Featured
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| Open AccessMitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease
Idiopathic Parkinson’s disease can be stratified according to the severity of neuronal respiratory complex I deficiency. The emerging disease subtypes show distinct molecular and clinical profiles.
- Irene H. Flønes
- , Lilah Toker
- & Charalampos Tzoulis
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Article
| Open AccessStructural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A
SV2A is a receptor for botulinum neurotoxin (BoNT) and new generation antiepileptic drugs (AEDs). Here the authors report cryo-EM structures of SV2A in complex with BoNT receptor binding domain and AEDs highlighting the difference in the binding affinity between AEDs.
- Atsushi Yamagata
- , Kaori Ito
- & Mikako Shirouzu
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Article
| Open AccessMultisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges
Repetitive audio-visual stimulation, or sensory flicker, can modulate oscillations in a non-invasive manner. Here the authors demonstrate the potential of flicker in individuals with epilepsy undergoing intracranial seizure monitoring.
- Lou T. Blanpain
- , Eric R. Cole
- & Annabelle C. Singer
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Article
| Open AccessPlasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer’s disease
The authors investigated associations of brain-derived-tau (BD-tau) with Aβ pathology, changes in cognition and MRI signatures. Staging Aβ-pathology according to neurodegeneration, using BD-tau, identifies individuals at risk of near-term cognitive decline and atrophy.
- Fernando Gonzalez-Ortiz
- , Bjørn-Eivind Kirsebom
- & Kaj Blennow
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Article
| Open AccessIntrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial
In the CELLTOP Phase I trial, stem cells were harvested from patients with spinal cord injury and injected into their central nervous system after processing. The procedure was safe, with no reported serious adverse events during the 2-year follow-up period.
- Mohamad Bydon
- , Wenchun Qu
- & Allan B. Dietz
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Article
| Open AccessPhosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures
Here, the authors use cryo-EM to show that phosphorylating or O-GlcNAcylating α-synuclein on serine 87 leads to the formation of two distinct fibril structures. Both structures display reduced neurotoxicity and propagation activity.
- Jinjian Hu
- , Wencheng Xia
- & Yan-Mei Li
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Article
| Open AccessThe effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease
A network of brain regions degenerates earlier in aging. Here the authors show that, this network is most vulnerable to diabetes, traffic-related pollution and alcohol consumption in terms of risk factors for dementia, and associated with the XG blood group genes.
- Jordi Manuello
- , Joosung Min
- & Gwenaëlle Douaud
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Article
| Open AccessUsing rare genetic mutations to revisit structural brain asymmetry
Asymmetry is a key organising principle of the brain. Here the authors leveraged rare genetic mutations to revisit structural brain asymmetry showing the planum temporale is susceptible to deletions & duplications of specific gene sets.
- Jakub Kopal
- , Kuldeep Kumar
- & Danilo Bzdok
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Article
| Open AccessParechovirus infection in human brain organoids: host innate inflammatory response and not neuro-infectivity correlates to neurologic disease
In comparison to PeV-A1, infection with PeV-A3 is associated with neurological illness in infants. Here, using brain organoids, the authors suggest that the innate inflammatory response as the underlying reason, and not replication kinetics.
- Pamela E. Capendale
- , Inés García-Rodríguez
- & Katja C. Wolthers
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Article
| Open AccessA blood-based biomarker workflow for optimal tau-PET referral in memory clinic settings
A screening strategy with plasma p-tau217, evaluated in two independent cohorts from Sweden and Canada, showed that this biomarker may effectively streamline tau-PET referrals in memory clinic settings, optimizing the prognostic work-up of Alzheimer’s disease.
- Wagner S. Brum
- , Nicholas C. Cullen
- & Oskar Hansson
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Article
| Open AccessA single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease
Vascular pathology may play important early role in Alzheimer’s disease (AD). Here, the authors show that β-amyloid induces transcriptomic signatures associated with accelerated apoptosis, impaired function and AD risk in human brain microvasculature.
