Brain communicationsPub Date : 2024-08-20eCollection Date: 2024-01-01DOI: 10.1093/braincomms/fcae272
Alice Tisserand, Frédéric Blanc, Candice Muller, Hélène Durand, Catherine Demuynck, Alix Ravier, Léa Sanna, Paulo Loureiro de Sousa, Anne Botzung, Mary Mondino, Nathalie Philippi
{"title":"Neuroimaging of autobiographical memory in dementia with Lewy bodies: a story of insula.","authors":"Alice Tisserand, Frédéric Blanc, Candice Muller, Hélène Durand, Catherine Demuynck, Alix Ravier, Léa Sanna, Paulo Loureiro de Sousa, Anne Botzung, Mary Mondino, Nathalie Philippi","doi":"10.1093/braincomms/fcae272","DOIUrl":"https://doi.org/10.1093/braincomms/fcae272","url":null,"abstract":"<p><p>Although deficits in learning and retrieving new information are well characterized in dementia with Lewy bodies, autobiographical memory has never been explored in this disease. Yet, autobiographical memory impairments are a pervasive feature of dementia, well characterized in other neurodegenerative diseases. Moreover, autobiographical memory corresponds to an extension over time of the self, which we hypothesize is altered in dementia with Lewy bodies and impairment of which could be linked to the insular atrophy occurring from an early stage of the disease. In this study, we sought to characterize autobiographical memory impairments and explore their neural correlates in dementia with Lewy bodies, on the assumption that insular damage could impact the self, including its most elaborate components, such as autobiographical memory. Twenty patients with prodromal to mild dementia with Lewy bodies were selected to participate in this exploratory study along with 20 healthy control subjects. The Autobiographical Interview was used to assess autobiographical memory. Performances were compared between patients and control subjects, and an analysis across life periods and recall conditions was performed. 3D magnetic resonance images were acquired for all participants, and correlational analyses were performed in the patient group using voxel-based morphometry. The behavioural results of the Autobiographical Interview showed that autobiographical memory performances were significantly impaired in dementia with Lewy body patients compared to control subjects in a temporally ungraded manner, for both the free recall and the specific probe conditions (<i>P</i> < 0.0001), though with greater improvement after probing in the patient group. Furthermore, autobiographical memory impairments were correlated with grey matter volume within right insular cortex, temporoparietal junction, precuneus, putamen, left temporal cortex, bilateral parahippocampus and cerebellum, using a threshold of <i>P</i> = 0.005 uncorrected. The behavioural results confirm the existence of temporally ungraded autobiographical memory impairments in dementia with Lewy bodies, from the early stage of the disease. As we expected, neuroimaging analysis revealed a role for the insula and the precuneus in autobiographical memory retrieval, two regions associated with elementary aspects of the self, among other brain regions classically associated with autobiographical memory, such as medial temporal lobe and temporoparietal junction. Our findings provide important insights regarding the involvement of the insula in the self and suggest that insular damage could lead to a global collapse of the self, including its more elaborated components, such as autobiographical memory.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11358644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115899","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}
Brain communicationsPub Date : 2024-08-20eCollection Date: 2024-01-01DOI: 10.1093/braincomms/fcae247
John B Coulton, Yingxin He, Nicolas R Barthélemy, Hong Jiang, David M Holtzman, Randall J Bateman
