@article {pmid40659932,
year = {2025},
author = {Castelnovo, V and Canu, E and Basaia, S and Spinelli, EG and Freri, F and Schito, P and Russo, T and Falzone, Y and Verde, F and Torre, S and Poletti, B and Tremolizzo, L and Appollonio, I and Ticozzi, N and Silani, V and Filippi, M and Agosta, F},
title = {Brain functional connectivity changes in amyotrophic lateral sclerosis with apathy and depression.},
journal = {Journal of neurology},
volume = {272},
number = {8},
pages = {509},
pmid = {40659932},
issn = {1432-1459},
support = {StG-2016_714388_NeuroTRACK//H2020 European Research Council/ ; Investment PE8 - Project Age-It: "Ageing Well in an Ageing Society"//Ministero dell'Università e della Ricerca/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/complications/psychology ; *Apathy/physiology ; Male ; Female ; Middle Aged ; *Depression/diagnostic imaging/physiopathology/etiology ; Aged ; *Brain/physiopathology/diagnostic imaging ; Magnetic Resonance Imaging ; Connectome ; Neural Pathways/physiopathology/diagnostic imaging ; },
abstract = {BACKGROUND: Apathy and depression are the most prevalent neuropsychiatric symptoms in amyotrophic lateral sclerosis (ALS). Although insufficiently investigated, their distinction holds important clinical relevance for accurate diagnosis of ALS with behavioural impairment and for patients' prognosis and management. In the present study, we aimed to assess both apathy and depressive symptoms in patients with ALS and whether they have similar or different functional neural correlates.

METHODS: Using graph analysis and connectomics, global and lobar nodal properties and regional functional brain connectivity were assessed in ALS patients without apathy/depression (ALSn, n = 42), with apathy without depression (ALSa, n = 14), with depressive symptoms without apathy (ALSd, n = 20), and with apathy and depressive symptoms (ALSad, n = 6), and 46 healthy controls. Correlations between brain functional properties, apathy and depressive symptoms were performed in all patients.

RESULTS: Depressive symptoms were related with reduced path length within bilateral basal ganglia (BG) network, and apathy was related with increased path length, decreased nodal strength and local efficiency within left BG network. ALSa patients showed altered functional nodal properties within BG network compared to ALSn and ALSd. Compared to healthy controls and all non-apathetic patients (ALSn and ALSd), all apathetic patients (ALSa and ALSad) exhibited altered functional nodal properties within parietal, occipital and frontal networks. Non-apathetic patients, compared to apathetic patients, showed relatively preserved functional nodal properties in the BG network.

CONCLUSIONS: Our findings indicate differences in brain functional neural organization associated with apathy and depression, underscoring the importance of distinguishing these symptoms in ALS and highlighting the need for targeted interventions.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/complications/psychology
*Apathy/physiology
Male
Female
Middle Aged
*Depression/diagnostic imaging/physiopathology/etiology
Aged
*Brain/physiopathology/diagnostic imaging
Magnetic Resonance Imaging
Connectome
Neural Pathways/physiopathology/diagnostic imaging

@article {pmid40659544,
year = {2025},
author = {Stenvall, E and Grönlund, KÅ and Rohan, Z and Zetterström, P and Nordin, A and Forsberg, K},
title = {Pathology of three ALS patients with FUS variants, including one likely benign Q23L variant lacking FUS inclusions.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddaf119},
pmid = {40659544},
issn = {1460-2083},
support = {FO2023-0088//Swedish Brain Foundation/ ; FO2024-0232//Swedish Brain Foundation/ ; //Börje Salming ALS Foundation/ ; 2023.10//Ulla-Carin Lindquist Foundation/ ; 2023.16//Ulla-Carin Lindquist Foundation/ ; //Neuroförbundet Association/ ; RV-1005785//Västerbotten County Council/ ; RV-1013622//Västerbotten County Council/ ; RV-993493//Västerbotten County Council/ ; RV-996234//Västerbotten County Council/ ; RV-1014212//Västerbotten County Council/ ; RV-996140//Västerbotten County Council/ ; },
abstract = {Fused in sarcoma (FUS) is an RNA-binding protein implicated in juvenile amyotrophic lateral sclerosis (ALS). Mutations in the FUS gene, particularly those affecting the nuclear localization signal (NLS), impair nuclear import and lead to cytoplasmic accumulation of FUS inclusions in motor neurons. However, the pathological and clinical significance of FUS variants outside the NLS remains less understood. Here, we describe clinical and histopathological findings from three ALS patients carrying FUS variants: two with NLS-region variants (R495X and P525L), and one with a variant in the N-terminal region outside the NLS (Q23L). The patients carrying NLS variants presented with aggressive, juvenile-onset spinal and bulbar ALS, characterized primarily by lower motor neuron involvement and rapid disease progression. In contrast, the Q23L patient exhibited a slowly progressive disease course, with predominantly upper motor neuron signs. Neuropathological analysis revealed cytoplasmic FUS inclusions in motor neurons of patients with NLS variants, consistent with typical FUS pathology. In contrast, the Q23L patient lacked FUS inclusions and instead displayed pTDP-43 pathology in the hippocampus, neocortex (including the motor cortex), nucleus olivaris, lentiform nucleus, striatum, and some lower motor neurons. Taken together, these results suggest that Q23L is most likely a benign variant. As antisense oligonucleotides (ASOs) targeting FUS are currently being explored in clinical trials, further neuropathological investigations are needed to determine whether ASO-mediated FUS silencing would be effective for patients carrying FUS variants outside the NLS region.},
}

@article {pmid40659018,
year = {2025},
author = {Yang, EJ},
title = {Combined herbal medicine (A. bidentata, G. elata, and C. sinensis) increases anti-inflammatory and anti-oxidative effects in a mouse model of amyotrophic lateral sclerosis.},
journal = {Pharmacology},
volume = {},
number = {},
pages = {1-21},
doi = {10.1159/000547388},
pmid = {40659018},
issn = {1423-0313},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the loss of motor neurons, finally leading to death by respiratory failure. However, no effective drug is available for treating patients with ALS owing to the complex pathological mechanisms. Herbal medicines are globally known for the effects of their multiple bioactive components and lack of adverse effects.

OBJECTIVE: This study investigated the effects of a combined herbal medicine formulation containing Achyranthes bidentata Blume, Gastrodia elata Blume, and Chaenomeles sinensis Koehne extracts on motor function and to analyze the underlying biological mechanisms in the gastrocnemius and tibia anterior muscles and spinal cord of hSOD1G93A mice.

METHODS: Rotarod and footprint analyses were performed to examine motor function. The biological mechanisms were examined using western blot and immunohistochemistry analyses of the muscles and spinal cord in hSOD1G93A mice.

RESULTS: Herbal medicine treatment improved motor function in hSOD1G93A mice by reducing the expression of inflammation-related proteins (glial fibrillary acidic protein and CD11b) and oxidative stress-related proteins (heme oxygenase 1 and ferritin) in the gastrocnemius and tibia anterior muscles and spinal cord. It also regulated autophagy in the muscles and spinal cord of hSOD1G93A mice.

CONCLUSIONS: Collectively, these findings suggest that the herbal medicine formulation reported herein may facilitate management of diseases with complex pathological mechanisms, such as ALS, or those with unclear pathological mechanisms.},
}

@article {pmid40658257,
year = {2025},
author = {Fasano, A and Vacchiano, V and Bonan, L and McMackin, R and Nasseroleslami, B and Hardiman, O and Liguori, R},
title = {Neurophysiological biomarkers of networks impairment in amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {272},
number = {8},
pages = {507},
pmid = {40658257},
issn = {1432-1459},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Biomarkers ; Transcranial Magnetic Stimulation ; *Nerve Net/physiopathology ; Electroencephalography ; Electromyography ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease involving motor system as well as cognitive domains. There is an urgent need for objective biomarkers that can subcategorize subjects into homogeneous groups based on disease pathobiology.In this review, we discuss novel neurophysiological techniques that provide detailed, multiscale and multidimensional insights into ALS networks impairment, spanning from the micro-columnar architecture of the motor cortex to motor and cognitive networks. Specifically, Transcranial Magnetic Stimulation (TMS) paradigms can be used to evaluate the status of excitatory and inhibitory networks within the layers of the motor cortex. Abnormalities in functional connectivity between the two motor areas, as well as within the frontal-temporal and frontal parietal networks, can be characterized using novel source-localization analysis of high-density electroencephalography (EEG). TMS and EEG techniques provide data that correlate with both motor and cognitive impairment. Furthermore, cortico-muscular coherence analysis can be used to assess functional dysregulation within the entire motor system, and novel surface electromyography (EMG) techniques, such as motor unit number estimation, motor unit number index, and nerve excitability testing studies provide useful insights into axonal loss and membrane ion channel dysfunctions in lower motor neurons.The integrated analysis of these biomarkers provides valuable insights into the clinical and biologic heterogeneity of the disease, aiding the intelligent design of next generation precision-based therapeutics.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis
Biomarkers
Transcranial Magnetic Stimulation
*Nerve Net/physiopathology
Electroencephalography
Electromyography

@article {pmid40655414,
year = {2025},
author = {Thiry, L and Sirois, J and Durcan, TM and Stifani, S},
title = {Derivation and Culture of Enriched Phrenic-Like Motor Neurons From Human iPSCs.},
journal = {Bio-protocol},
volume = {15},
number = {13},
pages = {e5363},
pmid = {40655414},
issn = {2331-8325},
abstract = {The fatal motor neuron (MN) disease amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of the phrenic MNs (phMNs) controlling the activity of the diaphragm, leading to death by respiratory failure. Human experimental models to study phMNs are lacking, hindering the understanding of the mechanisms of phMN degeneration in ALS. Here, we describe a protocol to derive phrenic-like MNs from human induced pluripotent stem cells (hiPSC-phMNs) within 30 days. During spinal cord development, phMNs emerge from specific MN progenitors located in the dorsalmost MN progenitor (pMN) domain at cervical levels, under the control of a ventral-to-dorsal gradient of Sonic hedgehog (SHH) signaling and a rostro-caudal gradient of retinoic acid (RA). The method presented here uses optimized concentrations of RA and the SHH agonist purmorphamine, followed by fluorescence-activated cell sorting (FACS) of the resulting MN progenitor cells (MNPCs) based on a cell-surface protein (IGDCC3) enriched in hiPSC-phMNs. The resulting cultures are highly enriched in MNs expressing typical phMN markers. This protocol enables the generation of hiPSC-phMNs and is highly reproducible using several hiPSC lines, offering a disease-relevant system to study mechanisms of respiratory MN dysfunction. While the protocol has been validated in the context of ALS research, it can be adopted to study human phrenic MNs in other research fields where these neurons are of interest. Key features • This protocol generates enriched hiPSC-derived phrenic motor neuron cultures. • The protocol can be used to develop models to study human respiratory motor neuron disease. • The protocol allows the generation of phrenic motor neuron preparations with potential for motor neuron replacement strategies. • The protocol requires experience in hiPSC culturing and FACS-based cell sorting for a successful outcome.},
}

@article {pmid40655294,
year = {2025},
author = {Rinofner-Kreidl, S},
title = {Ist das Gegebene noch zu retten? Über Chancen und Gefahren einer Politisierung der Phänomenologie.},
journal = {Husserl studies},
volume = {41},
number = {2},
pages = {267-302},
doi = {10.1007/s10743-025-09363-5},
pmid = {40655294},
issn = {0167-9848},
abstract = {Dieser Essay zielt darauf, eine Mehrdeutigkeit der Rede von "Politisierung" herauszuarbeiten, die sowohl für die Selbstkritik phänomenologischen Denkens als auch für die Kritik der Phänomenologie als eines öffentlichen Diskurses von Bedeutung ist. Die fraglichen Unterschiede betreffen das Verständnis dessen, was infolge einer Politisierung des Denkens anders konzipiert, kontextualisiert oder interpretiert wird, ob eine Politisierung intrinsisch oder extrinsisch motiviert und begründet ist und wie Art und Reichweite der daran geknüpften Ansprüche argumentiert werden können. Zwei Optionen werden erörtert: (1) eine interne Politisierung, die als phänomenologisch-methodischer Umgang mit Gegebenem und als kollektiv praktizierter Evidenzstil charakterisiert wird; (2) eine externe Politisierung, die sich als standort- und kontextabhängige weltanschauliche Idee und Praxis darstellt. Letztere versteht sich als eine politische Forderung und Erwartung, die eine thematisch einseitige bzw. verengte und / oder unreflektierte, unkritische, womöglich vorurteils- und ressentimentgeleitete phänomenologische Untersuchung korrigiert. Es wird argumentiert, dass interne Politisierung auf einer Metaebene stattfindet, auf der über Natur und Selbstbegrenzung der phänomenologischen Analyse nachgedacht wird. In konkreten Phänomenanalysen schlägt sich interne Politisierung lediglich indirekt, über deren methodische und theoretische Rahmung, nieder. Interne Politisierung ist mit autonomer Vernunftausübung verträglich. Dies gilt nicht für jede Form externer Politisierung, die als direkter Eingriff auf der gegenständlichen Ebene, im Zuge der Interpretation konkreter Phänomene, erfolgt. Zu klären ist: Wie können zulässige und eventuell unabdingbare Formen von Politisierung von unzulässigen unterschieden werden? Unter welchen Bedingungen unterliegt die Politisierung des Denkens einem Selbstwiderlegungseinwand?},
}

@article {pmid40654997,
year = {2025},
author = {Barbieri, EM and Linsenmeier, M and Whiteman, KR and Cheng, Y and Braganza, S and Copley, KE and Miranda-Castrodad, P and Lewis, B and Villafañe, K and Amado, DA and Davidson, BL and Shorter, J},
title = {Scouring the human Hsp70 network uncovers diverse chaperone safeguards buffering TDP-43 toxicity.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.10.653282},
pmid = {40654997},
issn = {2692-8205},
abstract = {Cytoplasmic aggregation and concomitant dysfunction of the prion-like, RNA-binding protein TDP-43 underpin several fatal neurodegenerative diseases, including amyotrophic lateral sclerosis. To elucidate endogenous defenses, we systematically scoured the entire human Hsp70 network for buffers of TDP-43 toxicity. We identify 30 J-domain proteins (2 DNAJAs, 10 DNAJBs, 18 DNAJCs), 6 Hsp70s, and 5 nucleotide-exchange factors that mitigate TDP-43 toxicity. Specific chaperones reduce TDP-43 aggregate burden and detoxify diverse synthetic or disease-linked TDP-43 variants. Sequence-activity mapping unveiled unexpected, modular mechanisms of chaperone-mediated protection. Typically, DNAJBs collaborate with Hsp70 to suppress TDP-43 toxicity, whereas DNAJCs act independently. In human cells, specific chaperones increase TDP-43 solubility and enhance viability under proteotoxic stress. Strikingly, spliceosome-associated DNAJC8 and DNAJC17 retain TDP-43 in the nucleus and promote liquid-phase behavior. Thus, we disambiguate a diverse chaperone arsenal embedded in the human proteostasis network that counters TDP-43 toxicity and illuminate mechanistic gateways for therapeutic intervention in TDP-43 proteinopathies.},
}

@article {pmid40654973,
year = {2025},
author = {Sangwan, S and Rieder, HE and Moore, D and Khanlou, N and Novitch, B and Geisberg, M and Eisenberg, DS},
title = {A structure-guided antibody detects SOD1 oligomers in diverse ALS genotypes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.05.652290},
pmid = {40654973},
issn = {2692-8205},
abstract = {Antibodies offer versatility as diagnostic and therapeutic tools to target specific protein epitopes. However, the transient nature of intermediate protein conformations, such as that of amyloid oligomers, poses a challenge for antibody development. We use a structure-guided approach to generate a monoclonal antibody against oligomers of Superoxide Dismutase 1 (SOD1). Mutations in SOD1 are linked to a subset of familial Amyotrophic Lateral Sclerosis (fALS), a fatal neurodegenerative disease. Based on the corkscrew-like features of non-native SOD1 oligomers previously determined, we generate an antibody specific to SOD1 oligomers. We show that the antibody, CSAb detects SOD1 oligomers, not fibrils or native SOD1, and alleviates the cytotoxic effects of SOD1 oligomers in a cell culture model of primary motor neurons. Immunohistochemical analyses of human ALS subjects show CSAb reactivity in both neuronal and non-neuronal cells. Finally, we provide evidence that CSAb reactive SOD1 oligomers are present in non-SOD1 linked fALS and sporadic ALS subjects. Together, our study provides a new probe against SOD1 oligomers and suggests that cytotoxic SOD1 oligomers are prevalent in diverse ALS genotypes.},
}

@article {pmid40654957,
year = {2025},
author = {Sheth, U and Harrison, R and Ferber, K and Rosenbaugh, EG and Bevis, A and Khillan, R and Benatar, M and Bjorklund, NL and Di Daniel, E and Harris, GA and Kahn, OI and Liu, Y and Zetterberg, H and Mitic, LL and Graham, D and Gendron, TF},
title = {Measuring neurofilament light in human plasma and cerebrospinal fluid: a comparison of five analytical immunoassays.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.05.652212},
pmid = {40654957},
issn = {2692-8205},
abstract = {OBJECTIVES: Neurofilament light (NfL) is an established biofluid marker of neuroaxonal injury for neurological diseases. Several high-throughput and sensitive immunoassays have been developed to quantify NfL in blood and cerebrospinal fluid (CSF), facilitating the use of NfL as a biomarker in research and clinical practice. However, because of the lack of rigorous comparisons of assays, it has been difficult to determine whether data are comparable and whether assay performance differs. Here, we compared the performance of five NfL immunoassays.

METHODS: To assess the five NfL immunoassays (Fujirebio, ProteinSimple, Quanterix, Roche and Siemens), we used pooled plasma or pooled CSF, as well as unique samples from 20 healthy controls and 20 individuals with El Escorial defined probable or definite amyotrophic lateral sclerosis (ALS), to evaluate precision, parallelism and/or bias. We also examined correlations between plasma and CSF NfL concentrations within and across assays and evaluated their ability to differentiate healthy controls from individuals with ALS.

RESULTS: Four of the five assays demonstrated exemplary performance based on our analyses of precision and parallelism. Across the five assays, NfL concentrations were lower in plasma than in CSF, although they displayed a high degree of correlation. We noted bias across assays; plasma NfL concentrations were lowest for the Roche assay and highest for the ProteinSimple assay. In addition, all assays reliably distinguished healthy controls from individuals with ALS using plasma or CSF NfL.

CONCLUSIONS: Four NfL assays demonstrated similar analytic performance. Alongside performance, other factors such as costs, accessibility, useability, footprint, and intended use, should be considered.},
}

@article {pmid40654715,
year = {2025},
author = {Van Zuiden, W and Meimoun, TD and Bar, C and Siany, A and Moshe, L and Yacovzada, NS and Weizman, E and Neumann, M and Buchman, AS and Wang, Y and Bennett, DA and Glass, JD and Trautwig, AN and Seyfried, NT and Cooper-Knock, J and Hornstein, E},
title = {TDP-43 toxic gain of function links ALS, FTD and Alzheimer's Disease through splicing dysregulation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.04.20.648873},
pmid = {40654715},
issn = {2692-8205},
abstract = {Loss of nuclear TDP-43 splicing activity is a common feature across neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but its relevance to Alzheimer's disease (AD) remains unclear. Here, we show that TDP-43 pathology in AD is broadly associated with splicing abnormalities, including aberrant splicing of amyloid precursor protein (APP). TDP-43 drives the formation of elongated APP isoforms, disrupting alternative splicing across ALS, FTLD-TDP and AD, providing a compelling mechanism for a long-standing observation of APP isoform dysregulation. We further establish a mechanistic link between TDP-43, APP splicing, and A-beta pathology. Surprisingly, the disruption to alternative APP splicing is mediated by a toxic gain of cytoplasmic TDP-43 function, rather than loss of its nuclear role. Using proximity proteomics and base editing in human iPSC-derived neurons, we show that TDP-43 pathology causes cytoplasmic co-sequestration of splicing regulators SCAF11, SRSF5, and TIAL1. Knockdown of these regulators also results in APP mis-splicing and increased A-beta burden, without affecting other TDP-43 targets such as STMN2 or UNC13A. Together, our findings suggest that TDP-43-mediated splicing dysfunction upstream of APP contributes to the pathogenesis of seemingly disparate neurodegenerative diseases, uniting AD and ALS/FTLD-TDP through a shared molecular mechanism.},
}

@article {pmid40653816,
year = {2025},
author = {Bozovic, I and Licina, E and Bjelica, B and Milicevic, O and Palibrk, A and Basta, I and Peric, S and Pavlovic, A and Stevic, Z and Mijajlovic, M},
title = {Transcranial Brain Parenchyma Sonographic Findings in Familial and Sporadic Amyotrophic Lateral Sclerosis.},
journal = {European journal of neurology},
volume = {32},
number = {7},
pages = {e70272},
doi = {10.1111/ene.70272},
pmid = {40653816},
issn = {1468-1331},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics/pathology ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; Aged ; *Ultrasonography, Doppler, Transcranial/methods ; Adult ; *Brain/diagnostic imaging ; *Substantia Nigra/diagnostic imaging ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. Transcranial sonography (TCS) is a valuable tool for assessing deep brain structures. This study aimed to analyze TCS findings in both sporadic (sALS) and familial ALS (fALS) patients and compare them to healthy controls (HC).