- Stergios Tsartsalis
- , Hannah Sleven
- & Paul M. Matthews
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Article
| Open AccessIdentification of four biotypes in temporal lobe epilepsy via machine learning on brain images
Brain imaging-based disease progression modelling is a promising technique for disease stratification. Here the authors characterize distinct ‘trajectories’ of brain atrophy in temporal lobe epilepsy and identify four subtypes with distinct neuroanatomical signatures.
- Yuchao Jiang
- , Wei Li
- & Dongmei An
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Article
| Open AccessIdentification of the growth cone as a probe and driver of neuronal migration in the injured brain
Structure and functions of the tip of migratory neurons remain elusive. Here, the authors show that the PTPσ-expressing growth cone senses extracellular matrix changes and drives neuronal migration in the injured brain, leading to the functional recovery.
- Chikako Nakajima
- , Masato Sawada
- & Kazunobu Sawamoto
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Article
| Open AccessFunctional analysis of the human perivascular subarachnoid space
Functional implications of subarachnoid space anatomy remain unclear. Here, the authors show by human in vivo imaging that an intrathecal tracer propagates antegrade along the major cerebral arteries within a perivascular subarachnoid space facilitating tracer passage towards the brain.
- Per Kristian Eide
- & Geir Ringstad
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Review Article
| Open AccessDiagnosis and management of subarachnoid haemorrhage
Aneurysmal subarachnoid haemorrhage, with its multisystem effects, presents a substantial challenge to clinicians. Here, the authors show the necessity for comprehensive multidisciplinary care and the urgent need for largescale studies to validate standardised treatment protocols for improved outcomes.
- Suneesh Thilak
- , Poppy Brown
- & Tonny Veenith
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Article
| Open AccessApplying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis
People who experience optic neuritis, a cause of potentially serious sudden vision loss, have up to a 50% chance of ultimately being diagnosed with multiple sclerosis. Here, the authors find that genetic information combined with age and sex helps predict risk of future diagnosis of multiple sclerosis.
- Pavel Loginovic
- , Feiyi Wang
- & Tasanee Braithwaite
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Article
| Open AccessMulti-night cortico-basal recordings reveal mechanisms of NREM slow-wave suppression and spontaneous awakenings in Parkinson’s disease
Using at-home intracranial DBS recordings in PD participants, the authors found subcortical beta has an inverse effect on cortical slow-wave in NREM sleep, rises before awakenings and found >88% accuracy in NREM vs Wake classification in brief 5 s epochs.
- Md Fahim Anjum
- , Clay Smyth
- & Simon Little
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Article
| Open AccessNAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice
Circulating monocytes contribute to the transition to pain chronicity but the molecular events that cause their deployment are still unclear. Using a mouse model of hyperalgesic priming, here the authors show that blood monocytes contribute to the emergence of chronic pain via a mechanism that requires a transient disruption of NAAA-regulated lipid signaling.
- Yannick Fotio
- , Alex Mabou Tagne
- & Daniele Piomelli
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Article
| Open AccessNoncanonical function of folate through folate receptor 1 during neural tube formation
Neural tube defects are common birth defects that have been shown to be reduced through periconceptional folate supplementation, though the mechanism for this effect is unclear. Here they show that FOLR1 is necessary for neural tube formation in human neural organoids and Xenopus laevis embryos, and that this role is independent of its folate transport function.
- Olga A. Balashova
- , Alexios A. Panoutsopoulos
- & Laura N. Borodinsky
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Article
| Open AccessDeep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome
Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined and the pathophysiology unknown. Here, the authors conduct deep phenotyping of a cohort of PI-ME/CFS patients.
- Brian Walitt
- , Komudi Singh
- & Avindra Nath
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Article
| Open AccessFunctional plasticity of glutamatergic neurons of medullary reticular nuclei after spinal cord injury in mice
Spinal cord injury disrupts the descending command from the brain necessary for locomotion. Here, the authors show the functional plasticity of glutamatergic reticulospinal neurons and how their recruitment can enhance spontaneous motor recovery.
