Aging Project, an ongoing longitudinal clinical-autopsy study. A nerve fascicle, obtained from a fixed popliteal segment of the tibial nerve, was separated from the blood vessels and adipose tissue for postmortem examination under an optical microscope. Morphometric characteristics of the myelinated nerve fibres were automatically segmented and quantified using our open-source software <i>AxonDeepSeg</i>. The participants (<i>N</i> = 140) had a mean age of 92.0 years (SD = 5.4) at death, and 72.1% (<i>N</i> = 101) were women. We examined 754 247 myelinated nerve fibres, with an average 5387 (SD = 3436) nerve fibres per participant. The average diameter of myelinated nerve fibres was 4.9 µm (SD = 3.1), axon diameter was 2.0 µm (SD = 1.4), myelin thickness was 1.4 µm (SD = 0.96) and the <i>g</i>-ratio (ratio of axon diameter to myelinated nerve fibre diameter) was 0.45 (SD = 0.17). The relationship between axon diameter and myelin thickness was nonlinear. Myelin was thicker in larger axons up to a diameter of 8 µm, beyond which myelin thickness plateaued. Older age at death was associated with smaller myelinated nerve fibres, smaller axons and thinner myelin. However, age at death was not correlated with myelinated nerve fibre density and was not associated with the average of <i>g</i>-ratio. The association between older age and smaller myelinated nerve fibres was largely attributable to a lower percentage of myelinated nerve fibres >8 µm. We conclude that the smaller tibial myelinated nerve fibres observed in older adults may reflect axonal atrophy rather than degeneration and regeneration of the myelinated nerve fibres. Further research is needed to investigate the pathologies and molecular mechanisms underlying these age-related morphometric changes and their clinical implications in older adults.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 4","pages":"fcaf267"},"PeriodicalIF":4.1,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12272163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep learning to predict progression independent of relapse activity at a first demyelinating event.","authors":"Llucia Coll, Deborah Pareto, Francisco Aparicio-Serrano, Susana Otero-Romero, Alvaro Cobo-Calvo, Evy Reinders, Manel Alberich, María Jesús Arévalo, Georgina Arrambide, Cristina Auger, Joaquín Castilló, Manuel Comabella, Ingrid Galán, Luciana Midaglia, Carlos Nos, Frederik Novak, Arnau Oliver, Jordi Río, Breogán Rodríguez-Acevedo, Jaume Sastre-Garriga, Ángela Vidal-Jordana, Ana Zabalza, Xavier Montalban, Àlex Rovira, Mar Tintoré, Xavier Lladó, Carmen Tur","doi":"10.1093/braincomms/fcaf243","DOIUrl":"10.1093/braincomms/fcaf243","url":null,"abstract":"<p><p>Progression independent of relapse activity is the main cause of irreversible disability in multiple sclerosis and is strongly associated with older age at symptom onset. Early and accurate prediction, at symptom onset, of which patients are at highest risk of progression independent of relapses, is an unmet need. This study aimed to develop a deep learning survival model using only routine MRI acquired at the first demyelinating attack to predict the risk of progression independent of relapses, and assess its ability to improve classical age-adjusted predictions. We analysed a prospective cohort of patients under 50, clinically assessed within three months of symptom onset, with available MRI (T1- and T2-Fluid-Attenuated Inversion Recovery sequences). An independent early multiple sclerosis cohort (≤1 year from symptom onset) from the Multiple Sclerosis Partners Advancing Technology and Health Solutions database (<i>N</i> = 32) was used for external validation. Patients were assessed for progression independent of relapse activity, defined as a 6-month confirmed increase in the Expanded Disability Status Scale without relapses. Our deep learning model used EfficientNet to estimate the cumulative probability of progression independent of relapses at 1-year intervals. We employed 5-fold cross-validation for model training and testing, assessing performance with the time-dependent concordance index. We also investigated the optimal cumulative probability threshold for binary risk stratification. The model's ability to improve a classical Cox regression model was evaluated. Additionally, we identified brain regions most relevant to deep learning-based progression independent of relapse activity predictions using an interpretability algorithm. A total of 259 patients were evaluated, 58 (22%) of whom experienced at least one event of progression independent of relapse activity over a median follow-up of 4.2 years. The deep learning model demonstrated high performance (time-dependent concordance index = 0.72) with an