BrainPub Date : 2025-06-04DOI: 10.1093/brain/awaf211
Lei Yu, Lianlian Du, Tianhao Wang, Lisa L Barnes, Jeffrey L Dage, Kristen A Russ, Tatiana Foroud, David A Bennett, Julie A Schneider, Patricia A Boyle
{"title":"Neuropathologic correlates of distinct plasma biomarker profiles in community-living older adults","authors":"Lei Yu, Lianlian Du, Tianhao Wang, Lisa L Barnes, Jeffrey L Dage, Kristen A Russ, Tatiana Foroud, David A Bennett, Julie A Schneider, Patricia A Boyle","doi":"10.1093/brain/awaf211","DOIUrl":"https://doi.org/10.1093/brain/awaf211","url":null,"abstract":"There has been a rapid growth in research on peripheral fluid biomarkers for Alzheimer’s Disease and Alzheimer’s Disease related dementias (AD/ADRD) because they are non-invasive, relatively inexpensive, and easily accessible. The most commonly used plasma biomarkers include β-amyloid (Aβ), phosphorylated tau (p-tau), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). The extent to which distinct profiles of multiple plasma biomarkers correlate with common neuropathologies is unclear. Using clinicopathologic data from 405 community-dwelling older adults, we applied latent profile analysis on 4 plasma biomarkers, i.e., Aβ42/40 ratio, p-tau217, NfL and GFAP, and examined the correlates of the latent profiles with 4 degeneration measures of AD, Lewy bodies, limbic-predominant age-related TDP-43 encephalopathy (LATE), hippocampal sclerosis, and 5 vascular measures including chronic macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis and arteriosclerosis. On average, participants died at the age of 89 and blood samples for plasma biomarkers were measured 3.9 years before death. Over 75% were female and 24% were non-Latino Black. We observed 3 distinct biomarker profiles. Profile #1, characterized by low p-tau217, low GFAP, low NfL and high Aβ42/40, represents most participants (55.6%) with better than average biomarker levels. Both Profile #2 and Profile #3 showed worse than average biomarker levels. Profile #2, representing 34.8% of the participants, was high in p-tau217 and GFAP. By contrast, Profile #3, representing 9.6% of the participants, was high in NfL and GFAP. Examination of neuropathologic correlates of these plasma biomarker profiles revealed that Profile #2 exemplifies older adults with a high burden of neurodegeneration; almost all participants (92.9%) in Profile #2 had a diagnosis of pathologic AD, and the group also had the highest percentage of participants with Lewy bodies (41.1%). In comparison, Profile #3 exemplifies older adults with more severe vascular conditions; participants in this group had the highest percentage of macroscopic infarcts (31.6%) and moderate or severe atherosclerosis (42.1%). Together, these findings suggest that common plasma biomarkers may exhibit profiles reflective of distinct pathophysiologic processes.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"247 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144218885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BrainPub Date : 2025-06-03DOI: 10.1093/brain/awae391
Federica Agosta, Silvia Basaia, Edoardo G Spinelli, Federica Facente, Laura Lumaca, Alma Ghirelli, Elisa Canu, Veronica Castelnovo, Elisa Sibilla, Chiara Tripodi, Fabiola Freri, Giordano Cecchetti, Giuseppe Magnani, Francesca Caso, Federico Verde, Nicola Ticozzi, Vincenzo Silani, Paola Caroppo, Sara Prioni, Cristina Villa, Lucio Tremolizzo, Ildebrando Appollonio, Ashish Raj, Massimo Filippi
{"title":"Modelling pathological spread through the structural connectome in the frontotemporal dementia clinical spectrum.","authors":"Federica Agosta, Silvia Basaia, Edoardo G Spinelli, Federica Facente, Laura Lumaca, Alma Ghirelli, Elisa Canu, Veronica Castelnovo, Elisa Sibilla, Chiara Tripodi, Fabiola Freri, Giordano Cecchetti, Giuseppe Magnani, Francesca Caso, Federico Verde, Nicola Ticozzi, Vincenzo Silani, Paola Caroppo, Sara Prioni, Cristina Villa, Lucio Tremolizzo, Ildebrando Appollonio, Ashish Raj, Massimo Filippi","doi":"10.1093/brain/awae391","DOIUrl":"10.1093/brain/awae391","url":null,"abstract":"<p><p>The ability to predict the spreading of pathology in patients with frontotemporal dementia (FTD) is crucial for early diagnosis and targeted interventions. In this study, we examined the relationship between network vulnerability and longitudinal progression of atrophy in FTD patients, using the network diffusion model (NDM) of the spread of pathology. Thirty behavioural variant FTD (bvFTD), 13 semantic variant primary progressive aphasia (svPPA), 14 non-fluent variant primary progressive aphasia (nfvPPA) and 12 semantic behavioural variant