METHODS: This cross-sectional study included 278 patients with sALS and 31 patients with genetically confirmed fALS, and 93 age- and gender- matched HC. TCS was used to assess substantia nigra (SN) and brainstem raphe (BR) echogenicity and third ventricle diameter (TVD). Functional disability was evaluated using the ALS Functional Rating Scale-Revised.

RESULTS: BR hypoechogenicity was more frequent in fALS (41.9%) and sALS (37.4%) patients, compared to HC (10.8%) (p < 0.001). Right SN hyperechogenicity was observed in 28.1% of sALS, 16.1% of fALS, and 8.6% of HC (p = 0.004). Left SN hyperechogenicity was found in 33.5% of sALS, 29.0% of fALS, and 4.3% of HC (p = 0.004). SN hyperechogenicity findings on either side were highest in sALS (48.4%) compared to fALS (31.0%) and HC (13.3%) (p < 0.001), with a borderline difference between fALS and sALS (p = 0.08). BR hypoechogenicity and SN hyperechogenicity were more common in male patients. Increased TVD correlated with older age, later disease onset, bulbar onset, and lower MMSE scores.

CONCLUSIONS: TCS is an easily applicable and sensitive diagnostic tool that offers novel insights into several brainstem structures and identify significant differences in their echogenicity between ALS patients and healthy controls, while pointing out similar but not identical patterns of echogenicity in both ALS forms.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics/pathology
Male
Female
Middle Aged
Cross-Sectional Studies
Aged
*Ultrasonography, Doppler, Transcranial/methods
Adult
*Brain/diagnostic imaging
*Substantia Nigra/diagnostic imaging

@article {pmid40653481,
year = {2025},
author = {Marabita, M and Marchioretti, C and Aravamudhan, A and Zito, S and Falconieri, A and Zuccaro, E and Andreotti, R and Gambarotto, L and Metti, S and Tonellato, M and Adami, V and Park, KH and Gunthorpe, MJ and Large, CH and Marasco, A and Vianello, S and Rosati, J and Belluzzi, E and Pozzuoli, A and Biz, C and Ruggieri, P and Basso, M and Poletti, A and Alvaro, G and Sorarù, G and Bonaldo, P and Rossetto, O and Pilati, N and Pennuto, M},
title = {Kv3 channel agonist ameliorates the phenotype of a mouse model of amyotrophic lateral sclerosis.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {153},
pmid = {40653481},
issn = {2051-5960},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism/genetics ; *Shaw Potassium Channels/agonists/metabolism/genetics ; Disease Models, Animal ; Humans ; Mice, Transgenic ; Mice ; Phenotype ; Muscle, Skeletal/metabolism/drug effects/pathology ; Male ; Mice, Inbred C57BL ; Female ; Superoxide Dismutase-1/genetics ; },
abstract = {Voltage-gated potassium channels, Kv3.1, Kv3.2, Kv3.3, and Kv3.4, facilitate rapid repolarization and shape action potentials, which are crucial to maintaining high-frequency firing. Little is known about the expression and function of Kv3 channels in skeletal muscle. We show that these channels are expressed in type IIa/IIx fibers, and their transcript levels progressively increase from postnatal age to adulthood in physiological context. In mature myofibers, the Kv3.1 and Kv3.4 channels are enriched in the muscle triads. The expression of the Kv3 channel is lost upon acute motor unit damage, in mouse models of amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), and the skeletal muscle of patients with sporadic ALS. Early treatment of ALS and SBMA mice with AUT00201, a positive allosteric modulator of Kv3 channels, improved the phenotype of ALS mice specifically, suggesting that positive modulation of Kv3 channels is a novel therapeutic option for patients with ALS.},
}

Animals
*Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism/genetics
*Shaw Potassium Channels/agonists/metabolism/genetics
Disease Models, Animal
Humans
Mice, Transgenic
Mice
Phenotype
Muscle, Skeletal/metabolism/drug effects/pathology
Male
Mice, Inbred C57BL
Female
Superoxide Dismutase-1/genetics

@article {pmid40655970,
year = {2023},
author = {Vardheim, EG and Toft, A and Nielsen, JE and Hasselbalch, SG and Simonsen, AH},
title = {Cerebrospinal fluid ubiquitin as a biomarker for neurodegenerative diseases: A systematic review.},
journal = {Neuroscience applied..},
volume = {2},
number = {},
pages = {102438},
pmid = {40655970},
issn = {2772-4085},
abstract = {Ubiquitin plays a vital role in neuronal proteostasis, as a major but often overlooked component of neurotoxic protein aggregates across neurodegenerative diseases. Although neuropathological changes can be present for years before clinical onset, early and accurate diagnosis remains an immense challenge in this disease category. The level of ubiquitin in cerebrospinal fluid (CSF) has been assessed as a biomarker for several disease entities. This systematic review compares current findings and evaluates the potential of CSF ubiquitin as a fluid biomarker. A systematic literature search identified studies comparing CSF ubiquitin levels between a control group and patients with one of the following diseases: Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), Lewy body dementia (DLB), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). All included studies were reviewed systematically by two independent authors. 171 studies were identified. A total of 17 studies met the eligibility criteria and were included. Nine out of 13 studies found a significant increase of CSF ubiquitin in AD patients compared with control groups. Correlations between CSF ubiquitin and other established biomarkers were demonstrated in seven studies. A single study was included for both HD and DLB respectively, each showing significantly higher CSF ubiquitin in patients compared to controls. In patients with PD, FTD or ALS, CSF ubiquitin levels were generally equal to those of the control groups, with two studies showing significantly decreased concentrations in a PD and an FTD cohort. Presently, the available body of research is insufficient to assess whether CSF ubiquitin could contribute to the clinical setting, alongside established markers of neurodegeneration. The correlation of elevated CSF ubiquitin with AD is well-founded, whilst validation of reduced or unchanged levels in the other neurodegenerative diseases will determine the usefulness of the biomarker in clinical practice.},
}

@article {pmid40653468,
year = {2025},
author = {Liu, Z and Sun, L and Gao, N and Li, W and Pang, L},
title = {Reciprocal regulation of GPNMB/HIF-1α for Inhibition of neuronal ferroptosis in delayed encephalopathy after acute carbon monoxide poisoning.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {154},
pmid = {40653468},
issn = {2051-5960},
support = {JJKH20231233KJ//Jilin Provincial Education Department/ ; Z2023LJL001//Tianhua Health Foundation of Jilin Province/ ; 82372211//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Ferroptosis/physiology/drug effects ; Rats ; *Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; *Carbon Monoxide Poisoning/metabolism/complications ; Male ; Rats, Sprague-Dawley ; *Neurons/metabolism/pathology ; *Membrane Glycoproteins/metabolism ; PC12 Cells ; *Brain Diseases/metabolism/etiology/pathology ; Oxidative Stress/physiology/drug effects ; },
abstract = {Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is the most common complication after acute carbon monoxide (CO) poisoning. However, the pathogenesis of DEACMP remains ambiguous. The neuroprotective role of GPNMB has been observed in amyotrophic lateral sclerosis and Parkinson's disease. GPNMB was elevated in the brain tissues of DEACMP rats, while its function in DEACMP remains unclear. In this study, a CO poisoning rat model and oxygen-glucose deprivation (OGD)-treated PC-12 cells were established as an in vivo and in vitro DEACMP model, respectively. The ferroptosis inhibitor Ferrostatin-1 (Fer-1) ameliorated cognitive impairment, inflammation and oxidative stress of rats with DEACMP as assessed by Morris Water Maze test, ELISA assay and commercial kits of oxidative markers. Immunofluorescence, qRT-PCR or western blot showed that GPNMB was elevated in CA1 hippocampal tissues of CO-poisoned rats. Additionally, TUNEL staining, ELISA assay and western blot revealed that GPNMB rescued OGD-induced cell apoptosis, inflammation and ferroptosis in PC-12 cells. Mechanistical study showed that STAT3 was a transcriptional activator of GPNMB as detected by luciferase and ChIP assays, and co-immunoprecipitation and immunofluorescence staining revealed that GPNMB stabilized HIF-1α by direct binding. Functionally, GPNMB protected against OGD-induced impairments via inducing HIF-1α. Furthermore, GPNMB attenuated cognitive impairment, oxidative stress and neuronal ferroptosis of rats with DEACMP. In conclusion, GPNMB/HIF-1α exhibited neuroprotective effects via suppressing ferroptosis in DEACMP.},
}

Animals
*Ferroptosis/physiology/drug effects
Rats
*Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
*Carbon Monoxide Poisoning/metabolism/complications
Male
Rats, Sprague-Dawley
*Neurons/metabolism/pathology
*Membrane Glycoproteins/metabolism
PC12 Cells
*Brain Diseases/metabolism/etiology/pathology
Oxidative Stress/physiology/drug effects

@article {pmid40653411,
year = {2025},
author = {Wei, Y and Zhang, Y and Yu, D},
title = {Low-dose IL-2 reinvigorates the immunoguardians of neurodegenerative diseases.},
journal = {Trends in immunology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.it.2025.07.004},
pmid = {40653411},
issn = {1471-4981},
abstract = {Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease caused by motor neuron loss. In a recent Phase 2b trial, Bensimon and colleagues report that the addition of low-dose interleukin 2 (LD-IL-2) immunotherapy to standard of care (SOC) shows promise in enhancing immune tolerance and improving survival in individuals with slower disease progression.},
}

@article {pmid40652712,
year = {2025},
author = {Brüge, A and Ponimaskin, E and Labus, J},
title = {Targeting the serotonergic system in the treatment of neurodegenerative diseases-emerging therapies and unmet challenges.},
journal = {Pharmacological reviews},
volume = {77},
number = {5},
pages = {100071},
doi = {10.1016/j.pharmr.2025.100071},
pmid = {40652712},
issn = {1521-0081},
abstract = {More than 65 million people worldwide experience neurodegenerative diseases, such as Alzheimer disease, frontotemporal dementia, Parkinson disease, and amyotrophic lateral sclerosis. As the risk of developing these diseases increases with age, increasing life expectancy will further accelerate their prevalence. Despite major advances in the understanding of the molecular mechanisms of neurodegeneration, no curative therapy is available to date. Neurodegenerative diseases are known to be associated with alterations in serotonergic neurotransmission, which might critically contribute to the pathogenesis of these diseases. Therefore, targeting the serotonergic system appears to be a promising therapeutic approach. In this review, we provide a comprehensive overview of pathological changes in serotonergic neurotransmission in different neurodegenerative diseases and discuss novel treatment strategies based on targeted modulation of the serotonergic system. We primarily focus on the therapeutic approaches modulating serotonin homeostasis, its biosynthesis, and the modulation of defined serotonin receptors. SIGNIFICANCE STATEMENT: A common feature of multiple neurodegenerative diseases is dysregulation of the serotonergic system at the cellular, molecular, and genetic levels that strongly contributes to specific pathological phenotypes. Targeting these alterations represents a suitable therapeutic strategy to combat disease-relevant pathomechanisms, slow down disease progression, and overcome pathological consequences.},
}

@article {pmid40651399,
year = {2025},
author = {Ma, Y and Wu, S and Liu, H and Ren, C and Xie, Y and Deng, G and Yao, S and Wang, X and Qin, C},
title = {Sodium lignosulfonate alkylates based-biosurfactants for efficient remediation of oily sludge.},
journal = {Journal of environmental management},
volume = {391},
number = {},
pages = {126553},
doi = {10.1016/j.jenvman.2025.126553},
pmid = {40651399},
issn = {1095-8630},
abstract = {An alkylated sodium lignosulphonate (ALS) was prepared for highly efficient thermal washing treatment of oily sludge. The ALS was characterized for their chemical structure and surface activity. Furthermore, ALS was used as a thermal cleaning agent to treat oily sludge under different conditions to obtain an optimal thermal washing process. Finally, the oily sludge before and after thermal washing were characterized to explore its structural and compositional changes. Results obtained from the Fourier Transform Infrared spectroscopy (FT-IR) and Two-dimensional Heteronuclear Single Quantum Coherence(2D-HSQC) confirmed the successful grafting of fatty acid chains(C12) onto the LS molecules. ALS was an ideal surfactant with suitable HLB value and excellent surface tension reduction, foaming and emulsification properties. The optimum thermal washing process for oily sludge was: thermal washing temperature 30 °C, ALS concentration 1.5 g/L.},
}

@article {pmid40651326,
year = {2025},
author = {Yang, S and Ma, Y and Fu, H and Wang, C and Zhang, Y},
title = {Association between allostatic load and trouble sleeping in U.S. adults.},
journal = {Journal of psychosomatic research},
volume = {196},
number = {},
pages = {112206},
doi = {10.1016/j.jpsychores.2025.112206},
pmid = {40651326},
issn = {1879-1360},
abstract = {OBJECTIVE: This study examined the association between allostatic load and trouble sleeping and assessed whether this relationship varies based on allostatic load score (ALS) criteria.

METHODS: This cross-sectional survey utilized nationally representative data from the National Health and Nutrition Examination Survey (NHANES). ALS was derived using empirical and clinical criteria based on eight biomarkers reflecting cardiovascular, metabolic, and immune function. Weighted multivariate logistic regression was employed to analyze the association between ALS and trouble sleeping, with subgroup analyses conducted to assess gender-specific differences.

RESULTS: Of 5331 participants included in this study, 1485 (29 %) reported trouble sleeping. In multivariate-adjusted logistic regression, higher ALS was associated with increased odds of trouble sleeping (empirical ALS: OR 1.13 [95 % CI 1.07-1.18]; clinical ALS: OR 1.08 [95 % CI 1.04-1.13]). Subgroup analyses confirmed the consistency of this association across genders.

CONCLUSION: This study provides robust evidence of a significant association between ALS and trouble sleeping, supported by observed OR of 1.13 (empirical) and 1.08 (clinical). The consistency of findings across both empirical and clinical ALS underscores the potential role of physiological dysregulation in sleep health, highlighting the need for integrated approaches to stress and sleep management.},
}

@article {pmid40651187,
year = {2025},
author = {Chang, J and Teo, AH and Shaw, TB and Dupuis, L and Ngo, ST and Steyn, FJ},
title = {Deciphering hypothalamic pathology in ALS: insights into non-motor symptoms and disease progression.},
journal = {EBioMedicine},
volume = {118},
number = {},
pages = {105845},
doi = {10.1016/j.ebiom.2025.105845},
pmid = {40651187},
issn = {2352-3964},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with highly heterogeneous clinical presentations. Among the non-motor features increasingly recognised as clinically relevant is the dysregulation of energy balance, with weight loss-particularly due to fat mass loss-emerging as a significant modifier of disease risk, progression, and survival. In this context, the hypothalamus-a key regulator of homeostatic and metabolic processes-has gained attention for its potential role in ALS pathophysiology. This Review synthesises emerging evidence of hypothalamic involvement in ALS, including neuronal loss, proteinopathy, and volume loss observed through histological and neuroimaging studies. We critically examine current imaging approaches and their technical limitations and explore neuroendocrine dysfunction across the hypothalamic-pituitary axes. Collectively, these findings suggest that hypothalamic dysfunction may contribute to clinically relevant metabolic, sleep, behavioural, and cognitive changes in ALS, adding to our understanding of ALS as a multisystem disease. Continued investigation of the hypothalamus may reveal novel biomarkers, inform risk stratification, and identify therapeutic opportunities to address disease heterogeneity and improve clinical outcomes.},
}

@article {pmid40650266,
year = {2025},
author = {Bashar, MA and Dash, N and Mitra, S and Dash, R},
title = {Disclosing Pathogenic Variant Effects on the Structural Dynamics of the VAPB MSP Domain Causing Familial ALS.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/ijms26136489},
pmid = {40650266},
issn = {1422-0067},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Molecular Dynamics Simulation ; *Vesicular Transport Proteins/genetics/chemistry/metabolism ; Protein Domains ; Mutation ; Protein Structure, Secondary ; Protein Binding ; },
abstract = {Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB) serves as a tethering factor that interacts with various proteins and recruits these proteins to the ER surface, exerting multiple functions, such as organelle membrane tethering, lipid transfer between organelles, regulation of calcium homeostasis, autophagy, and the unfolded protein response (UPR). Its interaction is often mediated by its MSP (major sperm) domain, which binds with FFAT (two phenylalanines in an acidic tract)-motif-containing proteins. However, pathogenic variations, such as P56S, P56H, and T46I, in the VAPB MSP domain lead to the familial form of amyotrophic lateral sclerosis (ALS8). Still, the underlying pathophysiology of ALS8 due to pathogenic variations in the VAPB MSP domain remains elusive. In this study, we conducted molecular dynamics (MD) simulations to understand the pathogenic-variant-derived changes in the structural dynamics of the VAPB MSP domain. We found that pathogenic variants altered the fluctuations and conformational dynamics of the VAPB protein. Analyzing the organizations of the secondary structure revealed that pathogenic variants changed the composition of secondary structure elements, especially increasing the proportion of α-helix while reducing β-sheet formation, which might affect the organelle tethering and other functions of VAPB, as well as VAPB homodimer and heterodimer formation. Taken together, these findings can be further investigated through in vivo and/or in vitro studies to not only clarify the pathophysiology of ALS8 resulting from VAPB MSP domain pathogenic variants but also develop novel therapeutics for the disease that restore the native structural organizations as well as fluctuations and motions.},
}

*Amyotrophic Lateral Sclerosis/genetics/metabolism
Humans
Molecular Dynamics Simulation
*Vesicular Transport Proteins/genetics/chemistry/metabolism
Protein Domains
Mutation
Protein Structure, Secondary
Protein Binding

@article {pmid40650046,
year = {2025},
author = {Cattaneo, M and Giagnorio, E and Lauria, G and Marcuzzo, S},
title = {Therapeutic Approaches for C9ORF72-Related ALS: Current Strategies and Future Horizons.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/ijms26136268},
pmid = {40650046},
issn = {1422-0067},
support = {//Italian Ministry of Health (RRC)/ ; T4-AN-09 prog. ZRPOS2//CALabria HUB per Ricerca Innovativa ed Avanzata- CALHUB.RIA "Creazione di Hub delle Sci-enze della Vita"/ ; prog. ZRA124//AriSLA foundation, "Bulb-Omics"/ ; PNRR-MCNT2-2023-12377336//the European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS,/ ; },
mesh = {Humans ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/pathology ; Animals ; DNA Repeat Expansion ; Gene Editing ; Genetic Therapy/methods ; Mutation ; Oligonucleotides, Antisense/therapeutic use ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. One of its major genetic causes is C9ORF72, where mutations lead to hexanucleotide repeat expansions in the C9ORF72 gene. These expansions drive disease progression through mechanisms, including the formation of toxic RNAs and the accumulation of damaged proteins such as dipeptide repeats (DPRs). This review highlights these pathogenic mechanisms, focusing on RNA foci formation and the accumulation of toxic DPRs, which contribute to neuronal damage. It also discusses promising targeted therapies, including small molecules and biological drugs, designed to counteract these specific molecular events. Small molecules such as G-quadruplex stabilizers, proteasome and autophagy modulators, and RNase-targeting chimeras show potential in reducing RNA foci and DPR accumulation. Furthermore, targeting enzymes involved in repeat-associated non-AUG (RAN) translation and nucleocytoplasmic transport, which are crucial for disease pathogenesis, opens new therapeutic avenues. Even some anti-viral drugs show encouraging results in preclinical studies. Biological drugs, such as antisense oligonucleotides and gene-editing technologies like CRISPR-Cas, were explored for their potential to specifically target C9ORF72 mutations and modify the disease's molecular foundations. While preclinical and early clinical data show promise, challenges remain in optimizing delivery methods, ensuring long-term safety, and improving efficacy. This review concludes by emphasizing the importance of continued research and the potential for these therapies to alter the disease trajectory and improve patient outcomes.},
}

Humans
*C9orf72 Protein/genetics/metabolism
*Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/pathology
Animals
DNA Repeat Expansion
Gene Editing
Genetic Therapy/methods
Mutation
Oligonucleotides, Antisense/therapeutic use