- Maxime Lemieux
- , Narges Karimi
- & Frederic Bretzner
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Article
| Open AccessA mutational atlas for Parkin proteostasis
Gene variants can affect folding and stability of the encoded protein. Here, the authors apply deep mutational scanning to provide genotype-phenotype information for 99% of the possible PRKN variants and reveal mechanistic details on how some variants cause loss-of-function and Parkinsons disease.
- Lene Clausen
- , Vasileios Voutsinos
- & Rasmus Hartmann-Petersen
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Article
| Open AccessRegulation of stress granule formation in human oligodendrocytes
Oligodendrocyte (OL) injury and loss is a pathologic hallmark of multiple sclerosis. Here, the authors show the presence of stress granules in OLs in multiple sclerosis lesions, and their in vitro studies in human OLs indicate that stress granules formation is a response to a combination of metabolic stress and pro-inflammatory conditions.
- Florian Pernin
- , Qiao-Ling Cui
- & Jack P. Antel
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Article
| Open AccessThe structure of tyrosine-10 favors ionic conductance of Alzheimer’s disease-associated full-length amyloid-β channels
The structural basis of membrane permeabilization by Alzheimer’s disease-related amyloid β (Aβ) peptides is elucidated. Membrane insertion of tyrosine-10 supports the most effective ionic conductance of the full-length Aβ1-42 compared to other isoforms.
- Abhijith G. Karkisaval
- , Rowan Hassan
- & Suren A. Tatulian
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Article
| Open AccessCompromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment
THOC2 is an essential subunit of Transcription mRNA Export complex of eukaryotic cells and its compromise causes adverse (neuro)development. Using mouse model and patient cells the authors unravel molecular pathology of the syndrome, from R-loops dysregulation, to altered transcriptome and DNA damage triggered cell death.
- Rudrarup Bhattacharjee
- , Lachlan A. Jolly
- & Jozef Gecz
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Article
| Open AccessEfficacy and safety of using auditory-motor entrainment to improve walking after stroke: a multi-site randomized controlled trial of InTandemTM
Post-stroke walking impairment is a significant public health concern. Here, the authors perform an interventional, randomized controlled trial evaluating the efficacy and safety of InTandem™, an autonomous neurorehabilitation system utilizing auditory-motor entrainment to improve walking after stroke.
- Louis N. Awad
- , Arun Jayaraman
- & Sabrina R. Taylor
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Article
| Open AccessA one-two punch targeting reactive oxygen species and fibril for rescuing Alzheimer’s disease
Toxic amyloid-beta plaque and harmful inflammation are two leading hallmarks of Alzheimer’s disease (AD), and precise AD therapy is elusive due to the lack of dual-targeting therapy function, limited blood-brain barrier penetration, and low imaging sensitivity. Here, the authors address these issues by designing a near-infrared-II aggregation-induced emission nanotheranostic for precise AD therapy.
- Jiefei Wang
- , Ping Shangguan
- & Ben Zhong Tang
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Article
| Open AccessDeath Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer’s disease and aging
Events that cause neurons to die in Alzheimer’s disease (AD) are poorly understood. Here, the authors provide evidence for a role of RNA interference in AD. Short RNAs causing neurotoxicity and DNA damage are seen in AD and aged brains, and are counteracted by nontoxic RNAs.
- Bidur Paudel
- , Si-Yeon Jeong
- & Marcus E. Peter
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Article
| Open AccessDigital automation of transdermal drug delivery with high spatiotemporal resolution
Microneedle patches that can actively address individual needles are challenging to realize. Here, the authors introduce a spatiotemporal on-demand patch for precise and personalized drug delivery, utilizing electrically triggered control with drug-loaded microneedles and biocompatible metallic membranes.