{"title":"Multi-peptide characterization of plasma neurofilament light chain in preclinical and mild Alzheimer's disease.","authors":"John B Coulton, Yingxin He, Nicolas R Barthélemy, Hong Jiang, David M Holtzman, Randall J Bateman","doi":"10.1093/braincomms/fcae247","DOIUrl":"10.1093/braincomms/fcae247","url":null,"abstract":"<p><p>Although neurofilament light chain is a well-known marker of neuronal damage, its characterization at the proteoform level is underdeveloped. Here, we describe a new method to profile and quantify neurofilament light chain in plasma at the peptide level, using three in-house monoclonal antibodies targeting distinct protein domains and nano-liquid chromatography coupled to high-resolution tandem mass spectrometry. This study profiled and compared plasma neurofilament light chain to CSF in 102 older individuals (73.9 ± 6.3 years old), 37 of which had a clinical dementia rating greater than 0. We observed elevated neurofilament light chain in preclinical Alzheimer's disease plasma for two measures (NfL101 and NfL324) and CSF for seven measures (NfL92, NfL101, NfL117, NfL137, NfL148, NfL165 and NfL530). We found five plasma peptides (NfL92, NfL101, NfL117, NfL324 and NfL530) significantly associated with age and two (NfL148 and NfL324) with body mass index.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11334934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142010116","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}
Brain communicationsPub Date : 2024-08-20eCollection Date: 2024-01-01DOI: 10.1093/braincomms/fcae193
Makoto T Tanaka, Yasuo Miki, Fumiaki Mori, Tomoya Kon, Tomonori Furukawa, Shuji Shimoyama, Yota Tatara, Taku Ozaki, Conceição Bettencourt, Thomas T Warner, Koichi Wakabayashi
{"title":"Intranasal administration of trehalose reduces α-synuclein oligomers and accelerates α-synuclein aggregation.","authors":"Makoto T Tanaka, Yasuo Miki, Fumiaki Mori, Tomoya Kon, Tomonori Furukawa, Shuji Shimoyama, Yota Tatara, Taku Ozaki, Conceição Bettencourt, Thomas T Warner, Koichi Wakabayashi","doi":"10.1093/braincomms/fcae193","DOIUrl":"10.1093/braincomms/fcae193","url":null,"abstract":"<p><p>Abnormal α-synuclein (αSyn), including an oligomeric form of αSyn, accumulates and causes neuronal dysfunction in the brains of patients with multiple system atrophy. Neuroprotective drugs that target abnormal αSyn aggregation have not been developed for the treatment of multiple system atrophy. In addition, treating diseases at an early stage is crucial to halting the progress of neuronal damage in neurodegeneration. In this study, using early-stage multiple system atrophy mouse model and <i>in vitro</i> kinetic analysis, we investigated how intranasal and oral administration of trehalose can improve multiple system atrophy pathology and clinical symptoms. The multiple system atrophy model showed memory impairment at least four weeks after αSyn induction. Behavioural and physiological analyses showed that intranasal and oral administration of trehalose reversed memory impairments to near-normal levels. Notably, trehalose treatment reduced the amount of toxic αSyn and increased the aggregated form of αSyn in the multiple system atrophy model brain. <i>In vitro</i> kinetic analysis confirmed that trehalose accelerated the aggregate formation of αSyn. Based on our findings, we propose a novel strategy whereby accelerated αSyn aggregate formation leads to reduced exposure to toxic αSyn oligomers, particularly during the early phase of disease progression.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11334933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142010115","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}
Brain communicationsPub Date : 2024-08-20eCollection Date: 2024-01-01DOI: 10.1093/braincomms/fcae283
Alejandra García-Colomo, David López-Sanz, Cornelis J Stam, Arjan Hillebrand, Martín Carrasco-Gómez, Carlos Spuch, María Comis-Tuche, Fernando Maestú
{"title":"Minimum spanning tree analysis of unimpaired individuals at risk of Alzheimer's disease.","authors":"Alejandra García-Colomo, David López-Sanz, Cornelis J Stam, Arjan Hillebrand, Martín Carrasco-Gómez, Carlos Spuch, María Comis-Tuche, Fernando Maestú","doi":"10.1093/braincomms/fcae283","DOIUrl":"10.1093/braincomms/fcae283","url":null,"abstract":"<p><p>Identifying early and non-invasive biomarkers to detect individuals in the earliest stages of the Alzheimer's disease continuum is crucial. As a result, electrophysiology and plasma biomarkers are emerging as great candidates in this pursuit due to their low invasiveness. This is the first magnetoencephalography study to assess the relationship between minimum spanning tree parameters, an alternative to overcome the comparability and thresholding problem issues characteristic of conventional brain network analyses, and plasma phosphorylated tau231 levels in unimpaired individuals, with different risk levels of Alzheimer's