@article {pmid40649976,
year = {2025},
author = {Jiménez-García, AM and Tortorella, ME and Nishimura, AL and Arias, N},
title = {The Differential Effects of Genetic Mutations in ALS and FTD Genes on Behavioural and Cognitive Changes: A Systematic Review and Meta-Analysis.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/ijms26136199},
pmid = {40649976},
issn = {1422-0067},
support = {PID2023-151715OB-IOO//Ministry of Science and Innovation/ ; PLEC2022-009464//European Union NextGeneration EU/PRTR/ ; CPP2022-009646//European Union NextGeneration EU/PRTR/ ; },
mesh = {Humans ; *Frontotemporal Dementia/genetics/psychology ; *Amyotrophic Lateral Sclerosis/genetics/psychology ; *Mutation ; *Cognition ; tau Proteins/genetics ; C9orf72 Protein/genetics ; Progranulins/genetics ; Superoxide Dismutase-1/genetics ; Endosomal Sorting Complexes Required for Transport/genetics ; RNA-Binding Protein FUS/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are linked by shared genetic mutations and overlapping clinical features, forming a clinical spectrum. This systematic review and meta-analysis analysed 97 studies, including 3212 patients with key ALS/FTD gene mutations, to identify gene-specific behavioural profiles. Chromosome 9 open reading frame 72 (C9orf72) mutations were strongly associated with psychotic symptoms and aggression, while superoxide dismutase 1 (SOD1) mutations had minimal cognitive effects. Progranulin (PGRN) mutations correlated with apathy and hallucinations, microtubule-associated protein tau (MAPT) mutations with disinhibition, and charged multivesicular body protein 2B (CHMP2B) with social impairments. Fused in sarcoma (FUS) mutations caused early sleep disturbances, TANK-binding kinase 1 (TBK1) led to disinhibition, and presenilin 1 and 2 (PSEN1/2) was linked to severe aggression. Prodromal cognitive changes in PGRN, MAPT, and CHMP2B mutations suggested early disease onset. Despite overlapping symptoms and clinical heterogeneity, understanding gene-specific patterns could inform tailored care strategies to enhance the quality of life for ALS and FTD patients. This study calls for refined guidelines integrating genetic behavioural profiles to improve patient and family support.},
}

Humans
*Frontotemporal Dementia/genetics/psychology
*Amyotrophic Lateral Sclerosis/genetics/psychology
*Mutation
*Cognition
tau Proteins/genetics
C9orf72 Protein/genetics
Progranulins/genetics
Superoxide Dismutase-1/genetics
Endosomal Sorting Complexes Required for Transport/genetics
RNA-Binding Protein FUS/genetics

@article {pmid40649921,
year = {2025},
author = {Neumann, S and Heumann, R},
title = {Is the Voltage-Dependent Anion Channel a Major Player in Neurodegenerative Diseases?.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/ijms26136138},
pmid = {40649921},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Voltage-Dependent Anion Channels/metabolism/genetics ; Animals ; Mitochondria/metabolism ; },
abstract = {The family of voltage-dependent anion channels (VDACs) comprises three isoforms (VDAC-1, VDAC-2, VDAC-3). VDACs have been extensively described as localised in the outer mitochondrial membrane where they are involved in the exchange of ions, metabolites, and ATP/ADP between mitochondria and cytosol. The VDAC interacts with disease-specific proteins and thus regulates the mitochondrial function and controls the cellular energy resources, explaining its involvement in cell death and apoptosis. In addition, VDAC-1 and -2 can also be found at other cellular locations such as in the sarcoplasmic reticulum, in the endoplasmic reticulum, as well as in the plasma membrane. Through single-channel pore regulation, oligomerisation, or changed expression levels the VDAC is involved in different neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and others. Here, we critically summarise current discussions about the VDAC as a common key player for these diseases. We suggest that the VDAC acts as a transmembrane multifunctional regulatory protein which might serve as a pharmacological target for the development of novel drugs against neurodegenerative diseases such as the application of recombinant antibody technology.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology
*Voltage-Dependent Anion Channels/metabolism/genetics
Animals
Mitochondria/metabolism

@article {pmid40649859,
year = {2025},
author = {Tomczak, J and Kapsa, A and Boczek, T},
title = {Adenylyl Cyclases as Therapeutic Targets in Neuroregeneration.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/ijms26136081},
pmid = {40649859},
issn = {1422-0067},
support = {2020/39/D/NZ4/01250//National Science Center/ ; },
mesh = {Humans ; *Adenylyl Cyclases/metabolism ; Animals ; *Nerve Regeneration/drug effects ; Signal Transduction/drug effects ; Cyclic AMP/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuronal Plasticity ; },
abstract = {Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling-a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac), and cAMP-response element-binding protein (CREB). Among the various AC isoforms, calcium-sensitive AC1, AC8, and AC5, as well as bicarbonate-responsive soluble AC (sAC), have emerged as crucial mediators of neuroplasticity and axon regeneration. These isoforms coordinate diverse cellular responses-including gene transcription, cytoskeletal remodeling, and neurotransmitter release-to metabolic, synaptic, and injury-related signals. Dysregulation of AC activity has been implicated in the pathophysiology of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, as well as in chronic pain syndromes. Pharmacological modulation of cAMP levels through AC activation, phosphodiesterase (PDE) inhibition, or pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor signaling has shown therapeutic promise in preclinical models by enhancing neurogenesis, remyelination, and synaptic repair. Conversely, targeted inhibition of specific AC isoforms, particularly AC1, has demonstrated efficacy in reducing maladaptive plasticity and neuropathic pain. This review highlights the diverse roles of ACs in neuronal function and injury response and discusses emerging strategies for their therapeutic targeting.},
}

Humans
*Adenylyl Cyclases/metabolism
Animals
*Nerve Regeneration/drug effects
Signal Transduction/drug effects
Cyclic AMP/metabolism
*Neurodegenerative Diseases/drug therapy/metabolism
Neuronal Plasticity

@article {pmid40648447,
year = {2025},
author = {Lovrinčević, M and Papa, I and Janeš, D and Hodak, L and Pentek, T and Đuka, A},
title = {New Possibilities of Field Data Survey in Forest Road Design.},
journal = {Sensors (Basel, Switzerland)},
volume = {25},
number = {13},
pages = {},
doi = {10.3390/s25134192},
pmid = {40648447},
issn = {1424-8220},
support = {HRZZ-UIP-2019-04-7766//Croatian Science Foundation/ ; },
abstract = {Field data, as the basis for planning and designing forest roads, must have high spatial accuracy. Classical (using a theodolite and a level) and modern (based on total stations and GNSSs) surveying methods are used in current field data survey for forest road design. This study analyzed the spatial accuracy of classical and modern surveying methods, the accuracy of spatial data recorded using a UAV equipped with an RGB camera at different flight altitudes, and the accuracy of lidar data of the Republic of Croatia. This study was conducted on a forest area where salvage logging was carried out, which enabled the use of a GNSS receiver in RTK mode as a reference method. The highest RMSE values of the spatial coordinates were recorded for measurements obtained with the classical surveying method (0.89 m) and a total station (0.33 m). The flight altitude of the UAV did not significantly affect the spatial error of the collected data, which ranged between 0.07 and 0.09 m. The cross-terrain slope, as one of the factors that significantly affect the amount of earthworks, did not differ statistically significantly between the methods. The ALS error was strongly influenced by the cross-terrain slope. The authors conclude that the new survey methods (SfM and lidar data) provide high-accuracy data but also draw attention to challenges in their use, such as vegetation and biomass on the ground.},
}

@article {pmid40646945,
year = {2025},
author = {Davì, F and Iaconis, A and Cordaro, M and Di Paola, R and Fusco, R},
title = {Nutraceutical Strategies for Targeting Mitochondrial Dysfunction in Neurodegenerative Diseases.},
journal = {Foods (Basel, Switzerland)},
volume = {14},
number = {13},
pages = {},
doi = {10.3390/foods14132193},
pmid = {40646945},
issn = {2304-8158},
abstract = {In neurons, mitochondria generate energy through ATP production, thereby sustaining the high energy demands of the central nervous system (CNS). Mitochondrial dysfunction within the CNS was implicated in the pathogenesis and progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, often involving altered mitochondrial dynamics like fragmentation and functional impairment. Accordingly, mitochondrial targeting represents an alternative therapeutic strategy for the treatment of these disorders. Current standard drug treatments present limitations due to adverse effects associated with their chronic use. Therefore, in recent years, nutraceuticals, natural compounds exhibiting diverse biological activities, have garnered significant attention for their potential to treat these diseases. It has been shown that these compounds represent safe and easily available sources for the development of innovative therapeutics, and by modulating mitochondrial function, nutraceuticals offer a promising approach to address neurodegenerative pathologies. We referred to approximately 200 articles published between 2020 and 2025, identified through a focused search across PubMed, Google Scholar, and Scopus using keywords such as "nutraceutical," "mitochondrial dysfunction," and "neurodegenerative diseases. The purpose of this review is to examine how mitochondrial dysfunction contributes to the genesis and progression of neurodegenerative diseases. Also, we discuss recent advances in mitochondrial targeting using nutraceuticals, focusing on their mechanisms of action related to mitochondrial biogenesis, fusion, fission, bioenergetics, oxidative stress, calcium homeostasis, membrane potential, and mitochondrial DNA stability.},
}

@article {pmid40644419,
year = {2025},
author = {Bertran-Recasens, B and Vidal-Notari, S and Hernández Guillamet, G and López Seguí, F and Vidal-Alaball, J and Jiménez-Balado, J and Rubio, MA},
title = {Epidemiology of amyotrophic lateral sclerosis: a population-based analysis, 2015-2020.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2025.2527887},
pmid = {40644419},
issn = {2167-9223},
abstract = {Background: Epidemiological data on amyotrophic lateral sclerosis (ALS) in Spain have primarily been derived from small cohort studies, with limited information on survival and comorbidities. This study presents a 10-year follow-up of a large, well-phenotyped community-dwelling ALS cohort in Catalonia, Spain. Methods: This observational study utilized data from the Information System for the Development of Research in Primary Care (SIDIAP), which includes health records for 6,301,095 individuals from 2015 to 2020. We assessed ALS incidence, prevalence, comorbidities, territorial distribution, mortality, and survival times. Results: From 2015 to 2020, 1173 ALS cases were identified, with a median age at diagnosis of 68 years, and 50.4% of cases were female. Incidence and prevalence were estimated at 2.39 per 100,000 person-years and 7.98 cases per 100,000 persons. Dementia was present in 6.8% of cases before ALS diagnosis, while depression and/or anxiety affected 45.7%. Median survival from diagnosis was 2.19 years. Multivariate analysis identified older age at diagnosis (HR: 1.04, 95% CI: 1.04-1.05, p value < 0.001), alcohol abuse (HR: 1.56, 95% CI: 1.04-2.56, p value = 0.017), history of stroke (HR: 1.47, 95% CI: 1.07-2.04, p = 0.006), and dementia (HR: 1.57, 95% CI: 1.18-2.12, p value = 0.001) as independent predictors of mortality. Conclusions: ALS incidence and prevalence in Catalonia are higher than previously estimated for Spain and align closely with rates observed in other Western countries. Older age at diagnosis, alcohol abuse, stroke history, and dementia were all significantly associated with reduced survival. These findings underscore important risk factors affecting prognosis, offering valuable insights into ALS progression.},
}

@article {pmid40644388,
year = {2025},
author = {Holanda Braga, CAO and Diniz, DS},
title = {Characterizing changes in functioning in Brazilian patients with ALS using a comprehensive ICF core set.},
journal = {Disability and rehabilitation},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/09638288.2025.2532124},
pmid = {40644388},
issn = {1464-5165},
abstract = {PURPOSE: To longitudinally describe the impact of amyotrophic lateral sclerosis (ALS) using a core set based on the International Classification of Functioning, Disability and Health (ICF).

PATIENTS AND METHODS: Between May 2021 and August 2022, 42 Brazilian patients with ALS (21 men/21 women, mean age 59.92 years, 23.8% with bulbar-onset ALS and 76.2% with spinal-onset ALS) were included. Patients diagnosed at least 6 months previously were assessed using 42 ICF categories at baseline and every six months thereafter for 16 months. The Friedman test was used to compare three time points, followed by Wilcoxon post hoc analyses. The Bonferroni method was applied. P-values ≤0.05 were considered significant. Overall and subgroup (bulbar-onset/spinal-onset ALS) analyses were performed.

RESULTS: Significant changes were found in 24/42 ICF categories. The most affected Body Functions included respiratory muscle functions (b445), power of muscles of one limb (b7301), muscle power (b730) and gait pattern (b770). Early disabilities involved pain sensation (b280) and respiratory functions. Limitations in Activities and Participation included transferring oneself (d420), hand and arm use (d445), dressing (d540), washing oneself (d510) and speaking (d330).

CONCLUSION: This ICF core set may help determine key facilitators and barriers to functioning and disability in ALS, guiding rehabilitation efforts.},
}

@article {pmid40643880,
year = {2025},
author = {Wang, P and Shang, H and Li, C},
title = {Association of creatinine level with neurodegenerative disorders: a prospective cohort study and Mendelian randomization analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40643880},
issn = {1590-3478},
support = {24NSFSC0358//Sichuan Science and Technology Program/ ; },
abstract = {BACKGROUND: Multiple evidence has suggested interaction between neurodegenerative disorders (NDDs) and creatinine, a metabolite derived from the high-energy product creatine. However, findings across studies have shown inconsistency, and the effect direction remains controversial. Here, we aimed to explore the link between creatinine and the risk of NDDs.

METHODS: Utilizing data from the UK Biobank, we investigated the association between baseline serum and urine creatinine and the risk of common NDDs using Cox proportional hazards regression analysis. Furthermore, we performed genetic correlation and Mendelian randomization analyses based on summary statistics from genome-wide association studies.

RESULTS: A higher level of serum creatinine at baseline was associated with a lower risk of incident amyotrophic lateral sclerosis (ALS) (beta=-0.013, SE = 0.004, P = 1.88E-03). From the genetic perspective, a significant and negative genetic correlation was identified between serum creatinine and ALS risk (genetic correlation: -0.17, P = 0.017). Mendelian randomization analysis corroborated the primary finding, indicating that serum creatinine was associated with a reduced risk of ALS (OR: 0.92, 95% CI: 0.86-0.98, P = 0.01). Moreover, a higher level of baseline serum creatinine was associated with a reduced risk of incident Alzheimer's disease (beta=-4.89E-03, SE = 2.24E-03, P = 0.03), though the effect size was small.

CONCLUSIONS: These findings enhance our understanding of creatinine's role in the risk of NDDS, suggest the potential of targeting creatinine as a biomarker of ALS, and hold implications for designing therapeutic interventions in clinical trials.},
}

@article {pmid40643479,
year = {2025},
author = {Sgromo, C and Tosi, M and Olgasi, C and De Marchi, F and Favero, F and Venturin, G and Piola, B and Cucci, A and Corrado, L and Mazzini, L and D'Alfonso, S and Follenzi, A},
title = {Identification of Transcriptomic Differences in Induced Pluripotent Stem Cells and Neural Progenitors from Amyotrophic Lateral Sclerosis Patients Carrying Different Mutations: A Pilot Study.},
journal = {Cells},
volume = {14},
number = {13},
pages = {},
doi = {10.3390/cells14130958},
pmid = {40643479},
issn = {2073-4409},
support = {N. 68155.//The study was supported by the AGING Project for Department of Excellence at the Department of Translational Medicine (DIMET), Università del Piemonte Orientale, Novara, Italy and DIG-ALS, AriSLA Foundation. AF was supported by CSP - Compagnia San Paolo T/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Induced Pluripotent Stem Cells/metabolism/pathology ; Pilot Projects ; Kruppel-Like Factor 4 ; *Mutation/genetics ; *Transcriptome/genetics ; *Neural Stem Cells/metabolism/pathology ; Female ; Middle Aged ; Male ; Cell Differentiation ; C9orf72 Protein/genetics ; Aged ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons with a phenotypic and genetic heterogeneity and elusive molecular mechanisms. With the present pilot study, we investigated different genetic mutations (C9orf72, TARDBP, and KIF5A) associated with ALS by generating induced pluripotent stem cells (iPSCs) from peripheral blood of ALS patients and healthy donors. iPSCs showed the typical morphology, expressed stem cell markers both at RNA (OCT4, SOX2, KLF4, and c-Myc) and protein (Oct4, Sox2, SSEA3, and Tra1-60) levels. Moreover, embryoid bodies expressing the three germ-layer markers and neurospheres expressing neural progenitor markers were generated. Importantly, the transcriptomic profiles of iPSCs and neurospheres were analyzed to highlight the differences between ALS patients and healthy controls. Interestingly, the differentially expressed genes (DEGs) shared across all ALS iPSCs are linked to extracellular matrix, highlighting its importance in ALS progression. In contrast, ALS neurospheres displayed widespread deficits in neuronal pathways, although these DEGs were varied among patients, reflecting the disease's heterogeneity. Overall, we generated iPSC lines from ALS patients with diverse genetic backgrounds offering a tool for unravelling the intricate molecular landscape of ALS, paving the way for identifying key pathways implicated in pathogenesis and the disease's phenotypic variability.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology
*Induced Pluripotent Stem Cells/metabolism/pathology
Pilot Projects
Kruppel-Like Factor 4
*Mutation/genetics
*Transcriptome/genetics
*Neural Stem Cells/metabolism/pathology
Female
Middle Aged
Male
Cell Differentiation
C9orf72 Protein/genetics
Aged

@article {pmid40643147,
year = {2025},
author = {Vélez-Gómez, B and Cabrera-Serrano, M and Paradas, C},
title = {Utilization of patient-reported outcome measures in amyotrophic lateral sclerosis management: a cross-sectional study of Spanish neurologists.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2025.2523940},
pmid = {40643147},
issn = {2167-9223},
abstract = {Objective: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that significantly impacts quality of life. Patient-Reported Outcome Measures (PROMs) offer a patient-centered approach by capturing self-reported assessments of symptoms and well-being. Despite their recognized value, PROM integration into ALS management remains inconsistent. This study evaluates the attitudes, practices, and barriers experienced by Spanish neurologists regarding PROM use in ALS care. Methods: A cross-sectional survey was distributed to Spanish neurologists specializing in neuromuscular disorders. The questionnaire assessed familiarity with and use of PROMs, as well as perceived benefits and barriers to their implementation. Statistical analysis included descriptive statistics, group comparisons, and exploratory factor analysis (EFA) to identify underlying factors influencing PROM use. Results: Among 60 neurologists surveyed, 93.3% were familiar with PROMs, yet only 18.3% used them routinely. PROM use did not vary significantly with years of experience, type of clinical setting, exclusive dedication to neuromuscular disorders, or the percentage of time spent on patient care. The only variable approaching significance was the number of ALS patients managed daily, with higher patient volumes associated with more frequent PROM use. Over 70% of non-users cited limited consultation time as a barrier; however, factor analysis indicated that time constraints were not a substantial limitation. PROMs were valued for supporting clinical decision-making, monitoring disease progression, and improving patient engagement. Conclusions: While PROMs are widely recognized for their potential in ALS care, barriers hinder their use. Targeted training, simplified tools, and culturally adapted PROMs are needed to facilitate broader adoption and improve outcomes.},
}

@article {pmid40642867,
year = {2025},
author = {Pang, C and Cao, W and Xie, J and Li, Y and Zhu, L and Yu, H and Fan, D and Deng, B},
title = {Prediagnosis Insights Into Amyotrophic Lateral Sclerosis: Clinical Symptoms and Medication Use.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {16},
number = {4},
pages = {e70003},
doi = {10.1002/jcsm.70003},
pmid = {40642867},
issn = {2190-6009},
support = {81901273//National Natural Science Foundation of China/ ; ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/epidemiology/mortality ; Female ; Male ; Aged ; Middle Aged ; Incidence ; United Kingdom/epidemiology ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) has a prolonged latency period, though its preclinical characteristics remain poorly understood. This study uses UK Biobank data to explore and compare ALS's pre-diagnostic features, including symptoms and medication use, aiming to provide insights into the disease's underlying mechanisms.

METHODS: Clinical symptoms and medications were identified from self-reports, hospital records, and death registry data. Propensity score matching was used to match ALS with Alzheimer's disease (AD) and Parkinson's disease (PD), ensuring balance in socioeconomic factors to compare symptoms 0-5 years before diagnosis. Cox regression analysis was applied to assess the associations between medication use and the risk of incident ALS and mortality after ALS diagnosis.

RESULTS: A total of 753 ALS cases were observed in 502 417 participants, with an incidence rate of 10.58 per 100 000 person-years. In the ALS cohort, the male-to-female ratio was 2.9, with a median age at onset of 64.61 years (Interquartile range (IQR): 56.80-71.31) and a median survival time post-diagnosis of 9.08 months (IQR: 3.18-18.98), while females (log-rank p = 0.038) and individuals with earlier (< 64.61 years) disease onset (log-rank p < 0.001) had longer survival periods. In the 5 years prior to diagnosis, ALS showed a higher incidence of falls compared to ad (11.3% vs. 3.2%, p < 0.001), but a lower incidence than PD (10.7% vs. 28.3%, p < 0.001). Additionally, ALS had a lower incidence of depression (4.6% vs. 25.6%, p < 0.001), anxiety (3.5% vs. 18.1%, p < 0.001), sleep disorders (1.4% vs. 7.2%, p < 0.001), hypotension (3.4% vs. 30.5%, p < 0.001), constipation (0.3% vs. 4.9%, p < 0.001), and urinary dysfunction (2.2% vs. 8.7%, p < 0.001) compared with PD. The use of calcium channel blockers may be a risk factor for incident ALS (adjusted HR 1.61, 95% CI: 1.22-2.12, p < 0.001).