- Yihang Wang
- , Zeka Chen
- & Wubin Bai
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Article
| Open AccessThe aging mouse CNS is protected by an autophagy-dependent microglia population promoted by IL-34
Microglia could have health-promoting capacities in age-associated neuroinflammation. Here, the authors describe an autophagy and IL-34 dependent neuroprotective microglia population in the aging brain as a potential therapeutic target.
- Rasmus Berglund
- , Yufei Cheng
- & Maja Jagodic
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Article
| Open AccessElevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer’s disease
Trans-synaptic tau spread drives neurodegeneration in Alzheimer’s disease. This study shows that GAP-43, a marker of synaptic abnormality, is linked to faster tau spread, showing that synaptic changes may contribute to tau spreading in Alzheimer’s disease.
- Nicolai Franzmeier
- , Amir Dehsarvi
- & Michael Schöll
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Article
| Open AccessPara-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses
COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.
- Benedict D. Michael
- , Cordelia Dunai
- & David K. Menon
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Article
| Open AccessSynaptic density affects clinical severity via network dysfunction in syndromes associated with frontotemporal lobar degeneration
Translational neurodegeneration needs characterisation of the downstream consequences of synaptic loss. A multimodal imaging approach reveals that synaptic loss affects clinical severity via reduced connectivity in frontotemporal lobar degeneration.
- David J. Whiteside
- , Negin Holland
- & James B. Rowe
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Article
| Open AccessANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells
LRP1 plays a key role in the clearance of Aβ peptides across the blood-brain barrier. Here, the authors report that ANKS1A promotes the LRP1-mediated Aβ clearance in brain endothelium, providing insights into the pathology of Alzheimer’s disease.
- Jiyeon Lee
- , Haeryung Lee
- & Soochul Park
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Article
| Open AccessAutomating General Movements Assessment with quantitative deep learning to facilitate early screening of cerebral palsy
General Movements Assessment (GMA) is useful in early prediction of cerebral palsy but necessitates trained professionals. Here, the authors show a quantitative deep learning-based method to automate GMA with strong performance, adhering to GMA principles and exhibiting robust interpretability.
- Qiang Gao
- , Siqiong Yao
- & Hui Lu
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Article
| Open AccessFatal iatrogenic cerebral β-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer’s disease
A 79-year-old woman received three doses of lecanemab, an experimental drug for Alzheimer’s disease, and suffered a seizure and cerebral edema. Neuropathological evaluation showed severe cerebral amyloid angiopathy, arteritis and microhemorrhages.
- Elena Solopova
- , Wilber Romero-Fernandez
- & Matthew Schrag
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Article
| Open AccessEpilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability
CDKL5 deficiency disorder is one of the most common genetic forms of epilepsy. Here the authors show that a model of CDKL5 deficiency disorder involves a channelopathy of CACNA1E gain-of-function, molecularly linking two distinct single-gene developmental and epileptic encephalopathies.
- Marisol Sampedro-Castañeda
- , Lucas L. Baltussen
- & Sila K. Ultanir
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Article
| Open AccessWake slow waves in focal human epilepsy impact network activity and cognition
Slow waves in sleep are crucial for homeostatic regulation of brain function. Here the authors show similar slow wave activity occurs during wakefulness in people with epilepsy to counter the impact of abnormal, epileptic, brain activity.
- Laurent Sheybani
- , Umesh Vivekananda
- & Matthew C. Walker
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Article
| Open AccessNR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease
Oral nicotinamide riboside (NR) at a dose of 3000 mg daily for 30 days is safe and associated with a pronounced systemic augmentation of the NAD metabolome, but no methyl donor depletion.
- Haakon Berven
- , Simon Kverneng
- & Charalampos Tzoulis
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Article
| Open AccessResting-state global brain activity affects early β-amyloid accumulation in default mode network
Why β-amyloid plaque initially accumulates in the default mode network of the cortex before Alzheimer’s disease diagnosis is not known. Here, the authors show that this accumulation is associated with a reduction of global brain activity in these regions.