disease. Seventy-six individuals with available magnetoencephalography recordings and phosphorylated tau231 plasma determination were included. The minimum spanning tree for the theta, alpha and beta bands for each subject was obtained, and the leaf fraction, tree hierarchy and diameter were calculated. To study the relationship between these topological parameters and phosphorylated tau231, we performed correlation analyses, for the whole sample and considering the two risk sub-groups separately. Increasing concentrations of phosphorylated tau231 were associated with greater leaf fraction and tree hierarchy values, along with lower diameter values, for the alpha and theta frequency bands. These results emerged for the whole sample and the higher risk group, but not for the lower risk group. Our results indicate that the network topology of cognitively unimpaired individuals with elevated plasma phosphorylated tau231 levels, a marker of Alzheimer's disease pathology and amyloid-β accumulation, is already altered, shifting towards a more integrated network increasing its vulnerability and hub-dependency, mostly in the alpha band. This is indicated by increases in leaf fraction and tree hierarchy, along with reductions in diameter. These results match the initial trajectory proposed by theoretical models of disease progression and network disruption and suggest that changes in brain function and organization begin early on.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127648","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}
Brain communicationsPub Date : 2024-08-20eCollection Date: 2024-01-01DOI: 10.1093/braincomms/fcae282
Jack Rivers-Auty, Christopher Hoyle, Ayesha Pointer, Catherine Lawrence, Stuart Pickering-Brown, David Brough, Sarah Ryan
{"title":"<i>C9orf72</i> dipeptides activate the NLRP3 inflammasome.","authors":"Jack Rivers-Auty, Christopher Hoyle, Ayesha Pointer, Catherine Lawrence, Stuart Pickering-Brown, David Brough, Sarah Ryan","doi":"10.1093/braincomms/fcae282","DOIUrl":"10.1093/braincomms/fcae282","url":null,"abstract":"<p><p>Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases with considerable clinical, genetic and pathological overlap. The most common cause of both diseases is a hexanucleotide repeat expansion in <i>C9orf72</i>. The expansion is translated to produce five toxic dipeptides, which aggregate in patient brain. Neuroinflammation is a feature of frontotemporal dementia and amyotrophic lateral sclerosis; however, its causes are unknown. The nod-like receptor family, pyrin domain-containing 3 inflammasome is implicated in several other neurodegenerative diseases as a driver of damaging inflammation. The inflammasome is a multi-protein complex which forms in immune cells in response to tissue damage, pathogens or aggregating proteins. Inflammasome activation is observed in models of other neurodegenerative diseases such as Alzheimer's disease, and inflammasome inhibition rescues cognitive decline in rodent models of Alzheimer's disease. Here, we show that a dipeptide arising from the <i>C9orf72</i> expansion, poly-glycine-arginine, activated the inflammasome in microglia and macrophages, leading to secretion of the pro-inflammatory cytokine, interleukin-1β. Poly-glycine-arginine also activated the inflammasome in organotypic hippocampal slice cultures, and immunofluorescence imaging demonstrated formation of inflammasome specks in response to poly-glycine-arginine. Several clinically available anti-inflammatory drugs rescued poly-glycine-arginine-induced inflammasome activation. These data suggest that <i>C9orf72</i> dipeptides contribute to the neuroinflammation observed in patients, and highlight the inflammasome as a potential therapeutic target for frontotemporal dementia and amyotrophic lateral sclerosis.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127643","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}
Brain communicationsPub Date : 2024-08-19eCollection Date: 2024-01-01DOI: 10.1093/braincomms/fcae280
Maria F Bandres, Jefferson L Gomes, Jacob Graves McPherson