CONCLUSIONS: Pre-diagnostic presentations of falls are more frequent in ALS than in AD, but less frequent than in PD. However, ALS exhibits fewer psychiatric symptoms and autonomic dysfunction compared with PD. The use of calcium channel blockers may be associated with an increased risk of developing ALS in the future.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/epidemiology/mortality
Female
Male
Aged
Middle Aged
Incidence
United Kingdom/epidemiology

@article {pmid40642215,
year = {2025},
author = {Ahmed, Z and Samaddar, S and Hassieb, M and Sadek, R and Morozova, V and Begum, S},
title = {Multi-path direct current spinal stimulation extended survival in the SOD1-G93A model of amyotrophic lateral sclerosis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1594169},
pmid = {40642215},
issn = {1664-2295},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons in the spinal cord and brain. We have developed a novel non-invasive approach, MultiPath-DCS, which utilizes direct current stimulation at multiple sites along the neural axis to provide simultaneous spinal and peripheral stimulation targeted at the affected limbs. MultiPath-DCS modulates the excitability of spinal cord neurons. This effect is significant for ALS, as motor neuron hyperexcitability is a fundamental characteristic of the disease.

METHODS: This study used a transgenic mouse model of ALS (SOD1-G93A). Anodal-MultiPath-DCS was applied with six electrodes: three on the spine (centered on T13 and with an anodal polarity), two on the sciatic nerves (one on each nerve), and one on the abdomen. Mice were divided into two groups (stimulated vs. unstimulated or sham-stimulated). The stimulated animals received stimulation for one hour a day, three times a week, for three weeks. Survival was calculated from the onset of the disease and birth until the animal's endpoint. We also performed various electrophysiological and molecular experiments to uncover the mechanism of action.

RESULTS: We demonstrated molecular changes induced by anodal MultiPath-DCS, including (a) reduced expression of mutant SOD1 protein, (b) decreased expression of elevated NKCC1, (c) reduced phosphorylated tau, (d) increased expression of HSP70, and (e) increased expression of LC3B. Additionally, we found that treatment with Anodal-MultiPath-DCS (anode on the spinal column) reduces long-term neuronal spinal excitability, slows the progression of muscle weakness, and extends the lifespan of stimulated mice. The mean survival time in the control group was 12.4 days. In comparison, the mean survival time in the stimulated group was 21.6 days using a therapeutic stimulation paradigm, representing a 74% increase in survival from disease onset. Spinal motor neuron survival showed a 54% increase in stimulated compared to non-stimulated groups.

DISCUSSION: Combined, this data provides evidence that Anodal-MultiPath-DCS reduces hyperexcitability and enhances the clearance of misfolded proteins by modulating autophagy and proteolytic systems. By decreasing spinal excitability and clearing toxic proteins from motor neurons, Anodal-MultiPath-DCS promotes survival and could serve as a disease-modifying intervention for ALS.},
}

@article {pmid40641248,
year = {2025},
author = {Yang, K and Liu, Y and Deng, W and Gong, Z and Huang, L and Li, Z and Zhang, M},
title = {Astrocytes Contribute to Motor Neuron Degeneration in ALS via the TRAIL-DR5 Signaling Pathway.},
journal = {Journal of neurochemistry},
volume = {169},
number = {7},
pages = {e70146},
doi = {10.1111/jnc.70146},
pmid = {40641248},
issn = {1471-4159},
support = {2024AOXIANG05//Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital/ ; 82271478//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Motor Neurons/pathology/metabolism ; Mice ; *TNF-Related Apoptosis-Inducing Ligand/metabolism ; *Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism ; *Signal Transduction/physiology ; *Astrocytes/metabolism/pathology ; *Nerve Degeneration/pathology/metabolism ; Mice, Transgenic ; Humans ; Superoxide Dismutase-1 ; Disease Models, Animal ; Superoxide Dismutase/genetics ; Mice, Inbred C57BL ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons. The mechanisms underlying the selective degeneration of motor neurons in ALS remain poorly understood, underscoring the need for further investigation into the factors driving this process. In this study, we utilized ALS mouse models and an in vitro NSC34 motor neuron cell line expressing the SOD1[G93A] mutation to identify a novel pathogenic mechanism wherein astrocyte-secreted Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to Death Receptor 5 (DR5)on motor neurons, leading to caspase-8 activation and subsequent neuronal death. Blocking DR5 with neutralizing antibodies significantly attenuated TRAIL-induced motor neuron death. These findings provide the first evidence that TRAIL may serve as a potential therapeutic target in ALS, offering new insights into the mechanisms of motor neuron degeneration in this disease.},
}

Animals
*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics
*Motor Neurons/pathology/metabolism
Mice
*TNF-Related Apoptosis-Inducing Ligand/metabolism
*Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism
*Signal Transduction/physiology
*Astrocytes/metabolism/pathology
*Nerve Degeneration/pathology/metabolism
Mice, Transgenic
Humans
Superoxide Dismutase-1
Disease Models, Animal
Superoxide Dismutase/genetics
Mice, Inbred C57BL

@article {pmid40641139,
year = {2025},
author = {Sun, Y and Wei, K and Liao, X and Wang, J and Gao, L and Pang, B},
title = {Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review).},
journal = {International journal of molecular medicine},
volume = {56},
number = {3},
pages = {},
doi = {10.3892/ijmm.2025.5580},
pmid = {40641139},
issn = {1791-244X},
mesh = {*Microglia/metabolism/pathology ; Humans ; *Lipid Metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and neuroinflammation, with microglial dysfunction emerging as a central driver of pathogenesis. Microglia, the central nervous system‑resident immune cells, exhibit dual pro‑inflammatory and anti‑inflammatory phenotypes, dynamically regulated by lipid metabolic reprogramming. Chronic activation of M1 microglia exacerbates neuronal damage, while M2 microglia promote tissue repair via phagocytic clearance and neurotrophic factor secretion. Lipid dysregulation‑marked by ceramide accumulation, cholesterol esterification defects and oxidized lipid‑driven neuroinflammation‑critically modulates microglial polarization. Mechanistic studies reveal that mitochondrial dysfunction, lysosomal stress and ferroptosis intersect with lipid metabolic pathways to amplify neurotoxicity. Therapeutic strategies targeting lipid homeostasis, such as TREM2 agonism, demonstrate efficacy in preclinical models by restoring microglial function and mitigating pathology. This review synthesizes emerging evidence linking microglial lipid metabolism to NDD progression, highlighting novel biomarkers and therapeutic avenues to disrupt the lipid‑neuroinflammation axis in neurodegeneration.},
}

*Microglia/metabolism/pathology
Humans
*Lipid Metabolism
Animals
*Neurodegenerative Diseases/metabolism/pathology/therapy

@article {pmid40640965,
year = {2025},
author = {Wright, K and Warren, F and Bucci, S and Dunn, BD and Jones, S and O'Mahen, H and Taylor, RS and Medina-Lara, A},
title = {A study protocol for a randomized controlled feasibility trial of behavioural therapy for interepisode bipolar symptoms (STABILISE).},
journal = {Pilot and feasibility studies},
volume = {11},
number = {1},
pages = {97},
pmid = {40640965},
issn = {2055-5784},
support = {NIHR302220//National Institute for Health and Care Research/ ; },
abstract = {BACKGROUND: In between episodes of (hypo) mania and major depression, people with bipolar disorder can experience ongoing low mood or mood instability, and these may also be present as part of cyclothymic disorder. This is a phase II evaluation of an adapted form of behavioural therapy (STABILISE) for inter-episode bipolar symptoms. The study aims to establish the feasibility and acceptability of the therapy and research procedures, including an economic component, to inform a future definitive trial.

METHODS: Patients will be randomised 1:1 to either Treatment as Usual (control arm) or Treatment as Usual plus STABILISE intervention (intervention arm). Follow up points will be at 14, 30 and 52 weeks post eligibility confirmation, with 30 weeks as the primary end point. We aim to recruit 60 individuals meeting diagnostic criteria for a Bipolar Spectrum Disorder, and reporting ongoing bipolar symptoms (low mood or mood instability) outside of a manic or severe depressive episode. Feasibility and acceptability will be examined through recruitment and retention rates, completion rates for the candidate primary outcome measures (PHQ9, ALS-SF, QoL.BD and BRQ) and feedback from participants on their experience of study participation and therapy. Proceeding to a definitive trial will be indicated if the following criteria are met: (i) trial participation is deemed, or can be made, sufficiently safe; (ii) recruitment rate indicates that larger-scale recruitment would be feasible (recruitment rate of at least two participants per month within at least one site, with mitigation plan if overall target sample size not met); (iii) for candidate primary outcome measure follow up data is available at 30 weeks from at least 75% of participants, or from between 55 and 74% with clear plan for improvement.

DISCUSSION: This study is a randomised, controlled feasibility trial that builds on an initial case series of the STABILISE approach. The findings will be used to establish whether a future, definitive trial is feasible and to refine the research procedures and therapy protocol.

TRIAL REGISTRATION: ISRCTN18207465. Registered 13th March 2024, https://www.isrctn.com/ISRCTN18207465 .},
}

@article {pmid40640916,
year = {2025},
author = {Lemarchant, S and Engelhardt, B and Cicchetti, F and Bix, GJ and Janus, A and Godfrin, Y and Blasco, H and Campbell, M and de Rus Jacquet, A},
title = {Restoring brain barriers: an innovative approach for treating neurological disorders.},
journal = {Fluids and barriers of the CNS},
volume = {22},
number = {1},
pages = {72},
pmid = {40640916},
issn = {2045-8118},
abstract = {The complex etiology of neurological disorders is a major challenge to the identification of therapeutic candidates. Tackling brain vascular dysfunction is gaining attention from the scientific community, neurologists and pharmaceutical companies, as a novel disease-modifying strategy. Here, we provide evidence that at least 41% of neurological diseases and related conditions/injuries display a co-pathology of blood-brain and blood-spinal cord barrier alterations and dysfunctions, and we discuss why this figure may represent only a fraction of a larger phenomenon. We further provide clinical evidence that barrier status may contribute to pathological and functional outcomes in patients. Finally, we discuss drug candidates under development to repair brain barriers.},
}

@article {pmid40640892,
year = {2025},
author = {Noh, MY and Kwon, HS and Kwon, MS and Nahm, M and Jin, HK and Bae, JS and Kim, SH},
title = {Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {82},
pmid = {40640892},
issn = {1750-1326},
support = {RS-2024-00348451//Korea Dementia Research Center/ ; },
abstract = {Recent advances in our understanding of non-cell-autonomous mechanisms in neurodegenerative diseases (NDDs) have highlighted microglial dysfunction as a core driver of disease progression. Conditions such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and frontotemporal dementia (FTD) share features of impaired microglial phagocytosis, chronic neuroinflammation, and metabolic dysregulation. These insights have prompted new therapeutic strategies targeting microglial function and emphasized the need for reliable biomarkers to monitor disease progression and treatment response. Well-established therapeutic targets, such as triggering receptor expressed on myeloid cells 2 (TREM2), progranulin (PGRN), and sortilin (SORT1), along with emerging candidates including LILRB4, P2Y6R, TAM receptors, and neuroinflammation-related markers, are discussed alongside novel blood, cerebrospinal fluid (CSF), and imaging biomarkers. Despite notable progress, many of these biomarkers remain restricted to preclinical studies and face translational challenges due to species-specific differences, lack of standardization, and clinical heterogeneity. Emerging technologies-including single-cell omics, spatial transcriptomics, and artificial intelligence (AI)-driven integration of multimodal data-offer new opportunities to align biomarker profiles with evolving disease states and improve patient stratification. Building on the model of companion diagnostics (CDx) in oncology, integrating multimodal biomarker strategies holds promise for guiding personalized interventions, improving clinical outcomes, and deepening our mechanistic understanding of microglial contributions across the neurodegenerative spectrum.},
}

@article {pmid40640855,
year = {2025},
author = {Soliman, SS and Talib, NFA and Elghobashy, MR and Rahman, MAA},
title = {Sustainable analysis of COVID-19 Co-packaged paxlovid: exploring advanced sampling techniques and multivariate processing tools.},
journal = {BMC chemistry},
volume = {19},
number = {1},
pages = {206},
pmid = {40640855},
issn = {2661-801X},
abstract = {The drawbacks of random sampling not only hinder the development of more reliable and efficient methods but also weaken their accuracy, predictive abilities, and validity across several domains. During the current study, a pioneering statistical technique namely, Latin Hypercube Sampling (LHS) was integrated with different multivariate chemometric models namely; Partial Least Squares (PLS), Genetic Algorithm‑Partial Least Squares (GA-PLS), Artificial Neural Networks (ANN), and Multivariate Curve Resolution‑Alternating Least Squares (MCR-ALS). This integration aimed to achieve full data coverage and thereby enhance the predictive powers of these models. Being of clinical significance, Paxlovid[®], a newly co-packaged antiCOVID-19 drug containing ritonavir (RNV)-boosted nirmatrelvir (NMV), was utilized as a study subject to demonstrate the powerful potentials of LHS in enhancing models' robustness and predictive accuracy. The LHS technique was able to provide well-interpreted and informative samples by capturing essential variabilities across the input space without any increase in sample numbers. It was compared and outperformed the random sampling Monte Carlo technique. A comprehensive comparison between the developed models was held where the RMSEP was relatively reduced by 14.1%, 8.9%, 53.1%, and 34.6% for RNV and NMV, respectively using the ANN and MCR-ALS models. Various preprocessing techniques were employed to improve signal quality for PLS construction, yielding superior results (RMSEC of 0.19 for both RNV and NMV) compared to the original, unprocessed spectral data (RMSEC of 0.21 for both RNV and NMV). The Principal Component Analysis score plot was constructed, confirming the consistency of the dataset and the absence of systematic errors, enhancing confidence in the models' robustness. A new hybrid variable selection strategy (GA-ICOMP-PLS) was developed to enhance the robustness and parsimony of the GA-PLS model. Prediction error values of 0.15 and 0.14 were successfully achieved for RNV and NMV, respectively, indicating strong predictive power and generalization. Consistent with sustainability and eco-friendly goals, the current study pioneers the usage of green-blue-white alternatives to conventional analytical methods. A comprehensive assessment was conducted using the "Sample Preparation Metric of Sustainability", the "Analytical Greenness metric for Sample Preparation" and the "Analytical Greenness metric" alongside two solvent sustainability evaluation tools. These evaluations yielded promising results, with green quadrant classification and high scores of 5.89, 0.67, and 0.82 for each metric, respectively, as well as satisfactory t- and F-test values. Moreover, the models achieved outstanding results on the RGB12 metric and Blueness Applicability Grade Index, scoring 96.8% and 82.5, respectively, highlighting their broad applicability, high efficiency, and alignment with eco-friendly analytical practices.},
}

@article {pmid40640528,
year = {2025},
author = {McGuigan, A and Blair, HA},
title = {Tofersen: A Review in Amyotrophic Lateral Sclerosis Associated with SOD1 Mutations.},
journal = {CNS drugs},
volume = {},
number = {},
pages = {},
pmid = {40640528},
issn = {1179-1934},
abstract = {Tofersen (QALSODY[®]) is the first drug approved for the treatment of amyotrophic lateral sclerosis (ALS) associated with superoxide dismutase 1 (SOD1) mutations. Tofersen is an antisense oligonucleotide that induces SOD1 mRNA degradation. In the 28-week, placebo-controlled, multinational, phase III VALOR trial, intrathecally administered tofersen reduced plasma concentrations of neurofilament proteins (biomarker for neuro-axonal injury) and total SOD1 protein in cerebrospinal fluid in patients with SOD1 mutation-associated ALS. These reductions were sustained in a long-term, open-label extension study. The decline in functional outcomes was not significantly reduced with tofersen treatment compared with placebo in the 28-week phase III trial, although in the longer-term open-label study, early tofersen initiation was associated with slowed functional decline versus delayed tofersen initiation. Tofersen had an acceptable tolerability profile in clinical trials with a favourable benefit-to-risk balance. In summary, tofersen is a new disease-modifying therapy for patients with ALS attributed to an SOD1 mutation, offering reductions in levels of a biomarker associated with neurodegeneration and disease progression, with an acceptable tolerability profile.},
}

@article {pmid40640025,
year = {2025},
author = {Kim, S and Yang, M and Ku, B and Cha, E and Seo, W and Son, I and Kang, H and Kim, D and Song, B and Yang, CS and Kim, S},
title = {Corrigendum to "Efficacy of mecasin for treatment of amyotrophic lateral sclerosis: A phase IIa multicenter randomized double-blinded placebo-controlled trial" [J. Ethnopharmacol. 320 (2023) 116670].},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120239},
doi = {10.1016/j.jep.2025.120239},
pmid = {40640025},
issn = {1872-7573},
}

@article {pmid40639550,
year = {2025},
author = {Mondal, M and Chouksey, A and Gurjar, V and Tiwari, R and Srivasatava, RK and Mishra, PK},
title = {Micro(nano)plastics in the brain: Epigenetic perturbations in progression to neurodegenerative diseases.},
journal = {Neurotoxicology and teratology},
volume = {},
number = {},
pages = {107521},
doi = {10.1016/j.ntt.2025.107521},
pmid = {40639550},
issn = {1872-9738},
abstract = {As global plastic production escalates, micro(nano)plastics (MNPs) have become pressing ecological and biomedical concerns. These pollutants are increasingly implicated in the pathogenesis of neurodegenerative diseases. Due to their nanoscale size and surface reactivity, MNPs can cross the blood-brain barrier, accumulating in neural tissues. Once internalized, they disrupt neuronal homeostasis by inducing oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, key processes in neurodegenerative progression. Mitochondria, central to neuronal energy and redox regulation, are particularly vulnerable, leading to impaired ATP production, elevated ROS, and pro-apoptotic signaling. Recent studies reveal that MNPs also induce epigenetic changes, including aberrant DNA methylation, histone modifications, and dysregulation of non-coding RNAs. These alterations can result in synaptic instability, persistent transcriptional reprogramming, and heightened susceptibility to diseases like Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. The mitochondrial epigenome is a vital target of MNP-induced disruption, offering potential biomarkers like methylated mtDNA and microRNAs for early diagnosis and prognosis. Understanding the molecular mechanisms behind these epigenetic alterations is essential for developing practical diagnostic tools and therapies. This review provides a comprehensive overview of MNP-induced neurodegeneration, focusing on mitochondrial and epigenetic disruptions. Moreover, it explores emerging biosensing technologies for detecting MNP-induced epigenetic alterations, highlighting the urgent need for further investigation to fully understand the neurotoxic potential of MNPs and develop preventive and therapeutic strategies for mitigating their effects on brain health.},
}

@article {pmid40637865,
year = {2025},
author = {Coleman, A and Touzé, A and Farag, M and Pengo, M and Murphy, MJ and Hassan, Y and Thackeray, O and Fayer, K and Field, S and Nakajima, M and Broom, EL and Hobbs, NZ and Huxford, B and Donkor, N and Camboe, E and Dey, KC and Zirra, A and Ahmed, A and Gameiro Costa, AR and Sorrell, H and Zampedri, L and Lombardi, V and Wade, C and Mangion, S and Fneich, B and Heslegrave, A and Zetterberg, H and Scahill, R and Noyce, A and Malaspina, A and Chataway, J and Tabrizi, SJ and Byrne, LM},
title = {Evaluating finger-prick blood collection for remote quantification of neurofilament light in neurological diseases.},
journal = {Journal of neurology},
volume = {272},
number = {8},
pages = {501},
pmid = {40637865},
issn = {1432-1459},
support = {MR/W026686/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; *Neurofilament Proteins/blood ; Male ; Female ; Middle Aged ; Biomarkers/blood ; Adult ; Aged ; *Blood Specimen Collection/methods/standards ; *Nervous System Diseases/blood/diagnosis ; Cohort Studies ; Parkinson Disease/blood ; Amyotrophic Lateral Sclerosis/blood ; Huntington Disease/blood/diagnosis ; Multiple Sclerosis/blood ; },
abstract = {Promising blood-based biomarkers of neuropathology have emerged with potential for therapeutic development and disease monitoring. However, these tools will require specialist tertiary services for integration into clinical management. Remote sampling for biomarker assessment could reduce burden of in-person clinical visits for such tests as well as increasing the sampling frequency and patient geographical outreach. Here, we evaluated a finger-prick blood collection approach for remote quantification of neurofilament light (NfL), a candidate blood-based biomarker evident in various neurological disorders, and other exploratory markers of neuronal injury and neuroinflammation (GFAP, tau). Matched samples from venepuncture and finger-prick were collected and processed into plasma and/or serum to directly compare analyte levels from a multi-disease discovery cohort (n = 54 healthy controls; n = 57 Huntington's disease (HD); n = 34 multiple sclerosis; n = 7 amyotrophic lateral sclerosis; n = 11 Parkinson's disease), and a HD confirmatory cohort (n = 57 healthy controls; n = 64 HD). Two delayed processing conditions were compared, three- and seven-day delay, simulating ambient shipment. Capillary NfL and GFAP concentrations were equivalent to those in venous serum and plasma in the multi-disease discovery cohort and HD confirmatory cohort. Only NfL remained stable after a seven-day processing delay in both venous and capillary serum samples. Using NfL concentrations from capillary blood, we replicated previously published disease group differences measured in venous blood. This data supports our finger-prick approach for remote collection and quantification of NfL. With the widespread applications for NfL across the spectrum of neurological disorders, this has the potential to transform disease monitoring, prognosis, and therapeutic development within clinical practice and research.},
}

Humans
*Neurofilament Proteins/blood
Male
Female
Middle Aged
Biomarkers/blood
Adult
Aged
*Blood Specimen Collection/methods/standards
*Nervous System Diseases/blood/diagnosis
Cohort Studies
Parkinson Disease/blood
Amyotrophic Lateral Sclerosis/blood
Huntington Disease/blood/diagnosis
Multiple Sclerosis/blood

@article {pmid40635530,
year = {2025},
author = {Manicardi, A and Mora, G and Araujo, ALS and Gaines, TA and Lozano-Juste, J and Torra, J},
title = {Analysis of multiple-herbicide resistant Amaranthus palmeri populations from Spain points to an introduction of the eccDNA from America.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.70034},
pmid = {40635530},
issn = {1526-4998},
support = {PRTR-C17.I1//European Union NextGenerationEU, AGROALNEXT, GVA/ ; 801586//H2020 Marie Skłodowska-Curie Actions/ ; PID2020-113229RB-C42//Spanish State Research Agency and the European Regional Development Fund, EU (ERDF)/ ; PID2021-128826OAI00//Spanish MCIN/AEI/ ; RYC2020-029097-I//Spanish MCIN/AEI/ ; RYC2018-023866-I//Spanish MCIN/AEI/ ; CISEJI/2022/26//Generalitat Valenciana, Plan GenT/ ; RED2022-134285-T(PalmerNET)//Spanish Ministry of Science and Innovation/ ; },
abstract = {BACKGROUND: The herbicide-resistant invasive weed species Amaranthus palmeri threatens agricultural production and native plant ecology in Spain, as well as in other European countries. Understanding whether herbicide resistance alleles evolve in situ or are introduced via gene flow remains unclear. To address this, we characterized multiple resistance to acetolactate synthase (ALS)-- and 5-enolpyruvylshikimate-3phosphate synthase (EPSPS)-inhibiting herbicides in two Spanish A. palmeri populations at the plant level. Additionally, we analyzed the extra-chromosomal circular DNA (eccDNA) to determine whether glyphosate resistance resulted from local selection pressure or was introduced by gene flow.