FTD (sbvFTD) patients underwent longitudinal T1-weighted MRI. Fifty young controls (20-31 years of age) underwent multi-shell diffusion MRI scan. An NDM was developed to model progression of FTD pathology as a spreading process from a seed through the healthy structural connectome, using connectivity measures from fractional anisotropy and intracellular volume fraction in young controls. Four disease epicentres were initially identified from the peaks of atrophy of each FTD variant: left insula (bvFTD), left temporal pole (svPPA), right temporal pole (sbvFTD) and left supplementary motor area (nfvPPA). Pearson's correlations were calculated between NDM-predicted atrophy in young controls and the observed longitudinal atrophy in FTD patients over a follow-up period of 24 months. The NDM was then run for all 220 brain seeds to verify whether the four epicentres were among those that yielded the highest correlation. Using the NDM, predictive maps in young controls showed progression of pathology from the peaks of atrophy in svPPA, nfvPPA and sbvFTD over 24 months. svPPA exhibited early involvement of the left temporal and occipital lobes, progressing to extensive left hemisphere impairment. nfvPPA and sbvFTD spread in a similar manner bilaterally to frontal, sensorimotor and temporal regions, with sbvFTD additionally affecting the right hemisphere. Moreover, the NDM-predicted atrophy of each region was positively correlated with longitudinal real atrophy, with a greater effect in svPPA and sbvFTD. In bvFTD, the model starting from the left insula (the peak of atrophy) demonstrated a highly left-lateralized pattern, with pathology spreading to frontal, sensorimotor, temporal and basal ganglia regions, with minimal extension to the contralateral hemisphere by 24 months. However, unlike the atrophy peaks observed in the other three phenotypes, the left insula did not show the strongest correlation between the estimated and real atrophy. Instead, the bilateral superior frontal gyrus emerged as optimal seeds for modelling atrophy spread, showing the highest correlation ranking in both hemispheres. Overall, NDM applied on the intracellular volume fraction connectome yielded higher correlations relative to NDM applied on fractional anisotropy maps. The NDM implementation using the cross-sectional structural connectome is a valuable tool to predict patterns of atrophy and spreading of pathology in FTD clinical vari","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1994-2007"},"PeriodicalIF":10.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12129736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BrainPub Date : 2025-06-03DOI: 10.1093/brain/awaf046
Richard S Bedlack
{"title":"Overstating harms can have consequences.","authors":"Richard S Bedlack","doi":"10.1093/brain/awaf046","DOIUrl":"10.1093/brain/awaf046","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e52-e53"},"PeriodicalIF":10.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BrainPub Date : 2025-06-03DOI: 10.1093/brain/awae376
Nils Hecht, Daisy Haddad, Konrad Neumann, Leonie Schumm, Nora F Dengler, Lars Wessels, Patrick Dömer, Simeon Helgers, Franziska Meinert, Sebastian Major, Coline L Lemale, Jens P Dreier, Peter Vajkoczy, Johannes Woitzik
{"title":"Reduced brain oxygen response to spreading depolarization predicts worse outcome in ischaemic stroke.","authors":"Nils Hecht, Daisy Haddad, Konrad Neumann, Leonie Schumm, Nora F Dengler, Lars Wessels, Patrick Dömer, Simeon Helgers, Franziska Meinert, Sebastian Major, Coline L Lemale, Jens P Dreier, Peter Vajkoczy, Johannes Woitzik","doi":"10.1093/brain/awae376","DOIUrl":"10.1093/brain/awae376","url":null,"abstract":"<p><p>Spreading depolarization (SD) describes a propagating neuronal mass depolarization within the cerebral cortex that represents a mediator of infarct development and strongly stimulates the metabolic rate of O2 consumption. Here, we investigated the influence of spreading depolarization on brain tissue partial pressure of O2 (ptiO2) within the peri-infarct tissue of patients suffering malignant hemispheric stroke. This prospective observational trial included 25 patients with malignant hemispheric stroke that underwent decompressive hemicraniectomy followed by subdural placement of electrodes for electrocorticography (ECoG) and neighbouring implantation of a ptiO2 probe within the peri-infarcted cortex. Continuous side-by-side ECoG + ptiO2 recordings were obtained for 3-6 days postoperatively and analysed for the occurrence of SD-independent and SD-coupled ptiO2 changes, radiological findings, as well as their association with clinical outcome