accuracy of 78% in the original cohort and 72% in the external cohort for predicting the risk of progression independent of relapse activity. Incorporating the deep learning-derived cumulative probability of progression independent of relapses significantly improved an age-adjusted Cox regression model, raising Harrell's C index from 0.62 to 0.74. Interpretability revealed the frontoparietal cortex as a key region in predicting progression independent of relapse activity. In conclusion, our deep learning survival model, based on routine MRI at the first demyelinating attack, can accurately identify patients at high risk of progression independent of relapses and may serve as a valuable tool in clinical practice.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 4","pages":"fcaf243"},"PeriodicalIF":4.1,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12226453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations between night/shift working and late-life brain health.","authors":"Josh King-Robson, Jennifer M Nicholas, Sarah-Naomi James, Ashvini Keshavan, Dylan M Williams, James Groves, Carole H Sudre, Kirsty Lu, Josephine Barnes, William Coath, David M Cash, Sarah E Keuss, Marcus Richards, Jason D Warren, Jonathan M Schott","doi":"10.1093/braincomms/fcaf264","DOIUrl":"10.1093/braincomms/fcaf264","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Sleep and circadian disturbances are associated with increased dementia risk. The mechanism remains poorly understood. We aimed to examine the relationship between night/shift working at age 31 and biomarkers of late-life brain health and to estimate the extent to which these relationships are mediated by unhealthy lifestyle behaviours. A prospective longitudinal cohort study, Insight 46, recruited participants from the Medical Research Council National Survey of Health and Development (NSHD) 1946 British Birth cohort. All born in the same week in 1946, participants were assessed at age 70 with multi-modal structural and molecular brain imaging and fluid biomarkers, from which whole-brain and hippocampal volumes, white matter hyper-intensity volume (WMHV), &lt;sup&gt;18&lt;/sup&gt;F-florbetapir amyloid-β PET Centiloids and plasma phosphorylated tau (p-tau)217 were derived. Prospective data collection included night/shift working at age 31, alongside smoking, alcohol intake, body mass index, exercise, blood pressure, Framingham risk score (FRS) at multiple timepoints from age 20 to 70 and dementia diagnosis or death by age 78. Analyses were adjusted for sex, age, education, socioeconomic position and, where appropriate, total intracranial volume or apolipoprotein E (&lt;i&gt;APOE&lt;/i&gt;) genotype. Night/shift working data were available for 431 Insight 46 participants {50% female, mean age 70.7 years [standard deviation (SD) 0.6]}. Night/shift workers had lower whole-brain volume [-19.9 mL, 95% confidence interval (CI) -31.9, -7.9, &lt;i&gt;P =&lt;/i&gt; 0.001], lower amyloid PET Centiloids (-9.45, 95% CI -14.7, -4.1, &lt;i&gt;P =&lt;/i&gt; 0.0008) and lower plasma p-tau217 concentration (-0.05 pg/mL, 95% CI -0.10, -0.001, &lt;i&gt;P =&lt;/i&gt; 0.04), without significant difference in hippocampal volume or WMHV. p-tau217 concentrations were also lower in night/shift workers from a wider sample from the NSHD cohort [&lt;i&gt;n&lt;/i&gt; = 1067, mean age 69.9 (SD 0.7), -0.05 pg/mL, 95% CI -0.08, -0.02, &lt;i&gt;P =&lt;/i&gt; 0.004]. By age 78, night/shift workers in the NSHD cohort (&lt;i&gt;n&lt;/i&gt; = 3040) had lower rates of all-cause (excluding vascular) dementia (hazard ratio 0.33, 95% CI 0.12, 0.92, &lt;i&gt;P&lt;/i&gt; = 0.03). Night/shift workers had 0.6% higher FRS (&lt;i&gt;P =&lt;/i&gt; 0.01) at age 36, smoked 5.9 more pack-years by age 53 (&lt;i&gt;P =&lt;/i&gt; 0.005), consumed 10.7 g/day more alcohol by age 63 (&lt;i&gt;P =&lt;/i&gt; 0.006) and had higher rates of &lt;i&gt;APOE&lt;/i&gt; ɛ4 allele carriage. Lifestyle behaviours mediated 28% of the lower brain volume in night/shift workers. Despite less healthy lifestyles, higher rates of &lt;i&gt;APOE&lt;/i&gt; ɛ4 allele carriage and smaller brains, night/shift workers had lower levels of Alzheimer's disease pathology as measured by amyloid PET and plasma p-tau217 and approximately one-third of the risk of dementia by age 78 compared with non-night/shift workers. Lower brain volume in night/shift workers was partially mediated by unhealthy behaviours. Reduced dementia risk in night/shift workers is unexpected and will require further stud","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 4","pages":"fcaf264"},"PeriodicalIF":4.1,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12268499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}