RESULTS: Both populations exhibit individuals that survived both herbicide MoA, with multiple resistance mechanisms to ALS- and EPSPS-inhibiting herbicides. Eight different ALS allele mutations were identified in resistant plants, including Pro-197-Ile, reported only in one species previously. Glyphosate resistance in the two populations is to the result of gene duplication mediated by eccDNA. Spanish and North American eccDNAs showed complete identity, with no single nucleotide polymorphisms (SNPs) found between the partial analyzed sequences of noncoding regions.

CONCLUSION: We confirm for the first time in Europe resistance to ALS and EPSPS inhibitors at both the population and individual levels in two Spanish A. palmeri populations. The absence of SNPs in the eccDNA from Spanish populations compared to the reference American sequence and the presence of target-site mutations in the ALS gene occurred without selective pressure from ALS herbicides, suggests that the origin of resistance traits may have evolved elsewhere and been introduced from the place of origin to Spain. However, it is important to note that the limited number of populations studied and the partial sequencing of eccDNA do not provide definitive confirmation of the exact origins of resistance mechanisms. This work raises concerns about the arrival of this and potentially other new herbicide-resistant A. palmeri populations in Europe posing challenges for management. © 2025 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.},
}

@article {pmid40633900,
year = {2025},
author = {Singh, N and Mishra, D and Gomes, J},
title = {Deleterious Sequestosome 1 mutations G262R and P438L in amyotrophic lateral sclerosis cause autophagy and oxidative stress imbalance.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.07.011},
pmid = {40633900},
issn = {1873-7544},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease (NDD) prevalent across the world. It is known that mutations in ALS associated genes can cause imbalances between cellular processes such as apoptosis, necroptosis, autophagy and proteasomal degradation that remove dysfunctional and aggregating proteins. Two rare missense variants namely G262R (G > A) and P438L (C > T) in Sequestosome 1 (SQSTM1), were identified by our group in a cohort of Indian ALS patients. SQSTM1 codes for p62, which is an autophagy adaptor protein involved in several signaling pathways. In this study, we investigated how these SQSTM1 mutations affect autophagy and the oxidative stress response pathway in SH-SY5Y cells through quantitative RT-PCR, immunoblotting and confocal microscopy. In addition, we examined how changes in the downstream signaling pathways alters nuclear-cytoplasmic localization of TDP-43 protein, a marker protein usually found in cytoplasmic inclusions in ALS patient tissues. We observed up-regulation of autophagy marker proteins LC3-II and ubiquitin, and down-regulation of oxidative stress marker protein Nrf2. Along with LC3-II, p-OPTN and ATG5, proteins that are also associated with autophagy were up-regulated. We also observed an increase in cytoplasmic localization of TDP-43 protein in cells expressing these p62 mutant proteins. Overall, our study provides evidence that the G262R (G > A) and P438L (C > T) mutations are deleterious through mechanisms that increase cytoplasmic localization of TDP-43, and adversely affect the autophagy and oxidative stress response pathway.},
}

@article {pmid40633079,
year = {2025},
author = {Al-Akeedi, JM and Khudiar, HH and Al Muhtaser, STM and Al-Fahham, AA},
title = {Genotypes of Candida albicans and its cooperative interaction with Streptococci isolated from throat infections.},
journal = {Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego},
volume = {53},
number = {3},
pages = {378-383},
doi = {10.36740/Merkur202503112},
pmid = {40633079},
issn = {1426-9686},
mesh = {*Candida albicans/genetics/isolation & purification/physiology ; Humans ; Genotype ; Biofilms/growth & development ; *Streptococcus/isolation & purification/genetics/physiology ; *Streptococcal Infections/microbiology ; *Pharyngitis/microbiology ; },
abstract = {OBJECTIVE: Aim: This study was aimed to detect and determine genotypes of Candida albicans and its cooperative interaction with streptococci isolated from throat infections.

PATIENTS AND METHODS: Materials and Methods: This survey was carried out during November 2023 and March 2024 to collect a total of 80 throat swab samples from patients in in Al-Sadr Medical City in Najaf during. Candida was isolated from culturing throat swab samples on Sabouraud agar, and Blood agar. Each isolate (Candida & Streptococci) enhanced in monoculture using enrichment media; Potato Dextrose broth. Molecular assay included detecting three of biofilm forming genes; Als1, Als2, Als3.

RESULTS: Results: Twelve out of fifteen Candida isolates showed increase in number after mixing with Streptococci and incubation. In contrast, three isolates showed no change or decrease after mixing in co-culture media. Five Candida isolates (out of 15 isolates) were positive in gel electrophoresis to three biofilm genes classified as first genotype (CALSG1). Four Candida isolates were negative in gel electrophoresis to three biofilm genes, classified as second genotype (CALSG2). Other Candida isolates were positive to one or two of three biofilm genes, classified with genotypes (CALSG3, CALSG4, CALSG5 and CALSG6).

CONCLUSION: Conclusions: Candida albicans has biofilm formation genes (Als), which attract other organisms, like streptococci resulting in synergistic interaction. Despite the presence of some Als genes, it's not necessary to found strong biofilm results as Als genes may not be translated to form biofilm.},
}

*Candida albicans/genetics/isolation & purification/physiology
Humans
Genotype
Biofilms/growth & development
*Streptococcus/isolation & purification/genetics/physiology
*Streptococcal Infections/microbiology
*Pharyngitis/microbiology

@article {pmid40632651,
year = {2025},
author = {Dos Santos, M and Bezprozvannaya, S and McAnally, JR and Cai, C and Liu, N and Olson, EN},
title = {A mechanistic basis of fast myofiber vulnerability to neuromuscular diseases.},
journal = {Cell reports},
volume = {44},
number = {7},
pages = {115959},
doi = {10.1016/j.celrep.2025.115959},
pmid = {40632651},
issn = {2211-1247},
abstract = {Neuromuscular diseases such as amyotrophic lateral sclerosis and sarcopenia cause muscle atrophy, which preferentially affects fast-twitch glycolytic myofibers. The mechanisms underlying the susceptibility of fast myofibers to disease remain unclear. To investigate this, we analyzed the transcriptional profiles of myonuclei from denervated muscle fibers. We found that the fast muscle gene program and the transcription factor Maf were repressed upon denervation. Overexpression of Maf in mice prevented loss of muscle mass caused by denervation by repressing atrophic genes and restoring fast gene expression. Similar repression of fast genes and Maf was observed in muscles from mice and humans with amyotrophic lateral sclerosis. Notably, Maf overexpression in human skeletal muscle cells in vitro prevented muscle atrophy and activated the expression of fast muscle genes. Our findings highlight a key role for Maf in maintaining muscle mass and could offer a promising therapeutic strategy to preserve muscle function during disease, aging, and injury.},
}

@article {pmid40632556,
year = {2025},
author = {Shaked, R and Katz, M and Cohen-Dvashi, H and Diskin, R},
title = {The prefusion structure of the HERV-K (HML-2) Env spike complex.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {28},
pages = {e2505505122},
doi = {10.1073/pnas.2505505122},
pmid = {40632556},
issn = {1091-6490},
support = {209/20//Israel Science Foundation (ISF)/ ; },
mesh = {*Endogenous Retroviruses/chemistry/metabolism/genetics ; Cryoelectron Microscopy ; Humans ; Models, Molecular ; *Gene Products, env/chemistry/metabolism ; },
abstract = {The human endogenous retrovirus K (HERV-K) is a retrovirus that got assimilated into the human genome in ancient times and has been inherited in our germline ever since. It enters cells using a class-I spike protein (Env) that mediates receptor recognition and membrane fusion. On top of having a biological role during development, HERV-K is activated in amyotrophic lateral sclerosis, various cancers, and other pathological conditions. Antibodies that target the HERV-K spike complex have therapeutic value, flagging the spike as a novel drug target. Here, we use cryo-EM to determine the trimeric structure of the HERV-K spike. The spike presents a distinct structure, which substantially differs from other class-I fusogens. Nevertheless, some general architectural features suggest a common origin with other retroviruses. The ability to structurally characterize the HERV-K spike may facilitate the development of antibody-based therapies.},
}

*Endogenous Retroviruses/chemistry/metabolism/genetics
Cryoelectron Microscopy
Humans
Models, Molecular
*Gene Products, env/chemistry/metabolism

@article {pmid40631777,
year = {2025},
author = {LaBarge, B and Lorenz, FJ and Gniady, JP},
title = {Association of Laryngeal Dystonia With Common Neurologic Disorders.},
journal = {The Laryngoscope},
volume = {},
number = {},
pages = {},
doi = {10.1002/lary.32407},
pmid = {40631777},
issn = {1531-4995},
support = {UL1 TR002014/TR/NCATS NIH HHS/United States ; },
abstract = {OBJECTIVE: Laryngeal dystonia is a heterogenous disorder consisting of involuntary spasms of laryngeal muscles. There are multiple forms including adductor, abductor, and mixed phenotypes. The disorder is thought to be multifactorial, with various reported associations with family history of dystonia or movement disorders. The relationship between laryngeal dystonia and various neurologic disorders is not well defined in the literature.

METHODS: We utilized the TriNetX de-identified electronic medical record database system spanning 2010-2023 to assess the prevalence of laryngeal dystonia with common neurologic disorders, compared to an age-sex matched control population. We included patients with the laryngeal spasm J38.5 ICD-10 code and 64617 CPT code, in order to categorize laryngeal dystonia patients undergoing chemodenervation.

RESULTS: The patient cohort consisted of approximately 4000 patients. 75% were female, 71% were white, and the mean age was 61 years. The laryngeal dystonia population had an elevated relative risk of Parkinson's disease (RR = 2.7, 1.8-3.9, 95% CI). In contrast, the relative risk of Alzheimer's disease was decreased in the laryngeal dystonia population (RR = 0.28, 0.16-0.48, 95% CI). There were no differences between the laryngeal dystonia and control populations for multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, migraine, muscular dystrophy, or cerebral palsy.

CONCLUSION: Laryngeal dystonia patients have a significantly greater association with Parkinson's disease and less association with Alzheimer's disease compared to the control population. There were no meaningful associations with the remainder of the neurologic conditions included in the study.},
}

@article {pmid40631187,
year = {2025},
author = {Scheutzow, AN and Thanthirige, S and Siffer, G and Sorkin, AD and Wohlever, ML},
title = {E3 ligase recruitment by UBQLN2 protects substrates from proteasomal degradation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.04.602059},
pmid = {40631187},
issn = {2692-8205},
abstract = {Ubiquilins are a family of proteins critical to cellular proteostasis that are also linked to several neurodegenerative diseases, with specific mutations in UBQLN2 causing dominant, X-linked ALS. Despite an initial characterization as proteasomal shuttle factors, Ubiquilins have paradoxically been reported to stabilize numerous substrates. The basis of this triage decision remains enigmatic. Many other fundamental aspects of Ubiquilin function are unclear at the mechanistic level, such as the physiological significance of Ubiquilin phase separation, the unique role of each Ubiquilin paralog, and the mechanistic defects of ALS mutants. To address these questions, we utilized a library of triple knockout (TKO) rescue cell lines with physiological expression of single Ubiquilin paralogs or disease mutants in an isogenic background. Our findings reveal that UBQLN2 has a unique ability to protect substrates from degradation and that substrate stabilization correlates with the recruitment of multiple E3 ligases, including SCF [bxo7] . We propose that E3 ligase recruitment promotes UBQLN2 phase separation, which protects substrates from proteasomal degradation. Consistent with this model, we demonstrate that ALS mutants, which were previously shown to have altered phase separation properties, also show a defect in substrate stabilization. Finally, we show that substrate stabilization appears to be a general feature of proteins that interact with the UBQLN2 Sti1 domains as amyloid precursor protein (APP) is also protected from proteasomal degradation by the formation of biomolecular condensates. This proposal unifies many existing observations in the field and presents a new paradigm for understanding Ubiquilin function in neurodegenerative disease.},
}

@article {pmid40630909,
year = {2025},
author = {Peller, J and Trevisan, MA and Bujia, G and Aguirre, F and Shalom, DE and Taitz, A and Henze, S and Bastola, S and Osik, J and Shewcraft, RA and Jiang, P and Schwartz, J and Heiman-Patterson, T and Sherman, ME and Wipperman, MF and Levy, O and Shou, G and Sillay, KA and Ostrow, LW and Fraenkel, E and Berry, JD and Navar Bingham, I and Roitberg, EG},
title = {Reliable monitoring of respiratory function with home spirometry in people living with amyotrophic lateral sclerosis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1588992},
pmid = {40630909},
issn = {1664-2295},
abstract = {INTRODUCTION: Monitoring respiratory function is essential for assessing the progression of Amyotrophic Lateral Sclerosis (ALS) and planning interventions. Remote pulmonary function testing offers a promising alternative to in-clinic visits by reducing participant burden and enabling more frequent and accessible measurements.

METHODS: To evaluate the feasibility and reliability of home-based spirometry in ALS, we built on the Radcliff Study, a fully remote, longitudinal, exploratory study conducted at home by 67 people with ALS (pALS). After an initial training period, participants managed their coaching autonomously, performing spirometry independently or requesting assistance from trained personnel.

RESULTS: We demonstrate that combining flexible coaching with a predefined automatic quality control protocol yields consistent and reliable spirometry results for tracking respiratory function over time. This approach reveals that home-measured Slow Vital Capacity (SVC) and Forced Vital Capacity (FVC) evolve similarly and follow a linear trajectory throughout the study period (7.7 ± 4.0 months), in both slow and fast progressor subpopulations.

DISCUSSION: The observed linearity in respiratory trajectories supports the potential for early and accurate estimation of progression, reinforcing the feasibility of less frequent monitoring without compromising assessment precision and reducing the burden on both pALS and the healthcare system. Furthermore, our results align with reported in-clinic pulmonary tests, validating remote monitoring as a means to promote more equitable and accessible clinical trial designs.},
}

@article {pmid40629851,
year = {2025},
author = {Lawless, MJ and Chan, N and Patel, K and Wang, M and Colter, DC},
title = {Qualification of a electrochemiluminescence assay for the detection of human urinary neurotrophin receptor p75.},
journal = {Bioanalysis},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/17576180.2025.2529147},
pmid = {40629851},
issn = {1757-6199},
abstract = {The extracellular domain of the neurotrophin receptor p75 has been shown to be a prominent biomarker for both disease diagnosis and progression for amyotrophic lateral sclerosis. This urinary analyte may serve as a valuable fluid biomarker which greatly increases the ease of sample collection in both healthy volunteers and patients. In this paper, the method development and validation for an electrochemiluminescence assay is described. This assay completely uses commercially available reagents and can be performed using common lab equipment found in most bioanalytical labs. This method shows good accuracy and precision, high sensitivity as well as good parallelism illustrating the ability of the method to detect and report on urinary concentrations of neurotrophin receptor p75. The assay can quantitate as low as 78 pg/mL of neurotrophin receptor p75 and > 98% of healthy urine samples tested fell within the dynamic range of the assay.},
}

@article {pmid40629698,
year = {2025},
author = {Murdock, BJ and Park, J and Jang, DG and Zhao, B and Teener, SJ and Webber-Davis, IF and Zhao, L and Feldman, EL and Goutman, SA},
title = {In Vitro Modeling of Natural Killer Cell Cytotoxicity to Inform Personalized ALS Therapeutics.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70127},
pmid = {40629698},
issn = {2328-9503},
support = {//Sinai Medical Staff Foundation/ ; //Coleman Discovery Fund/ ; //Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar Fund/ ; //NeuroNetwork for Emerging Therapies at the University of Michigan/ ; R01TS000339/ACL/ACL HHS/United States ; R01NS120926/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; AL200064//U.S. Department of Defense/ ; 20-IIA-431//ALS Association/ ; //Hiller and Novak Families/ ; //Peter R. Clark Fund for ALS Research/ ; //Scott L. Pranger/ ; },
abstract = {OBJECTIVE: Natural killer (NK) cells might contribute to motor neuron death in amyotrophic lateral sclerosis (ALS) through direct cytotoxicity, a process that could be inhibited with the FDA-approved JAK/STAT pathway inhibitor, tofacitinib. This study aimed to verify that tofacitinib can suppress NK cell cytotoxicity, investigate if immune cell profiles can predict responsiveness to tofacitinib, and assess the role of NK cell cytotoxicity in ALS progression.

METHODS: Primary NK cells were isolated from peripheral blood samples of ALS participants and healthy controls. NK cells were then co-cultured with target cancer cells, with or without tofacitinib, to assess their cytotoxic activity. Flow cytometry was used to generate immune profiles for each participant, based on 154 immune markers, to explore correlations with NK cell cytotoxicity and response to tofacitinib. The potential association between NK cell cytotoxicity and disease severity, as measured by the revised ALS Functional Rating Scale, was also assessed. All analyses were stratified by age and sex.

RESULTS: Tofacitinib effectively reduced the cytotoxicity of primary NK cells isolated from the blood of ALS participants (n = 80) and healthy controls (n = 71), with immune cell profiles correlating with the response to tofacitinib. However, NK cell cytotoxicity was lower in ALS participants compared to healthy controls and showed no association with ALS progression.

INTERPRETATION: These findings confirm that tofacitinib suppresses NK cell cytotoxicity, and that immune profiling may help identify treatment responder groups. However, further research is needed to fully understand the role and timing of NK cell activity in ALS pathogenesis.},
}

@article {pmid40629595,
year = {2025},
author = {Liu, G and Liu, N and Xu, Y and Su, F},
title = {Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: A bibliometric analysis.},
journal = {Medicine},
volume = {104},
number = {27},
pages = {e43180},
doi = {10.1097/MD.0000000000043180},
pmid = {40629595},
issn = {1536-5964},
support = {202134068//Jinan City 2021 Science and Technology Innovation Development Program/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Lobar Degeneration/genetics ; *Bibliometrics ; C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics ; Mutation ; },
abstract = {OBJECTIVE: This study analyzes the research hotspots and future directions of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis.

METHODS: Relevant literature was searched using the Web of Science database and analyzed using econometric tools such as CiteSpace and VOSviewer.