{"title":"Intraspinal microstimulation of the ventral horn has therapeutically relevant cross-modal effects on nociception.","authors":"Maria F Bandres, Jefferson L Gomes, Jacob Graves McPherson","doi":"10.1093/braincomms/fcae280","DOIUrl":"10.1093/braincomms/fcae280","url":null,"abstract":"<p><p>Electrical stimulation of spinal networks below a spinal cord injury is a promising approach to restore functions compromised by inadequate and/or inappropriate neural drive. The most translationally successful examples are paradigms intended to increase neural transmission in weakened yet spared descending motor pathways and spinal motoneurons rendered dormant after being severed from their inputs by lesion. Less well understood is whether spinal stimulation is also capable of reducing neural transmission in pathways made pathologically overactive by spinal cord injury. Debilitating spasms, spasticity and neuropathic pain are all common manifestations of hyperexcitable spinal responses to sensory feedback. Whereas spasms and spasticity can often be managed pharmacologically, spinal cord injury-related neuropathic pain is notoriously medically refractory. Interestingly, however, spinal stimulation is a clinically available option for ameliorating neuropathic pain arising from aetiologies other than spinal cord injury, and the limited evidence available to date suggests that it holds considerable promise for reducing spinal cord injury-related neuropathic pain, as well. Spinal stimulation for pain amelioration has traditionally been assumed to modulate sensorimotor networks overlapping with those engaged by spinal stimulation for rehabilitation of movement impairments. Thus, we hypothesize that spinal stimulation intended to increase the ability to move voluntarily may simultaneously reduce transmission in spinal pain pathways. To test this hypothesis, we coupled a rat model of incomplete thoracic spinal cord injury, which results in moderate to severe bilateral movement impairments and spinal cord injury-related neuropathic pain, with <i>in vivo</i> electrophysiological measures of neural transmission in networks of spinal neurons integral to the development and persistence of the neuropathic pain state. We find that when intraspinal microstimulation is delivered to the ventral horn with the intent of enhancing voluntary movement, transmission through nociceptive specific and wide dynamic range neurons is significantly depressed in response to pain-related sensory feedback. By comparison, spinal responsiveness to non-pain-related sensory feedback is largely preserved. These results suggest that spinal stimulation paradigms could be intentionally designed to afford multi-modal therapeutic benefits, directly addressing the diverse, intersectional rehabilitation goals of people living with spinal cord injury.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362490","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}
Brain communicationsPub Date : 2024-08-19eCollection Date: 2024-01-01DOI: 10.1093/braincomms/fcae281
Joana Gomes-Ribeiro, João Martins, José Sereno, Samuel Deslauriers-Gauthier, Teresa Summavielle, Joana E Coelho, Miguel Remondes, Miguel Castelo-Branco, Luísa V Lopes
{"title":"Mapping functional traces of opioid memories in the rat brain.","authors":"Joana Gomes-Ribeiro, João Martins, José Sereno, Samuel Deslauriers-Gauthier, Teresa Summavielle, Joana E Coelho, Miguel Remondes, Miguel Castelo-Branco, Luísa V Lopes","doi":"10.1093/braincomms/fcae281","DOIUrl":"10.1093/braincomms/fcae281","url":null,"abstract":"<p><p>Addiction to psychoactive substances is a maladaptive learned behaviour. Contexts surrounding drug use integrate this aberrant mnemonic process and hold strong relapse-triggering ability. Here, we asked where context and salience might be concurrently represented in the brain during retrieval of drug-context paired associations. For this, we developed a morphine-conditioned place preference protocol that allows contextual stimuli presentation inside a magnetic resonance imaging scanner and investigated differences in activity and connectivity at context recall. We found context-specific responses to stimulus onset in multiple brain regions, namely, limbic, sensory and striatal. Differences in functional interconnectivity were found among amygdala, lateral habenula, and lateral septum. We also investigated alterations to resting-state functional connectivity and found increased centrality of the lateral septum in a proposed limbic network, as well as increased functional connectivity of the lateral habenula and hippocampal 'cornu ammonis' 1 region, after a protocol of associative drug-context. Finally, we