- Feng Han
- , Xufu Liu
- & Xiao Liu
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Article
| Open AccessAssociations of myeloid cells with cellular and humoral responses following vaccinations in patients with neuroimmunological diseases
Patients with autoimmune diseases require immunosuppressive treatments that affect their responses to infection and vaccination. Here, using mass cytometry, the authors to identify a role for myeloid cells in cellular and humoral responses following vaccination against SARS-CoV-2 in patients with neuroimmunological diseases.
- Meng Wang
- , Adeline Dehlinger
- & Chotima Böttcher
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Article
| Open AccessBrain-to-gut trafficking of alpha-synuclein by CD11c+ cells in a mouse model of Parkinson’s disease
Despite being implicated in several neurological diseases, the gut-brain axis remains poorly understood. Here the authors describe a mechanism of communication between the brain and the gut in a Parkinson’s disease mouse model mediated by CD11c+ macrophages.
- Rhonda L. McFleder
- , Anastasiia Makhotkina
- & Chi Wang Ip
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Article
| Open AccessPathogenesis-adaptive polydopamine nanosystem for sequential therapy of ischemic stroke
Reperfusion is a main strategy for restoring blood supply after ischemic stroke, but it induces neuroinflammation that undergoes dynamic progression, hindering the treatment of ischemic stroke. Here, the authors report a pathogenesis-adaptive nanosystem for sequential and on-demand regulation of reperfusion-induced dynamic neuroinflammation for ischemic stroke therapy.
- Di Wu
- , Jing Zhou
- & Zhong Chen
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Article
| Open AccessCovariance patterns between sleep health domains and distributed intrinsic functional connectivity
The relationship between sleep health and brain functional connectivity is not well understood. Here, the authors reveal a composite sleep health dimension which covaries with connectivity of the attentional and thalamic networks.
- Yulin Wang
- , Sarah Genon
- & Xu Lei
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Article
| Open AccessProteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis
Precise biomarkers for multiple sclerosis prognosis are vital for treatment decisions. Here, the authors identify specific proteins in cerebrospinal fluid that can predict short-term disease activity and long-term disability outcomes in persons with multiple sclerosis.
- Julia Åkesson
- , Sara Hojjati
- & Mika Gustafsson
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Article
| Open AccessStress-induced red nucleus attenuation induces anxiety-like behavior and lymph node CCL5 secretion
Exposure to stressors can trigger or exacerbate anxiety through an inflammatory response. Here, the authors demonstrate the function of a “brain-lymph node” axis in anxiety and provide insights into lymph nodes as stress-responsive endocrine organs.
- Dong-Dong Shi
- , Ying-Dan Zhang
- & Zhen Wang
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Article
| Open AccessThe α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases
A PET tracer for α-synuclein would help diagnosis and treatment of α-syn-related diseases. Here the authors show that ACI-12589 shows an uptake in the cerebellar white matter in patients with multiple-system atrophy.
- Ruben Smith
- , Francesca Capotosti
- & Oskar Hansson
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Article
| Open AccessPlasma biomarkers predict Alzheimer’s disease before clinical onset in Chinese cohorts
Performance of plasma biomarkers of amyloid (A), tau (T) and neurodegeneration (N) for Alzheimer’s disease (AD) in Chinese cohorts is unknown. Here, the authors report that plasma ATN biomarkers can predict AD 8–10 years before symptoms in Chinese cohorts.
- Huimin Cai
- , Yana Pang
- & Longfei Jia
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Article
| Open AccessSoluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer’s disease
In this study, the authors found that sTREM2 attenuates tau hyperphosphorylation by activating transgelin-2. They developed an active peptide that mimics the protective effect of sTREM2, which may be an innovative therapeutic intervention for AD.
- Xingyu Zhang
- , Li Tang
- & Zhentao Zhang