RESULTS: A total of 145 articles were included in this study, involving 317 research institutions in 31 countries and regions. Acta Neuropathologica is a prominent journal in terms of issuance and influence, and countries such as the United States and Japan, as well as institutions such as the University of Pennsylvania, occupy an important position in the research. The keywords cover various aspects such as disease characteristics and gene mutations; highly-cited literature focuses on TDP-43 protein and C9orf72 gene mutations. Research hotspots include TDP-43 protein disease-driven pathomechanisms, RNA-related studies, clinical manifestations of the disease and genetic studies, etc. In recent years, research focus has shifted to RNA, C9orf72 gene and so on.

CONCLUSION: To our knowledge, this study is the first econometric evaluation of the FTLD-ALS literature, and although there are limitations such as relying on the number of documents and citation relationships, and a single source of data, it provides a valuable reference for research in this field and helps to promote subsequent research.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
*Frontotemporal Lobar Degeneration/genetics
*Bibliometrics
C9orf72 Protein/genetics
DNA-Binding Proteins/genetics
Mutation

@article {pmid40629407,
year = {2025},
author = {Choi, Y and Chung, WS},
title = {Glial phagocytosis for synapse and toxic proteins in neurodegenerative diseases.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {81},
pmid = {40629407},
issn = {1750-1326},
support = {2020M3E5D9079912//Ministry of Science and ICT, South Korea/ ; 2021R1A2C3005704//Ministry of Science and ICT, South Korea/ ; 2022M3E5E8081188//Ministry of Science and ICT, South Korea/ ; IBS-R025-A1//Institute for Basic Science/ ; },
abstract = {Glia, as resident immune and supportive cells of the central nervous system, play a critical role in maintaining brain homeostasis. One of their key homeostatic functions is phagocytic capacity in pruning synapses and removing cellular debris/protein aggregates, a process vital for synaptic plasticity and brain maintenance. However, these phagocytic functions are often dysregulated with aging and in neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. This review aims to examine the phagocytic roles of glia under both physiological and pathological conditions, with a special focus on their interactions with misfolded protein aggregates, including amyloid beta, tau, alpha synuclein, prion, huntingtin, and TAR DNA-binding protein 43. We also explore the fate of ingested molecules after being phagocytosed by glia-whether they are degraded, accumulate intracellularly, or are transferred between cells-and their implications for disease progression. Finally, we review current therapeutic strategies and the potential approaches for modulating glial phagocytosis to mitigate several NDs. We believe that understanding the exact mechanisms of glial phagocytosis and clearance will serve as key elements in developing future treatments for NDs.},
}

@article {pmid40629298,
year = {2025},
author = {Douglas, A and McPhee, M and Fisher, F and Cheng, C and Henders, A and Ziser, L and Stout, JC and Kiernan, MC and Osborne, R and Mathers, S},
title = {Using cluster analysis to identify the health literacy strengths and challenges of people living with motor neurone disease in Australia.},
journal = {BMC health services research},
volume = {25},
number = {1},
pages = {942},
pmid = {40629298},
issn = {1472-6963},
abstract = {BACKGROUND: There is growing appreciation of the role health literacy plays in population health and health care design. Health literacy encompasses an individual's capacity to manage their health and the responsiveness of the health system. Our aim was to identify the health literacy strengths and challenges in an Australian cohort living with motor neurone disease (MND), including both people living with the disease and their carers.

METHODS: This study used the Health Literacy Questionnaire and eHealth Literacy Questionnaire for health literacy assessment. Using a secure online platform, an anonymous survey was disseminated which included demographic data and clinical measurements. Descriptive statistical analysis and cluster analysis were employed to describe the sample and to identify different health literacy patterns in subgroups of people living with MND and their carers.

RESULTS: A total of 227 people participated (171 people living with MND and 56 carers). Cluster analysis generated fifteen cluster profiles for the cohort living with MND and seven cluster profiles for carers. The variability and potential significance of patterns of health literacy strengths and challenges within the MND community are described. There was extensive diversity within the sampled population, with a mix of sociodemographic backgrounds across each cluster profile.

CONCLUSIONS: The health literacy cluster profiles created from this study provide insight into the full spectrum of where the challenges and strengths exist for individuals and subgroups of people managing this fatal disease. The results from this study pave the way for generating system wide interventions that address health literacy diversity, to create more enabling health care environments for all those affected by MND.},
}

@article {pmid40629037,
year = {2025},
author = {Wood, H},
title = {Brain-computer interface restores naturalistic speech to a man with ALS.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {40629037},
issn = {1759-4766},
}

@article {pmid40627876,
year = {2025},
author = {Zeinab, EM and Lynn, K and Mohammad, M and Houssein, HA},
title = {Meckel's diverticulum in patient with early-onset ALS: A case report.},
journal = {International journal of surgery case reports},
volume = {133},
number = {},
pages = {111585},
doi = {10.1016/j.ijscr.2025.111585},
pmid = {40627876},
issn = {2210-2612},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease primarily affecting the neuromuscular system. Gastrointestinal manifestations are typically functional in nature, while mechanical obstructions are rarely reported. Meckel's diverticulum (MD), a congenital gastrointestinal anomaly, is often asymptomatic but can cause obstruction in rare adult cases.

CASE REPORT: We present the case of a 30-year-old male with early-onset ALS who presented with signs of intestinal obstruction, including severe abdominal pain, vomiting, and obstipation. Imaging revealed a closed-loop small bowel obstruction. Emergency laparotomy identified a torsed Meckel's diverticulum as the underlying cause. Surgical resection was performed, and the postoperative course was managed with tracheostomy and PEG placement due to progressive ALS-related respiratory and swallowing impairment. The patient was successfully stabilized and discharged with ongoing multidisciplinary support. The patient was discharged three weeks later in a stable condition and remains alive under multidisciplinary follow-up.

DISCUSSION: This case highlights the diagnostic challenge of distinguishing mechanical from functional gastrointestinal symptoms in patients with advanced ALS. While neurodegenerative progression often explains GI complaints in ALS, this case emphasizes the need to consider alternative etiologies, including surgical emergencies like MD-related obstruction.

CONCLUSION: Mechanical small bowel obstruction due to Meckel's diverticulum in ALS is exceedingly rare. Timely diagnosis and intervention, supported by multidisciplinary perioperative care, are critical for favorable outcomes in this high-risk population. Despite significant ALS-related comorbidities, the patient's outcome was favorable with stable discharge and ongoing respiratory and nutritional support.},
}

@article {pmid40626770,
year = {2025},
author = {Devrim, İ and Ergun, D and Kaçar, P and Çelebi, MY and Özer, A and Koyun, E and Koç, Y and Yıldız, ÖD and Akgül, E and Ayhan, FY and Bayram, N},
title = {The Comparison of Flushing With Prefilled Saline Syringes Versus Manually Prepared Saline Syringes on Colonization of Peripheral Intravenous Catheters in Children.},
journal = {Journal of infusion nursing : the official publication of the Infusion Nurses Society},
volume = {48},
number = {4},
pages = {247-252},
pmid = {40626770},
issn = {1539-0667},
mesh = {Humans ; *Syringes ; Child ; *Saline Solution/administration & dosage ; *Catheterization, Peripheral/adverse effects ; Turkey ; *Catheter-Related Infections/prevention & control ; *Catheters, Indwelling/microbiology ; Infusions, Intravenous ; Child, Preschool ; },
abstract = {We appreciate the study performed and described by Devrim et al, who practice at Dr. Behçet Uz Children's Diseases and Surgery Training and Research Hospital in Izmir, Turkey. This study aimed to compare the colonization rates of short-term PIVC tips between patients' catheters flushed with manually prepared saline syringes and single-use prefilled saline syringes. The practice of manually preparing saline syringes for use in flushing intravenous catheters is uncommon in many health care organizations. While many health care organizations have permanently exchanged manual flush syringe preparation for prefilled single-use saline syringes, we are respectful of professionals and organizations who serve in areas where practice is different. As noted, we appreciate Devrim et al's study and described findings. The conclusion of this study affirms and further substantiates the INS Infusion Therapy Standards of Practice described in Standard 38. Flushing and Locking. Practice Recommendation - A. Use single-dose systems (eg, single-dose vials and syringes or prefilled labeled syringes) for all VAD flushing and locking. Additional recommendations are listed in A.2. and A.3. Use commercially manufactured prefilled flush syringes (when available) to reduce the risk of catheter-associated bloodstream infection (CABSI) and device failure, save time for syringe preparation, and aid optimal flushing technique and objectives. 3. Do not use IV solution containers (eg, bags or bottles) as a source for obtaining flush solutions (see Standard 56, Compounding and Preparation of Parenteral Solutions and Medications).},
}

Humans
*Syringes
Child
*Saline Solution/administration & dosage
*Catheterization, Peripheral/adverse effects
Turkey
*Catheter-Related Infections/prevention & control
*Catheters, Indwelling/microbiology
Infusions, Intravenous
Child, Preschool

@article {pmid40626296,
year = {2025},
author = {Li, D and Wang, P and Zhang, M and Zhang, X and Yao, H and Liu, X},
title = {Advances in examination methods for adolescent idiopathic scoliosis.},
journal = {Pediatric discovery..},
volume = {3},
number = {1},
pages = {e2518},
pmid = {40626296},
issn = {2835-5598},
abstract = {The purpose of this article is to provide an overview of techniques for evaluating patients with adolescent idiopathic scoliosis (AIS). It encompasses the history, clinical examinations, and diagnostic imaging methods for AIS. These methods include digital radiological examination, EOS® imaging, nuclear medicine, ultrasound, body surface topography techniques such as the Moiré pattern technique, raster stereophotography, and DIERS formetric 4D as well as computed tomography and magnetic resonance imaging (MRI). Traditionally, full-spine standing X-rays have been the standard for diagnosing AIS. High-quality clinical assessments may continue as a reference for assessing other spinal deformities. However, the new diagnostic imaging methods aim to reduce radiation exposure while maintaining image quality and practicality. Emerging technologies demonstrate strong reliability and effectiveness in diagnostic imaging of AlS. These techniques may be beneficial for diagnosing and monitoring AIS and its progression without requiring high levels of radiation exposure. The article is a search and summary of the PubMed electronic database to understand the current and future status of AIS imaging technology, which can not only help to introduce other researchers to the field but also serve as a valuable source for healthcare professionals to study existing methods, develop new ones, or select evaluation strategies.},
}

@article {pmid40625857,
year = {2025},
author = {Khorrami, F and Gupta, N and Zhou, X and Liang, Y and Yucel, YH},
title = {A Novel Retinal Nerve Fiber Layer Biomarker of Amyotrophic Lateral Sclerosis (ALS) Identified Using Longitudinal in vivo Ocular Imaging.},
journal = {Eye and brain},
volume = {17},
number = {},
pages = {69-79},
pmid = {40625857},
issn = {1179-2744},
abstract = {PURPOSE: Like motor neurons, retinal ganglion cells (RGCs) have long axons and high metabolic demands, making them vulnerable to disruption of axonal transport. Unlike motor neurons, the RGC axons are accessible to high-resolution non-invasive optical imaging in their intraocular portion. A non-invasive in vivo retinal imaging biomarker can be valuable for amyotrophic lateral sclerosis (ALS) diagnosis and monitoring. We aim to assess the presence of inner retinal pathology in a mouse model of ALS and its possible progression with age.

METHODS: Transgenic SOD1G93A mice (n=8, 4M/4F) and age-matched controls (n=8, 4M/4F) underwent in vivo retinal imaging with confocal scanning laser ophthalmoscopy (cSLO) coupled with optical coherence tomography (OCT) at 20 weeks of age. Another group of SOD1G93A mice (n=20, 6M/14F) and age-matched controls (n=20, 6M/14F) underwent longitudinal in vivo retinal imaging with the same device. Each retinal imaging session included infrared reflectance (IR) and blue reflectance (BR) cSLO coupled with OCT. Hyperreflective puncta located in the retinal nerve fiber layer (RNFL) were counted in a blinded fashion in ALS and control mice. The number of puncta at 20 weeks of age in ALS mice was compared with controls using Wilcoxon test. The rates of increase of puncta number were analyzed using a Generalized Linear Mixed-Effect Model (GLMM) for genotype, time, and sex.

RESULTS: IR-cSLO coupled with OCT revealed hyperreflective puncta located in the RNFL of ALS mice. IR-cSLO fundus imaging at the age of 20 weeks showed ALS mice had significantly higher number of puncta compared to controls (2.1±2.3 vs 0.5±0.8; (mean±SD), respectively, p=0.036). GLMM analysis showed both ALS mutation and age were significantly associated with the rate of increase of puncta number (p=0.000232 and p=0.000366, respectively). In addition, female ALS mice had a steeper increase of puncta compared to male ALS mice (0.21±0.04 log number puncta/week vs 0.16±0.04, respectively; p=0.037).

CONCLUSION: Our findings demonstrate distinct inner retinal nerve fiber layer pathology, detected using cSLO coupled with OCT, which worsens over time. These findings support the potential of retinal imaging as a translationally relevant, non-invasive biomarker for ALS diagnosis or disease monitoring in humans.},
}

@article {pmid40625110,
year = {2025},
author = {Luo, Y and Xiong, S and Ehdaie, A and Sun, H and Yang, G and Luo, D and Li, J and Wang, X and Zhang, Z and Cai, L and Liu, H and Shehata, M},
title = {Predictive Parameters for Impending Steam Pops During High-Power Short-Duration Ablation for Atrial Fibrillation.},
journal = {Pacing and clinical electrophysiology : PACE},
volume = {},
number = {},
pages = {},
doi = {10.1111/pace.70003},
pmid = {40625110},
issn = {1540-8159},
support = {20240216//Liu Hanxiong Famous Doctor Studio of Chengdu/ ; 2024NSFSC1709//the Natural Science Foundation of Sichuan Province/ ; CSY-YN-01-2023-041//Scientific Research Project of The Third People's Hospital of Chengdu/ ; },
abstract = {BACKGROUND: High-power short-duration (HPSD) radiofrequency ablation (RFA) for atrial fibrillation (AF) treatment carries the risk of steam pops (SPs) due to rapid tissue heating. However, methods to predict impending SP during HPSD-RFA remain undefined.

OBJECTIVE: This study aims to establish a quantitative criterion for predicting SPs during HPSD-RFA.

METHODS: Retrospective analysis was performed on 489 patients undergoing HPSD-RFA for AF, focusing on corresponding RFA parameters in those who experienced SPs.

RESULTS: Among 1943 ablation lesions (ALs) delivered in 18 patients with SPs, 24 ALs had SP occurrence. Tip temperature, RFA duration, and ablation index were not significantly different between SP ALs and non-SP ALs. The mean contact force was significantly higher in SP ALs (12 g vs. 9, p < 0.001). All SPs adhered to the following criteria: impedance drop ≥8Ω during the first 4 s of RFA, impedance variability <5Ω within the first 4 s of RFA (24/24 vs. 79/247, p < 0.001), no events in the posterior wall of the left atrium, impedance drop ≥12Ω within 4-12 s. By halting delivery of RFA early with this finding in approximately five ALs per patient, the risk of SP complications could be significantly mitigated.

CONCLUSION: Monitoring impedance trends in the initial 4 s of HPSD-RFA can effectively predict impending SP occurrences. Automated algorithms should be developed to halt RFA delivery in this setting.},
}

@article {pmid40624572,
year = {2025},
author = {Pham, TK and Verber, N and Turner, MR and Malaspina, A and Collins, MO and Mead, RJ and Shaw, PJ},
title = {Glutathione oxidation in cerebrospinal fluid as a biomarker of oxidative stress in amyotrophic lateral sclerosis.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {36},
pmid = {40624572},
issn = {2047-9158},
support = {MRC/S004920/1/MRF_/MRF_/United Kingdom ; NIHR203321//NIHR Sheffield Biomedical Research Centre/ ; },
}

@article {pmid40624208,
year = {2025},
author = {Tavares, M and Lúcio, MJ and Borges, J and Carriço, F and Guimarães, MJ and Drummond, M},
title = {The impact of obstructive sleep apnea and the prognostic role of level III polysomnography at the onset of amyotrophic lateral sclerosis.},
journal = {Sleep & breathing = Schlaf & Atmung},
volume = {29},
number = {4},
pages = {235},
pmid = {40624208},
issn = {1522-1709},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/physiopathology/mortality ; *Polysomnography ; *Sleep Apnea, Obstructive/diagnosis/physiopathology/therapy ; Male ; Female ; Middle Aged ; Prognosis ; Cross-Sectional Studies ; Aged ; Noninvasive Ventilation ; Adult ; },
abstract = {PURPOSE: Sleep disturbances are considered an early manifestation of Amyotrophic lateral sclerosis (ALS). However, sleep-disordered breathing (SDB) in ALS remains underexplored. The primary outcome of this study is to describe the clinical, functional and polygraphic characteristics of ALS patients with baseline SDB and to compare those with and without obstructive sleep apnea (OSA) in level III polysomnography (PSG) at diagnosis. Secondary outcomes included identification of baseline factors predictive of non-invasive ventilation (NIV) initiation/death during follow-up and assessing the role of level III PSG performed at the initial clinical evaluation in ALS prognosis regarding timing to NIV initiation and death.

METHODS: A cross-sectional study was conducted on 74 patients between September 2023 and September 2024. For the primary outcome, only patients that exhibited baseline SDB were included (45 patients). The population (45) was divided into 2 groups: Group 1 (n = 26; obstructive apnea/hypopnea index ≥ 5) and Group 2 (n = 19; obstructive apnea/hypopnea index < 5). For the secondary outcomes, all 74 patients were included regardless of sleep events.

RESULTS: Patients with OSA had a higher baseline body mass index (p = 0.03) and lower nocturnal average oxygen saturation (p = 0.03). A lower forced vital capacity (p < 0.001) and higher transcutaneous carbon dioxide (p = 0.005) at baseline were predictive of timing to NIV initiation.

CONCLUSIONS: Our study highlights the importance of performing respiratory functional testing and transcutaneous carbon dioxide assessment in ALS prognosis, regarding timing to NIV initiation. Although level III PSG is vital in the diagnosis and treatment of SDB, further studies are needed to clarify its role at disease onset and identify additional potentially predictors of timing to NIV initiation/death in ALS patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/complications/physiopathology/mortality
*Polysomnography
*Sleep Apnea, Obstructive/diagnosis/physiopathology/therapy
Male
Female
Middle Aged
Prognosis
Cross-Sectional Studies
Aged
Noninvasive Ventilation
Adult

@article {pmid40622763,
year = {2025},
author = {Tra, NT and Kiryu-Seo, S and Kida, H and Wakatsuki, K and Tashiro, Y and Tsutsumi, M and Ataka, M and Iguchi, Y and Nemoto, T and Takahashi, R and Katsuno, M and Kiyama, H},
title = {Absence of the axon initial segment in sensory neuron enhances resistance to amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf182},
pmid = {40622763},
issn = {1460-2156},
support = {21K19310//Japan Society for the Promotion of Science/ ; 23H04229//Japan Society for the Promotion of Science/ ; 24K02350//Japan Society for the Promotion of Science/ ; 23K24695//Japan Society for the Promotion of Science/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Proteasome dysfunction in ALS is considered to cause the accumulation of protein aggregates, which leads to motor neuron degeneration; however, the resilience of motor neurons to ALS pathology might be impaired long before the appearance of protein aggregates. Intriguingly, sensory dorsal root ganglion (DRG) neurons are not susceptible to ALS pathology despite their processes coexisting with axons of motor neurons in the same spinal nerves. Both DRG neurons and motor neurons in ALS model mice express activating transcription factor 3 (ATF3), a well-known marker of nerve injury and disease progression, suggesting that both types of neurons respond to ALS pathology. However, it remains unknown why only DRG neurons are resilient to ALS pathological damage. To address this issue, we used a nerve injury model in combination with unique injury-induced genetically engineered mice, in which genetic control with an Atf3 regulatory element enables proteasome ablation and mitochondrial visualization specifically in damaged neurons. Using the strategy, we found that DRG neurons are resistant to damage in proteasome-deficient conditions, whereas spinal motor neurons degenerate in the same conditions. This might be because DRG neurons lack the typical axon initial segment (AIS), which normally exists in mature neurons and acts as a gate for the selective transport of cargo to axons. The absence of a typical AIS in DRG neurons facilitated increased entry of mitochondria into the axon upon injury, with or without proteasome function. In contrast, damaged motor neurons lacking the proteasome failed to disassemble the AIS, which prevented increased mitochondrial influx into axons and led to energy depletion and degeneration. In the absence of the AIS, DRG neurons in the ALS mouse model are able to deliver sufficient mitochondria into the axon to prevent pathological damage. However, impaired proteasome function in ALS motor neurons results in retention of the AIS gate and failure of mitochondrial transport to axons. This is a possible reason why DRG neurons have greater resilience to ALS pathological damage compared with spinal motor neurons. Collectively, this study opens new directions for the understanding of neurodegenerative diseases at early stages of disturbed protein homeostasis.},
}

@article {pmid40622676,
year = {2025},
author = {Wei, Y and Li, D and Yang, R and Liu, Y and Luo, X and Zhao, W and Yang, H and Chen, Z and Shen, C and Wang, Y and Huang, Z},
title = {TIA1-mediated stress granules promote neurodegeneration by sequestering HSP70 mRNA in C9orf72 mice.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf248},
pmid = {40622676},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease with progressive loss of motor neurons in the central nervous system. Recent studies have reported that there are mutations at the T cell antigen-1 (TIA1) domain site in some ALS patients. TIA1 is a key component of stress granules (SGs), but its role and mechanism in ALS pathogenesis remain unclear. In this study, we found that TIA1 was upregulated in the motor cortex of postmortem ALS patients as well as in the motor cortex neurons of C9orf72-poly-GA mice (ALS mice). TIA1 knockout in the central nervous system (TIA1Nestin-CKO mice) alleviated motor neuron loss, neuroinflammation and motor dysfunction in C9orf72-poly-GA mice. Mechanistically, RNA-sequencing combined with the C9orf72-ALS/FTD patient (snRNA-seq) database revealed that mRNA of heat shock protein 70 (HSP70) family member genes such as HSPa1b were up-regulated in the motor cortex of TIA1Nestin-CKO ALS mice. We further found that TIA1-mediated SGs formation was increased during ALS pathogenesis, leading to HSP70 mRNA being sequestered into SGs. This reduced HSP70 expression, impairing the degradation of poly-GA aggregates by the UBQLN2-HSP70 pathway and exacerbating C9orf72-ALS progression. Taken together, these findings highlight a previously unrecognized role of TIA1-mediated SGs in promoting ALS pathogenesis by sequestering HSP70 mRNA, suggesting potential therapeutic targets for ALS treatment.},
}

@article {pmid40621723,
year = {2025},
author = {Anani, T and Pradat-Peyre, JF and Delbot, F and Desnuelle, C and Rolland, AS and Devos, D and , and Pradat, PF},
title = {Feature selection using metaheuristics to predict annual amyotrophic lateral sclerosis progression.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/21678421.2025.2522399},
pmid = {40621723},
issn = {2167-9223},
abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease with no curative treatment and affecting motor neurons, leads to motor weakness, atrophy, spasticity and difficulties with speech, swallowing, and breathing. Accurately predicting disease progression and survival is crucial for optimizing patient care, intervention planning, and informed decision-making.