found that pre- conditioned place preference resting-state connectivity of the lateral habenula and amygdala was predictive of inter-individual conditioned place preference score differences. Overall, our findings show that drug and saline-paired contexts establish distinct memory traces in overlapping functional brain microcircuits and that intrinsic connectivity of the habenula, septum, and amygdala likely underlies the individual maladaptive contextual learning to opioid exposure. We have identified functional maps of acquisition and retrieval of drug-related memory that may support the relapse-triggering ability of opioid-associated sensory and contextual cues. These findings may clarify the inter-individual sensitivity and vulnerability seen in addiction to opioids found in humans.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127647","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}
Brain communicationsPub Date : 2024-08-16eCollection Date: 2024-01-01DOI: 10.1093/braincomms/fcae262
Rebecca W Roth, Deena Schwen Blackett, Ezequiel Gleichgerrcht, Janina Wilmskoetter, Chris Rorden, Roger Newman-Norlund, Souvik Sen, Julius Fridriksson, Natalie Busby, Leonardo Bonilha
{"title":"Long-range white matter fibres and post-stroke verbal and non-verbal cognition.","authors":"Rebecca W Roth, Deena Schwen Blackett, Ezequiel Gleichgerrcht, Janina Wilmskoetter, Chris Rorden, Roger Newman-Norlund, Souvik Sen, Julius Fridriksson, Natalie Busby, Leonardo Bonilha","doi":"10.1093/braincomms/fcae262","DOIUrl":"10.1093/braincomms/fcae262","url":null,"abstract":"<p><p>Among stroke survivors, linguistic and non-linguistic impairments exhibit substantial inter-individual variability. Stroke lesion volume and location do not sufficiently explain outcomes, and the neural mechanisms underlying the severity of aphasia or non-verbal cognitive deficits remain inadequately understood. Converging evidence supports the idea that white matter is particularly susceptible to ischaemic injury, and long-range fibres are commonly associated with verbal and non-verbal function. Here, we investigated the relationship among post-stroke aphasia severity, cognition, and white matter integrity. Eighty-seven individuals in the chronic stage of stroke underwent diffusion MRI and behavioural testing, including language and cognitive measures. We used whole-brain structural connectomes from each participant to calculate the ratio of long-range fibres to short-range fibres. We found that a higher proportion of long-range fibres was associated with lower aphasia severity, more accurate picture naming, and increased performance on non-verbal semantic memory/processing and non-verbal reasoning while controlling for lesion volume, key damage areas, age, and years post stroke. Our findings corroborate the hypothesis that, after accounting for age and lesion anatomy, inter-individual differences in post-stroke aphasia severity, verbal, and non-verbal cognitive outcomes are related to the preservation of long-range white matter fibres beyond the lesion.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057582","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}
Brain communicationsPub Date : 2024-08-16eCollection Date: 2024-01-01DOI: 10.1093/braincomms/fcae277
Pietro Scaduto, Michela Marcatti, Nemil Bhatt, Rakez Kayed, Giulio Taglialatela
{"title":"Calcineurin inhibition prevents synaptic plasticity deficit induced by brain-derived tau oligomers.","authors":"Pietro Scaduto, Michela Marcatti, Nemil Bhatt, Rakez Kayed, Giulio Taglialatela","doi":"10.1093/braincomms/fcae277","DOIUrl":"10.1093/braincomms/fcae277","url":null,"abstract":"<p><p>Compelling evidence suggests that cognitive decline in Alzheimer's disease is associated with the accumulation and aggregation of tau protein, with the most toxic aggregates being in the form of oligomers. This underscores the necessity for direct isolation and analysis of brain-derived tau oligomers from patients with Alzheimer's disease, potentially offering novel perspectives into tau toxicity. Alzheimer's brain-derived tau oligomers are potent inhibitors of synaptic plasticity; however, the involved mechanism is still not fully understood. We previously reported a significantly reduced incidence of Alzheimer's disease in ageing humans chronically treated with a Food and Drug Administration-approved calcineurin inhibitor, FK506 (tacrolimus), used as an immunosuppressant after solid organ transplant. Using a combination of electrophysiological and RNA-sequencing techniques, we provide here evidence that FK506 has the potential to block the acute toxic effect of brain-derived tau oligomers on synaptic plasticity, as well as to restore the levels of some key synaptic mRNAs. These results further support FK506 as a promising novel therapeutic strategy for the treatment of Alzheimer's disease.