at 6 months. During the combined ECoG + ptiO2 monitoring period of 2604 h and among 1022 SDs, 483 (47%) SD-coupled ptiO2 variations were identified as biphasic (59%), hypoxic (36%) or hyperoxic (5%) ptiO2 responses that differed significantly (P < 0.0001). Among the remaining 538/1022 (53%) SDs, no SD-coupled ptiO2 response was detected, which we categorized as 'No response'. The overall infarct progression was 1.7% (interquartile range -2.5-10.9). SD characteristics regarding type, duration and frequency, as well as SD-independent baseline ptiO2 had no association with outcome. In contrast, a high occurrence rate and amplitude of SD-coupled variations in ptiO2 were associated with improved outcome at 6 months (occurrence: r = -0.62, P = 0.035; amplitude: r = -0.57, P = 0.024; Spearman correlation). In conclusion, an absent or reduced ptiO2 response to SD could indicate tissue-at-risk and help direct targeted treatment strategies in ischaemic stroke, which is further evidence that not all SDs are the same but tissue responses coupled to SD such as ptiO2 contain prognostic information. In particular, a lack of SD-coupled ptiO2 variations appears to be a predictor of worse outcome in large hemispheric stroke.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1924-1935"},"PeriodicalIF":10.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12129726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BrainPub Date : 2025-06-03DOI: 10.1093/brain/awaf099
Bing Chen, Siddharth Gaikwad, Robert H Powell, Hang Jin Jo, Allison B Kessler, David Chen, Charles J Heckman, Linda Jones, James D Guest, Jonathan R Wolpaw, Martin Oudega, Andrew R Blight, Monica A Perez
{"title":"Combinatorial approaches increasing neuronal activity accelerate recovery after spinal cord injury.","authors":"Bing Chen, Siddharth Gaikwad, Robert H Powell, Hang Jin Jo, Allison B Kessler, David Chen, Charles J Heckman, Linda Jones, James D Guest, Jonathan R Wolpaw, Martin Oudega, Andrew R Blight, Monica A Perez","doi":"10.1093/brain/awaf099","DOIUrl":"10.1093/brain/awaf099","url":null,"abstract":"<p><p>Combinatorial approaches targeting multiple aspects of spinal cord injury (SCI) pathophysiology are needed to maximize functional recovery. We hypothesized that enhancing neuronal activity-by strengthening corticospinal synapses through Hebbian stimulation and increasing neuronal transmission with 4-aminopyridine (4-AP), a potassium blocker-could accelerate locomotor recovery in individuals with chronic SCI. Participants were randomly assigned to receive 10 mg of 4-AP or placebo, where both groups followed with 60 min of Hebbian stimulation targeting corticospinal-motor neuronal synapses supplying leg muscles involved in locomotion and 60 min of standard exercise rehabilitation for 40 sessions over 8-14 weeks. During Hebbian stimulation, 720 paired pulses were delivered to elicit corticospinal action potentials via electrical stimulation of the thoracic spine, ensuring volleys reached the spinal cord 1-2 ms before motor neurons were retrogradely activated through bilateral electrical stimulation of the femoral, common peroneal, and posterior tibial nerves (targeting the quadriceps femoris, tibialis anterior and soleus muscles, respectively). Results showed that participants who received 4-AP exhibited significantly greater improvements in walking speed and endurance, corticospinal excitability, and light touch sensation compared to those who received the placebo. The minimal clinically important difference in walking speed and endurance was achieved after 20 sessions in the 4-AP group, but was not consistently reached in the placebo group. Although walking continued to improve in both groups over the course of 40 sessions, the 4-AP group demonstrated significantly greater progress. Improvement in the 4-AP group was still present approximately 12 months later. These findings suggest that 4-AP represents a strategy to potentiate and accelerate Hebbian stimulation effects on motor recovery in individuals with chronic SCI.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1911-1923"},"PeriodicalIF":10.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BrainPub Date : 2025-06-03DOI: 10.1093/brain/awaf047
Michael Benatar, Christopher J McDermott, Martin R Turner, Ruben P A van Eijk
{"title":"Reply: Overstating harms can have consequences.","authors":"Michael Benatar, Christopher J McDermott, Martin R Turner, Ruben P A van Eijk","doi":"10.1093/brain/awaf047","DOIUrl":"10.1093/brain/awaf047","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e54"},"PeriodicalIF":10.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}