METHODS: Data were gathered from the PRO-ACT database (4659 patients), clinical trial data from ExonHit Therapeutics (384 patients) and the PULSE multicenter cohort aimed at identifying predictive factors of disease progression (198 patients). Machine learning (ML) techniques including logistic/linear regression (LR), K-nearest neighbors, decision tree, random forest, and light gradient boosting machine (LGBM) were applied to forecast ALS progression using ALS Functional Rating Scale (ALSFRS) scores and patient survival over one year. Models were validated using 10-fold cross-validation, while Kaplan-Meier estimates were employed to cluster patients according to their profiles. To enhance the predictive accuracy of our models, we performed feature selection using ANOVA and differential evolution (DE).

RESULTS: LR with DE achieved a balanced accuracy of 76.05% on validation (ranging from 68.6% to 79.8% per fold) and 76.33% on test data, with an AUC of 0.84. With Kaplan-Meier's estimates, we identified five distinct patient clusters (C-index = 0.8; log-rank test p value ≤0.0001). Additionally, LGBM predictions for ALSFRS progression at 3 months yielded an RMSE of 3.14 and an adjusted R[2] of 0.764.

CONCLUSION: This study showcases the potential of ML models to provide significant predictive insights in ALS, enhancing the understanding of disease dynamics and supporting patient care.},
}

@article {pmid40621427,
year = {2025},
author = {Gunduz, A and Akıncı, T and Kargın, OA and Tutuncu, M and Arslan, S and Uzun, N},
title = {Correlation analysis between excitability in the somatosensory cortex and structural changes in amyotrophic lateral sclerosis.},
journal = {Clinical neurophysiology practice},
volume = {10},
number = {},
pages = {202-208},
pmid = {40621427},
issn = {2467-981X},
abstract = {OBJECTIVE: We aimed to investigate the excitability of the somatosensory cortex and its relationship to structural changes in motor and sensory pathways, and motor excitability in amyotrophic lateral sclerosis (ALS).

PATIENTS AND METHOD: We included all consecutive individuals with ALS, fulfilling the "definite" or "probable" ALS criteria. We recorded surround inhibition (SI) and recovery function (RC) of somatosensory evoked potentials (SEPs), resting motor threshold, and cortical silent period (cSP), and performed volumetric analysis and diffusion tensor imaging (DTI).

RESULTS: We included 15 patients with ALS and 12 healthy individuals of similar age and sex. At the group level, the mean SEP-RC% at ISI 5 ms was higher in the ALS group than in healthy participants (all SEP-RC% at 5 ms p < 0.001). SEP-SI was lost in one-third of individuals with ALS. A negative correlation was found between the duration of the cSP and SEP-RC%, whereas no correlations were observed between SEP parameters and radiological volumetric analysis of the corticospinal tract, medial lemniscus, or cortical thickness of the precentral and postcentral gyri.

CONCLUSION: Somatosensory hyperexcitability is present in ALS, and SI is lost in a subset of patients with ALS.

SIGNIFICANCE: Somatosensory hyperexcitability correlates well with cSP but not with structural changes.},
}

@article {pmid40621236,
year = {2025},
author = {Rani, D and Chandan, SK and Devi, E},
title = {Motor Unit Number Estimation for Evaluating Disease Progression and Comparison With Functional Rating Scale Scores in Patients With Amyotrophic Lateral Sclerosis.},
journal = {Cureus},
volume = {17},
number = {6},
pages = {e85348},
pmid = {40621236},
issn = {2168-8184},
abstract = {Introduction Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease characterized by degeneration of motor neurons in the brain, brainstem, and spinal cord. While the ALS Functional Rating Scale-Revised (ALSFRS-R) is commonly used to assess functional decline, its limitations highlight the need for more objective biomarkers. Motor unit number estimation (MUNE) is an electrophysiological technique that may provide a more sensitive measure of disease progression. This study aims to evaluate the utility of MUNE as a biomarker in ALS and compare its performance with ALSFRS-R. Methods This was a prospective, single-center, observational study conducted over 18 months. A total of 31 patients with definite or probable ALS, diagnosed per the Revised El Escorial Criteria, were enrolled. MUNE and ALSFRS-R assessments were performed at baseline and after six months. MUNE was calculated using the multi-point incremental method in the upper extremity. Data were analyzed using paired t-tests and Pearson's correlation coefficients. Subgroup analyses by age, sex, and symptom onset site were also conducted. Results Both MUNE and ALSFRS-R scores declined significantly over six months. The mean MUNE decreased from 16.36 ± 5.22 to 13.37 ± 4.96 (p < 0.0001), while the ALSFRS-R score declined from 42.06 ± 3.24 to 36.72 ± 4.89 (p < 0.0001). The mean rate of decline was significantly greater for MUNE (23.6 ± 15.31) than for ALSFRS-R (13.91 ± 8.18; p = 0.001). No significant associations were observed between MUNE and patient age, sex, or site of symptom onset. Correlation between MUNE and ALSFRS-R was weak at both time points. Conclusions MUNE demonstrated a significantly greater rate of decline than ALSFRS-R, suggesting higher sensitivity to motor neuron loss over time. These findings support using MUNE as a reliable and objective biomarker for monitoring disease progression in ALS. Incorporating MUNE into clinical practice and research may improve prognostication, enable earlier therapeutic intervention, and enhance patient stratification in clinical trials. Further large-scale studies are needed to validate its routine use.},
}

@article {pmid40621104,
year = {2025},
author = {Rosene, MJ and Benitez, BA},
title = {Cysteine string protein α and a link between rare and common neurodegenerative dementias.},
journal = {NPJ dementia},
volume = {1},
number = {1},
pages = {15},
pmid = {40621104},
issn = {3005-1940},
abstract = {The maintenance of protein homeostasis and overall protein quality control dysfunction are associated with dementia. Cysteine string protein α (CSPα) is an endolysosomal cochaperone that facilitates the fusion of secretory and synaptic vesicles to the cell membrane. CSPα interacts with multiple proteins related to the proteostasis network and exocytic pathways and is often dysfunctional in synaptopathies. Since the initial discovery of CSPα 30 years ago, subsequent research has demonstrated a protective role of CSPα, especially in synaptic maintenance. However, the discovery of heterozygous CSPα mutations in 2011 causing adult-onset neuronal ceroid lipofuscinosis (ANCL) shifted the back-then prevalent dogma of unique synaptic function to include an endolysosomal role for CSPα. Recently, CSPα has been involved in the exocytosis of aggregate-prone proteins through either the misfolding-associated protein secretion (MAPS) or unconventional secretory pathways linking the molecular mechanism of rare and common neurodegenerative diseases. Here, we propose a novel molecular and pathophysiological model of CSPα-associated dementia, outline the increasing evidence of a broader role of CSPα in neurodegeneration, propose the role of CSPα in the synaptic secretion of neurodegenerative-associated proteins, and discuss the modulation of CSPα as a molecular target for common dementias.},
}

@article {pmid40620778,
year = {2025},
author = {Pavlenko, TA and Chesnokova, NB and Beznos, OV and Shikareva, NN and Nodel, MR and Shevtsova, KV and Panina, UV and Shteinberg, DA and Kukharskaya, OA and Sukhanova, IS and Pukaeva, NE and Kukharsky, MS and Ovchinnikov, RK},
title = {Superoxide dismutase activity in tear fluid and blood of patients and mouse model of amyotrophic lateral sclerosis: a pilot study.},
journal = {PeerJ},
volume = {13},
number = {},
pages = {e19623},
pmid = {40620778},
issn = {2167-8359},
mesh = {*Amyotrophic Lateral Sclerosis/enzymology/blood ; Animals ; Humans ; Pilot Projects ; *Tears/enzymology ; Mice ; Disease Models, Animal ; Male ; Middle Aged ; Mice, Transgenic ; Female ; Superoxide Dismutase-1/blood/metabolism ; *Superoxide Dismutase/blood/metabolism ; Aged ; Adult ; RNA-Binding Protein FUS/genetics/metabolism ; Biomarkers/blood ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive degeneration of motor neurons and skeletal muscle atrophy. The heterogeneity of clinical symptoms and the lack of reliable biomarkers hamper diagnostics of ALS. The dysfunction of superoxide dismutase 1 (SOD1) protein is considered one of the molecular mechanisms underlying ALS pathology. We measured total SOD activity in the tear fluid and blood serum of ALS patients, healthy volunteers, and in the ALS mouse model, harboring the human truncated form of fused in sarcoma (FUS) protein-FUS (1-359). The average SOD activity in tear fluid did not differ between ALS patients and the control group. However, an increased proportion of patients with low SOD activity in tear fluid was observed compared to the control group. In contrast, SOD activity in blood serum was higher in the ALS group. Transgenic FUS (1-359) mice showed decreased SOD activity in tear fluid at both presymptomatic and symptomatic stages of ALS. SOD activity in blood serum did not differ between transgenic and control animals. These findings suggest that changes in SOD activity in the tear fluid of ALS patients and transgenic FUS (1-359) mice reflect local metabolic disturbances in the eyes associated with ALS.},
}

*Amyotrophic Lateral Sclerosis/enzymology/blood
Animals
Humans
Pilot Projects
*Tears/enzymology
Mice
Disease Models, Animal
Male
Middle Aged
Mice, Transgenic
Female
Superoxide Dismutase-1/blood/metabolism
*Superoxide Dismutase/blood/metabolism
Aged
Adult
RNA-Binding Protein FUS/genetics/metabolism
Biomarkers/blood

@article {pmid40620684,
year = {2025},
author = {Chen, P and Wang, F and Ling, B and Zhu, Y and Lin, H and Huang, J and Wang, X},
title = {Mesenchymal Stem Cell-Derived Extracellular Vesicles: Emerging Therapies for Neurodegenerative Diseases.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {8547-8565},
pmid = {40620684},
issn = {1178-2013},
mesh = {Humans ; *Extracellular Vesicles/transplantation/metabolism ; *Neurodegenerative Diseases/therapy ; *Mesenchymal Stem Cells/cytology/metabolism ; Animals ; Mesenchymal Stem Cell Transplantation ; },
abstract = {Neurodegenerative diseases are a group of chronic diseases characterized by a gradual loss of neurons that worsens over time and dysfunction. These diseases are extremely harmful, not only affecting the physical health of the patients, but also having a serious impact on their quality of life. They mainly include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), etc. Their pathogenesis is complex, and it is difficult for the existing treatments to effectively slow down the progression of the disease. In recent years, Mesenchymal Stem Cells (MSCs) have received widespread attention for their anti-inflammatory, immunomodulatory and neuroprotective properties. In this context, MSC-derived Extracellular Vesicles (MSC-EVs) have demonstrated unique therapeutic potential as a cell-free therapeutic strategy. MSC-EVs are rich in bioactive substances such as proteins, lipids, mRNAs and miRNAs, which can pass through the blood-brain barrier and be targeted to the diseased area to regulate neuronal survival, synaptic plasticity and neuroinflammatory responses. In addition, compared with stem cell therapy, MSC-EVs have the advantages of low immunogenicity, easy storage and transportation, and avoiding ethical controversies. However, their clinical application still faces challenges: standardized isolation and purification techniques have not been unified, vesicle loading efficiency and targeting need to be further optimized, and long-term safety needs to be systematically evaluated. This review focuses on the role of MSC-EVs in the development of neurological diseases and explores their possible dual roles, both favorable and unfavorable, in the context of neurological diseases. In addition, this review provides a review of current studies on EVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases and provides a comprehensive review of the prospects and challenges of MSC-EVs in clinical applications.},
}

Humans
*Extracellular Vesicles/transplantation/metabolism
*Neurodegenerative Diseases/therapy
*Mesenchymal Stem Cells/cytology/metabolism
Animals
Mesenchymal Stem Cell Transplantation

@article {pmid40619865,
year = {2025},
author = {Vogel, E},
title = {Value-Scapes of Death: Livestock Veterinarians and the Regulation of Farm Animal Life in the Netherlands.},
journal = {Medical anthropology},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/01459740.2025.2527089},
pmid = {40619865},
issn = {1545-5882},
abstract = {This article examines the crucial role of veterinarians in making animal death valuable, enabling productive life, and managing uncontrolled dying. Based on ethnographic fieldwork on dairy farms in the Netherlands, and considering veterinarians as gatekeepers of the food chain, health practitioners, and governance actors, I articulate the "value-scapes" of food production that shape which animals die, when, and how, and whether death is desirable, a waste, or a warning. Veterinization here narrates how veterinary expertise is shaped by diverse societal concerns like food security, public health, animal welfare, and ecological sustainability, and knotted into shifting and multifaceted formations of Dutch-European animality.},
}

@article {pmid40619836,
year = {2025},
author = {Feng, Y and Wang, X and Chen, C and Wang, D and Hou, C and Wang, Y and Hu, H and Chen, P and Qin, L and Wan, Q and Yao, X and He, ML},
title = {Carbon Quantum Dots Assisted Virus Tracking: From Skin to Brain.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e2508464},
doi = {10.1002/adma.202508464},
pmid = {40619836},
issn = {1521-4095},
support = {11104020//RGC General Research Fund of Hong Kong Special Administrative Region/ ; C1018-23G//Collaborative Research Fund/ ; 7005874//Strategic funds/ ; 7020032//Strategic funds/ ; 9680149//Strategic funds/ ; //City University of Hong Kong/ ; JCYJ20240813153107010//Shenzhen Basic Research Program/ ; 9229501-14-YX//IDM Project/ ; 2025A1515011479//Basic and Applied Basic Research Foundation of Guangdong Province/ ; },
abstract = {Incurable infection by herpes simplex virus 1 (HSV-1) can cause severe encephalitis and neurodegenerative diseases, e.g., Alzheimer's disease (AD) and amyotrophic lateral sclerosis. How HSV-1 reaches the brain from the initial infection site remains inconclusive. Here, an innovative approach combining carbon quantum dots (CQDs) with dissolving microneedles (dMN) for real-time tracking of HSV-1 from skin to brain is presented. Upon application, CQDs-HSV-1 is released from the dMN through the swelling of interstitial fluid (ISF) in skin and subsequently monitored by living imaging. Remarkably, it is observed that HSV-1 preferentially infects peripheral skin nerves, almost all viruses directly enter to brain via the spinal cord within 10-30 min, while few viruses enter the brain through the bloodstream via tail vein injection at the same time. Spinal cord injury (SCI) significantly delays the HSV-1 transport from skin to brain but has no effect on the virus's travel from blood to brain. In a microfluid system, HSV-1 shows preferential neurite infection, then transports to the cell body of differentiated SH-SY5Y cells, highlighting the viral traffic process in neurons. The integration of CQDs-virus labelling technology and dMN delivery model presents a promising tool for investigating the in vivo transport routes of neurotropic viruses with initial skin infections.},
}

@article {pmid40619651,
year = {2025},
author = {Chauhan, S and Maan, P and Panghal, A},
title = {TDP-43 Proteinopathies in ALS and FTLD: Mechanistic Insights and Therapeutic Approaches.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273374466250617085832},
pmid = {40619651},
issn = {1996-3181},
abstract = {TAR DNA-binding protein 43 (TDP-43) is a vital RNA/DNA-binding protein involved in RNA metabolism, playing a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Approximately 97% of sporadic ALS (sALS), familial ALS (fALS) and FTLD cases are associated with pathological inclusions of hyperphosphorylated and ubiquitinated TDP-43 and genetic mutations in TAR DNA binding protein (TARDBP). Besides TARDBP, mutations in other genes such as C9ORF72, SOD1, FUS, and NEK1 are also linked to other fALS cases. Cytoplasmic mislocalization, aberrant post-translational modifications, and amyloid- like aggregation characterize TDP-43 pathology. These pathological changes impair essential cellular processes, including gene expression, mRNA stability, and RNA metabolism. Mechanisms of TDP-43-induced toxicity include disruption of endocytosis, mitochondrial dysfunction, and progressive cellular damage. Additionally, liquid-liquid phase separation (LLPS) and prion-like propagation are emerging as central features of its pathological spread. This review summarizes advances in understanding TDP-43's physiological functions and pathological mechanisms in ALS and FTLD. It highlights key processes underlying TDP-43 toxicity, such as aggregation, selective neuronal vulnerability, and regional susceptibility. Finally, this review summarizes evolving therapeutic strategies aimed at mitigating TDP-43-related toxicity through disaggregation, targeting mislocalization, and addressing upstream dysfunctions and challenges faced in the development of effective therapies for ALS and FTLD.},
}

@article {pmid40618857,
year = {2025},
author = {Balbi, M and Torazza, C and Altosole, T and Ravera, S and Farinini, E and Tessitore, S and Bacchetti, F and Rosso, F and Musante, I and Alfei, S and Cerminara, M and Puliti, A and Filaci, G and Fenoglio, D and Leardi, R and Fedele, E and Bonanno, G and Milanese, M and Bonifacino, T},
title = {The complex phenotype and function of spinal cord microglia during ALS progression and the impact of metabotropic glutamate receptor type 5 down-regulation in SOD1[G93A] mice.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107017},
doi = {10.1016/j.nbd.2025.107017},
pmid = {40618857},
issn = {1095-953X},
abstract = {Over the last few decades, scientists' attention has shifted from neuronal to non-neuronal cells to explain the mechanisms at the basis of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). ALS is a multifactorial and multicellular disease in which microglia have a central role, during disease progression. We previously demonstrated that metabotropic glutamate receptor 5 (mGluR5) is dysfunctional in the spinal cord of the SOD1[G93A] ALS mice, and its in-vivo genetic or pharmacological dampening ameliorates disease outcome and astrocyte and microglia reactivity. Here, we studied the expression of typical phenotype-related markers during the disease progression in spinal cord microglia cells acutely isolated from early asymptomatic and late symptomatic SOD1[G93A] ALS mice. Moreover, we investigated whether reducing mGluR5 affected the microglia phenotype and function. In contrast to what we previously observed in astrocytes, mGluR5 expression decreased during disease progression in microglia acutely isolated from adult SOD1[G93A] mice. In-vivo genetic mGluR5 downregulation did not affect microglia phenotype-relevant markers, which evidenced a unique expression distribution. Conversely, mGluR5 reduction ameliorated redox balance and bioenergetics of adult microglia. Microglia cultured from the spinal cord of SOD1[G93A] pups showed that in-vitro mGluR5 pharmacological manipulation by the negative allosteric modulator CTEP partially modified their bioenergetic and oxidative microglia status. Overall, our results suggest that mGluR5 manipulation ameliorates microglia phenotype and function in ALS by both direct and indirect mechanisms. Consequently, we hypothesised that the improvement of microglia reactive status by in-vivo mGluR5 downregulation or CTEP pharmacological modulation is supported by ameliorated bioenergetic metabolism, and the indirect astrocyte's phenotype change that promotes an improvement of the surrounding environment.},
}