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11375858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142142051","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}
Brain communicationsPub Date : 2024-08-14eCollection Date: 2024-01-01DOI: 10.1093/braincomms/fcae274
Monica Siqueiros-Sanchez, Erpeng Dai, Chloe A McGhee, Jennifer A McNab, Mira M Raman, Tamar Green
{"title":"Impact of pathogenic variants of the Ras-mitogen-activated protein kinase pathway on major white matter tracts in the human brain.","authors":"Monica Siqueiros-Sanchez, Erpeng Dai, Chloe A McGhee, Jennifer A McNab, Mira M Raman, Tamar Green","doi":"10.1093/braincomms/fcae274","DOIUrl":"https://doi.org/10.1093/braincomms/fcae274","url":null,"abstract":"<p><p>Noonan syndrome and neurofibromatosis type 1 are genetic conditions linked to pathogenic variants in genes of the Ras-mitogen-activated protein kinase signalling pathway. Both conditions hyper-activate signalling of the Ras-mitogen-activated protein kinase pathway and exhibit a high prevalence of neuropsychiatric disorders. Further, animal models of Noonan syndrome and neurofibromatosis type 1 and human imaging studies show white matter abnormalities in both conditions. While these findings suggest Ras-mitogen-activated protein kinas pathway hyper-activation effects on white matter, it is unknown whether these effects are syndrome-specific or pathway-specific. To characterize the effect of Noonan syndrome and neurofibromatosis type 1 on human white matter's microstructural integrity and discern potential syndrome-specific influences on microstructural integrity of individual tracts, we collected diffusion-weighted imaging data from children with Noonan syndrome (<i>n</i> = 24), neurofibromatosis type 1 (<i>n</i> = 28) and age- and sex-matched controls (<i>n</i> = 31). We contrasted the clinical groups (Noonan syndrome or neurofibromatosis type 1) and controls using voxel-wise, tract-based and along-tract analyses. Outcomes included voxel-wise, tract-based and along-tract fractional anisotropy, axial diffusivity, radial diffusivity and mean diffusivity. Noonan syndrome and neurofibromatosis type 1 showed similar patterns of reduced fractional anisotropy and increased axial diffusivity, radial diffusivity, and mean diffusivity on white matter relative to controls and different spatial patterns. Noonan syndrome presented a more extensive spatial effect than neurofibromatosis type 1 on white matter integrity as measured by fractional anisotropy. Tract-based analysis also demonstrated differences in effect magnitude with overall lower fractional anisotropy in Noonan syndrome compared to neurofibromatosis type 1 (<i>d</i> = 0.4). At the tract level, Noonan syndrome-specific effects on fractional anisotropy were detected in association tracts (superior longitudinal, uncinate and arcuate fasciculi; <i>P</i> < 0.012), and neurofibromatosis type 1-specific effects were detected in the corpus callosum (<i>P</i> < 0.037) compared to controls. Results from along-tract analyses aligned with results from tract-based analyses and indicated that effects are pervasive along the affected tracts. In conclusion, we find that pathogenic variants in the Ras-mitogen-activated protein kinase pathway are associated with white matter abnormalities as measured by diffusion in the developing brain. Overall, Noonan syndrome and neurofibromatosis type 1 show common effects on fractional anisotropy and diffusion scalars, as well as specific unique effects, namely, on temporoparietal-frontal tracts (intra-hemispheric) in Noonan syndrome and on the corpus callosum (inter-hemispheric) in neurofibromatosis type 1. The observed specific effects not only confirm prior observati","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11358645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115898","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}