@article {pmid40618376,
year = {2025},
author = {Scirocco, E and Allen, MD and Giacomelli, E and Ajroud-Driss, S and Andrews, J and Banack, S and Bede, P and Benatar, M and Cheung, K and Corcia, P and de Carvalho, M and Elman, L and Fink, JK and Genge, A and Hardiman, O and Harms, M and Heitzman, D and Jang, G and Kano, O and Kiernan, MC and Lee, I and Ludolph, A and Mehta, P and Ozdinler, H and Rezania, K and Schito, P and Sherman, AV and Silani, V and Sorenson, E and Turner, MR and Van Den Berg, L and Mitsumoto, H and Paganoni, S},
title = {Toward therapeutic trials in primary lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/21678421.2025.2527123},
pmid = {40618376},
issn = {2167-9223},
abstract = {Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder primarily affecting the upper motor neurons. People living with PLS experience progressive physical and communication disability, which typically evolves slowly over several years. In contrast to amyotrophic lateral sclerosis (ALS), life expectancy is anticipated to be normal. Disease-modifying medications are not available and PLS drug development has been challenging. This review considers recent advances and ongoing initiatives aimed at promoting clinical trial readiness for PLS. Ongoing clinical research efforts include patient registries and biorepositories, natural history studies, outcome measure validation, and biomarker development. These international collaborative efforts are essential for developing the first therapeutic trials for people living with PLS.},
}

@article {pmid40618341,
year = {2025},
author = {Asghari Jafari, E and Arabi, M and Bereimipour, A},
title = {Integrated genomic and molecular insights into astrocyte- and oligodendrocyte-derived amyotrophic lateral sclerosis: focus on miRNAs and extracellular vesicles.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {71},
number = {6},
pages = {1-8},
doi = {10.14715/cmb/2025.71.6.1},
pmid = {40618341},
issn = {1165-158X},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *MicroRNAs/genetics/metabolism ; Humans ; *Astrocytes/metabolism/pathology ; *Oligodendroglia/metabolism/pathology ; *Extracellular Vesicles/metabolism/genetics ; Computational Biology/methods ; *Genomics/methods ; Signal Transduction ; },
abstract = {Motor neurons in the brain and spinal cord begin to die off in Amyotrophic lateral sclerosis (ALS), a disease that can be fatal. Molecular pathways in neurological disease, especially ALS, remain a challenge in the medical sciences. In this disease, a disorder in both astrocytes and oligodendrocytes can cause the disease to progress. This study aimed to investigate the molecular mechanisms and find key elements between these two cells in ALS with a bioinformatics perspective. In this study, using integrated and continuous bioinformatics analytics by various tools and databases, we investigated genes, protein products, and miRNAs between astrocytes and oligodendrocytes. The obtained data were involved in the Cellular senescence, actin cytoskeleton, and cell cycle signaling pathways. Then, after careful evaluation of the information, TP53, MDM2, KRAS, PTPRC, and GSK proteins were candidates, which are regulated by hsa-miR-564, hsa-miR-496-5p, hsa-miR-324-5p, hsa-miR-296-5p, and hsa-miR-4258-3p miRNAs. Finally, the four genes had a more robust and better relationship in this study between astrocyte and oligodendrocyte-derived ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism
*MicroRNAs/genetics/metabolism
Humans
*Astrocytes/metabolism/pathology
*Oligodendroglia/metabolism/pathology
*Extracellular Vesicles/metabolism/genetics
Computational Biology/methods
*Genomics/methods
Signal Transduction

@article {pmid40618260,
year = {2025},
author = {Zhang, J and Ma, W and Liu, R and Li, X and Yuan, Z and Cheng, J},
title = {Neuromodulatory role and therapeutic potential of N6-methyladenosine RNA methylation in neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-01648},
pmid = {40618260},
issn = {1673-5374},
abstract = {N6-methyladenosine RNA methylation, an essential post-transcriptional modification, dynamically regulates RNA metabolism and plays a crucial role in neuronal function. Growing evidence suggests that dysregulated N6-methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. However, the precise mechanisms by which N6-methyladenosine modification influences these conditions remain unclear. This review summarizes the role of m6A modification and its associated regulators in neurodegeneration, focusing on their involvement in key pathological processes. In Alzheimer's disease, m6A modification contributes to synaptic dysfunction, mitochondrial damage, and neuronal apoptosis. Evidence from APP/PS1, 5XFAD, tau transgenic, and Drosophila models demonstrates that regulators such as METTL3 and FTO influence Alzheimer's disease progression through neuroinflammation, circRNA dysregulation, and autophagy-related mechanisms. In Parkinson's disease, altered N6-methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs. In multiple sclerosis and amyotrophic lateral sclerosis, N6-methyladenosine affects immune activation, myelin repair, and the regulation of disease-associated genes such as TDP- 43. Beyond N6-methyladenosine, other RNA methylation modifications-such as m1A, m5C, m7G, uracil, and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function, RNA metabolism, and neuronal stress responses. Additionally, N6- methyladenosine exhibits cell type-specific functions: in microglia, it regulates inflammatory activation and phagocytic function; in astrocytes, it modulates metabolic homeostasis and glutamate-associated neurotoxicity; in neurons, it affects synaptic function and neurodegeneration-related gene expression; and in adult neural stem cells, it controls differentiation, neurogenesis, and cognitive plasticity. Recently, several small-molecule inhibitors targeting METTL3 or FTO have been developed to modulate N6-methyladenosine modification, providing new opportunities for disease intervention, with the targeting of N6-methyladenosine-related pathways emerging as a promising therapeutic strategy. However, challenges persist in optimizing the specificity and delivery of these therapeutic approaches.},
}

@article {pmid40618254,
year = {2025},
author = {Singh, A and Subramanian, M and Singh, A},
title = {MicroRNAs in the pathogenesis of neurodegenerative disorders: Potential as therapeutic targets.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00402},
pmid = {40618254},
issn = {1673-5374},
abstract = {Neurodegenerative diseases (neurodegenerative disorders) are marked by the progressive degeneration of the structure and function of the central nervous system. They may result in the deterioration of cognitive, motor, and functional abilities. Diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis represent some of the most prominent examples of neurodegenerative disorders. Despite scientific advancement in understanding disease pathology and prognosis, the therapeutic strategies available for management remain limited. In recent years, microRNAs, small non-coding RNA molecules, have emerged as key players in the pathogenesis of neurodegenerative disorders. Therefore, understanding how these microRNAs affect disease pathology and pathway signaling is essential, and may open microRNAs as new avenues for potential therapeutic intervention. This review explores the role of microRNAs in various neurodegenerative diseases, discuss how microRNAs affect signaling pathways, and examine the potential of microRNAs as therapeutic targets.},
}

@article {pmid40617623,
year = {2025},
author = {Faure-de Baets, J and Besnard, J and Cassereau, J and Emmelin, E and Allain, P},
title = {Assessment of social cognition in patients with amyotrophic lateral sclerosis: protocol for a cross-sectional comparative study at Angers University Hospita.},
journal = {BMJ open},
volume = {15},
number = {7},
pages = {e097543},
doi = {10.1136/bmjopen-2024-097543},
pmid = {40617623},
issn = {2044-6055},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Cross-Sectional Studies ; *Social Cognition ; Neuropsychological Tests ; Male ; Female ; Case-Control Studies ; Research Design ; Middle Aged ; Cognition ; },
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder primarily affecting motor neurons. In addition to motor impairments, ALS frequently involves cognitive and behavioural disturbances, including deficits in social cognition, which can impact interpersonal interactions and decision-making. Despite increasing recognition of these impairments, existing assessment tools often rely on static stimuli, limiting their ecological validity.

METHODS AND ANALYSIS: This cross-sectional, single-centre study aims to assess social cognition abilities in patients with ALS compared with healthy controls using a combination of dynamic and static neuropsychological tools. The primary outcome measure will be performance on the Movie for the Assessment of Social Cognition, an ecologically valid test evaluating theory of mind. Secondary outcomes will include emotion recognition (static and dynamic tasks: Ekman Faces and French Emotion Evaluation Test), mood assessments (Hospital Anxiety and Depression Scale) and clinical variables such as disease severity (ALS Functional Rating Scale-Revised), cognitive function (Edinburgh Cognitive and Behavioural Screen, Mini-Mental State Examination) and disease staging (King's ALS Clinical Staging System). A total of 74 participants (37 patients with ALS and 37 matched healthy controls) will be recruited. Group differences will be analysed using analysis of variance, while regression models will explore associations between social cognitive deficits and clinical markers of ALS progression.

ETHICS AND DISSEMINATION: This study has been approved by the French Ethics Committee (CPP) Ouest I under reference 2020-A01213-36. Data collection and processing comply with French and European data protection regulations (GDPR, Loi Informatique et Libertés). Findings will be disseminated through peer-reviewed journals and scientific conferences and will contribute to improving neuropsychological assessment methods for ALS.

TRIAL REGISTRATION NUMBER: NCT04406675.},
}

Humans
*Amyotrophic Lateral Sclerosis/psychology
Cross-Sectional Studies
*Social Cognition
Neuropsychological Tests
Male
Female
Case-Control Studies
Research Design
Middle Aged
Cognition

@article {pmid40616089,
year = {2025},
author = {Al Kamaly, O and Al-Khateeb, LA and Halim, MK and Katamesh, NS and Magdy, G and Abbas, AEF},
title = {D-optimal candexch algorithm-enhanced machine learning UV-spectrophotometry for five-analyte determination in novel anti-glaucoma formulations and ocular fluids: four-color sustainability framework with NQS assessment and UN-SDG integration.},
journal = {BMC chemistry},
volume = {19},
number = {1},
pages = {198},
pmid = {40616089},
issn = {2661-801X},
support = {PNURSP2025R917//Princess Nourah Bint Abdulrahman University/ ; },
abstract = {The novel anti-glaucoma ophthalmic preparation containing latanoprost, netarsudil, and benzalkonium chloride has posed a significant challenge due to its complexity and the lack of environmentally sustainable quantification methods, with only a single published method available for its quantification that lacks environmental consideration. This study aims to address this crucial gap by presenting a novel and sustainable approach using machine learning-enhanced UV-spectrophotometric chemometric models for the concurrent quantification of latanoprost, netarsudil, benzalkonium chloride, and two related compounds in ophthalmic preparations and aqueous humour. A strategic multi-level, multi-factor experimental design creates a 25-mixture calibration set for four models (PLS, GA-PLS, PCR, and MCR-ALS). The key novelty was using the D-optimal design generated by MATLAB's candexch algorithm to construct a robust validation set, overcoming random data splitting limitations in machine learning chemometric methods and ensuring unbiased evaluation across concentrations. The optimized MCR-ALS model outperforms in predictive ability, with recovery percentages of 98-102%, low root mean square errors of calibration and prediction, favorable bias-corrected mean square error of prediction, relative root mean square error within acceptable limits, and adequate limits of detection for pharmaceutical analysis. The Greenness Index Spider Charts and the Green Solvents Selection Tool were applied to replace hazardous solvents. A total of seven advanced evaluation tools were employed to assess the method's greenness, blueness, violetness, and whiteness, highlighting its eco-friendly profile, practical relevance, and innovation potential. Additionally, the method's environmental and societal benefits were further validated using the Need, Quality, Sustainability (NQS) index. Overall, this machine learning-based framework contributes meaningfully to ten United Nations Sustainable Development Goals (UN-SDGs), underscoring its value for future-oriented pharmaceutical research.},
}

@article {pmid40616030,
year = {2025},
author = {Kikkawa, Y and McIntosh, L and Mavin, TJ and Barlow, M and O'Brien, L and Hodge, S and Janssens, S},
title = {Developing a learning tool for advanced life support and resuscitation: Performance Reflection Model for Resuscitation (PRM-Resus).},
journal = {BMC medical education},
volume = {25},
number = {1},
pages = {1001},
pmid = {40616030},
issn = {1472-6920},
support = {AQIRF100-2020-CV//Advance Queensland/ ; 2615//Betty McGrath Mater Research/ ; },
abstract = {BACKGROUND: Acquiring proficiency in advanced life support (ALS) can pose challenges for novice learners. Simulation-based training (SBT) is widely used to address this, offering learners opportunities to practise and receive feedback during debriefing. However, existing performance tools often lack the clarity, behavioural specificity, and educational scaffolding required to support deep reflective learning. This study aimed to develop and evaluate the Performance Reflection Model for Resuscitation (PRM-Resus) and to integrate it with the ALS Team Model and structured video exemplars as a comprehensive learning package to enhance ALS training.

METHODS: The study involved four phases. Phase 1 created the ALS Team Model to clarify individual roles. Phase 2 focused on co-designing PRM-Resus, using team expertise and the Team Model to create behaviourally anchored performance descriptors. In Phase 3, video scenarios were produced to represent ALS team performance at varying proficiency levels. Phase 4 evaluated the PRM-Resus through expert think-aloud studies. Qualitative content analysis was used alongside Cronbach's alpha to assess internal consistency and its use for SBT.

RESULTS: The PRM-Resus comprises four domains-clinical skills, clinical knowledge, team management, and leadership-each defined by behavioural descriptors across three performance levels. The participating experts endorsed the tool's clarity, structure, and educational value for novice learners. Internal consistency was high (α > 0.95). When used alongside the ALS Team Model and video exemplars, PRM-Resus facilitated deeper performance analysis, which had potential for enhancing post-simulation reflection and supporting faculty development.

CONCLUSIONS: This study presents a novel, interdisciplinary framework that integrates PRM-Resus, the ALS Team Model, and video exemplars to support reflective learning in ALS simulation. Together, these tools help novice learners build a concrete understanding of effective team performance and enable educators to deliver more structured feedback. Further research should explore its impact on learner development and potential translation into improved clinical outcomes.},
}

@article {pmid40615926,
year = {2025},
author = {Chen, C and Zhu, S and Zheng, Z and Ding, X and Shi, W and Xia, T and Gu, X},
title = {A Genome-wide study on the genetic and causal effects of smoking in neurodegeneration.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {743},
pmid = {40615926},
issn = {1479-5876},
support = {82171193//Natural Science Foundation for Young Scientists of Shanxi Province/ ; ZDXK202232//Jiangsu Provincial Medical Key Discipline/ ; },
abstract = {BACKGROUND: Smoking represents the largest preventable risk factor for human health, yet previous studies have failed to establish conclusive evidence regarding the causal relationship between smoking and neurodegenerative diseases. This study employs genetic correlation and Mendelian randomization analyses to investigate the potential association between smoking and neurodegenerative disorders.

METHODS: This study analyzed summary data from genome-wide association studies (GWAS) on smoking and neurodegenerative diseases. Genetic correlations were evaluated using linkage disequilibrium score regression (LDSC), and causal relationships were assessed through multiple Mendelian randomization methods including inverse-variance weighted (IVW), MR-Egger regression, weighted median (WME), weighted mode (WM), and simple mode (SM). sensitivity analyses were performed to examine heterogeneity, horizontal pleiotropy, and conduct leave-one-out analysis.

RESULTS: whether an individual had ever smoked regularly (SmkInit) is positively correlated with an increased risk of Alzheimer's disease (AD) (rg = 0.134, P = 2.74 × 10⁻⁸) and negatively correlated with the risk of Parkinson's disease (PD) (rg = - 0.100, P = 1.8 × 10⁻[4]). cigarettes per day (CigDay) are associated with a higher risk of AD (rg = 0.162, P = 4.26 × 10⁻⁵). Smoking cessation (SmkCes) is linked to an elevated risk of AD (rg = 0.1466, P = 1.5 × 10⁻[4]), whereas age of initiation of regular smoking (AgeSmk) is negatively correlated with AD risk (rg = - 0.181, P = 8.63 × 10⁻⁶) but positively correlated with PD risk (rg = 0.170, P = 2.0 × 10⁻[4]). Results suggest that both SmkInit and CigDay significantly increase AD risk (OR = 1.030, P = 1.74 × 10⁻⁴; OR = 1.022, P = 5.04 × 10⁻⁴), while SmkCes is associated with a reduced risk of PD (OR = 0.638, P = 1.91 × 10⁻⁶) and amyotrophic lateral sclerosis (ALS) (OR = 0.830, P = 5.29 × 10⁻⁶).

CONCLUSION: This study identified significant genetic associations between smoking behaviors and neurodegenerative diseases. CigDay and SmkInit increased AD risk, while SmkCes was linked to reduced risks of PD and ALS.},
}

@article {pmid40614949,
year = {2025},
author = {Sarkar, SK and Gubert, C and Hannan, AJ},
title = {The microbiota-inflammasome-brain axis as a pathogenic mediator of neurodegenerative disorders.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106276},
doi = {10.1016/j.neubiorev.2025.106276},
pmid = {40614949},
issn = {1873-7528},
abstract = {In various neurodegenerative disorders, inflammation and associated inflammasome activation play an important role. The most prevalent and extensively researched inflammasomes are NLRP3 inflammasomes, which are triggered by pathogens or danger signals mediating inflammatory reaction. Extracellular ATP also activates NLRP3 by stimulating the purinergic receptor P2X7 (P2X7R). Central and peripheral cells, including those in the gut, have been shown to have activated inflammasomes during pathological changes co-occurring with inflammation in neurodegenerative disorders. Gut injury or dysfunction is increasingly recognised as one of the peripheral pathogenic characteristics of many neurodegenerative disorders and has been found to associate with changes in gut microbes. In this article, we review data from studies on humans and rodents regarding the involvement of NLRP3 inflammasomes and the purinergic receptor P2X7R in the pathophysiology of major CNS disorders involving neurodegeneration, including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), Huntington's disease (HD), and the most common form of motor neuron disease, amyotrophic lateral sclerosis (ALS). We also scrutinised the relationship of NLRP3 inflammasomes to intestinal microbiota alterations in these diseases. Both NLRP3 inflammasomes and P2X7R have been shown to play important roles in the progression of these neurodegenerative diseases. However, most studies have focused on central nervous system pathology, particularly within the brain, with comparatively less attention given to their contribution to gut pathology. Additionally, changes in the microbial environment of the intestine have also been correlated to these disorders. However, the association between gut microbiota alteration and inflammasome activity in the pathology of these neurodegenerative disorders has been poorly understood. Therefore, further investigation is needed to explore the microbiota-inflammasome-brain axis in these conditions, with the aim of better understanding their contribution to disease progression and identifying novel therapeutic targets.},
}

@article {pmid40614636,
year = {2025},
author = {Hirayama, T and Nagasawa, J and Shibukawa, M and Morioka, H and Yokoyama, T and Tsuda, H and Bokuda, K and Ogino, M and Takao, H and Morita, M and Takahashi, Y and Nakamura, R and Atsuta, N and Urushitani, M and Yamanaka, K and Izumi, Y and Kano, O},
title = {Survey research on the awareness and usage of accessibility features of information and communication technology devices among patients with amyotrophic lateral sclerosis.},
journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia},
volume = {139},
number = {},
pages = {111434},
doi = {10.1016/j.jocn.2025.111434},
pmid = {40614636},
issn = {1532-2653},
abstract = {We aimed to explore perceptions of digital technology and the usage of information and communication technology (ICT) devices among patients with amyotrophic lateral sclerosis (ALS) and their caregivers. In October 2023, we held a nationwide webinar titled "ALS Café" and distributed a self-report questionnaire to patients with ALS and caregivers, including family members, which covered topics such as awareness, usage of accessibility features, and current support for the use of ICT devices. Thirty-one patients with ALS and 24 of their caregivers responded (average age: 57.1 ± 10.1). The ALS Functional Rating Scale-Revised (ALSFRS-R) score was 26.6 ± 14.1. Overall, 69.6 % of respondents were aware of accessibility features, 71.4 % of those under 70, and 50.0 % of those over 70. Frequently used features included browsing assistance (32.1 %), voice operation (30.4 %), mouse or touch pen operation (26.8 %), synthesized voice reading (23.2 %), gaze input operation (19.6 %), and switch operation (14.3 %). Self-help assistance for ICT devices was used by 65.8 % of respondents with an ALSFRS-R score ≥ 20 and 11.8 % with an ALSFRS-R score < 20. Regarding government services, 85 % of respondents were unaware of ICT support centers for persons with disabilities. This study revealed the awareness and usage of accessibility features of ICT devices among patients with ALS and their caregivers. Raising awareness of accessibility features among older adults and improving support systems for those with mild symptoms are necessary.},
}

@article {pmid40614501,
year = {2025},
author = {Yu, H and Wang, C and Phuntsho, S and He, T and Naidu, G and Han, DS and Shon, HK},
title = {Highly selective lithium recovery from seawater desalination brine using Li2TiO3 membrane-coated capacitive deionization.},
journal = {Water research},
volume = {285},
number = {},
pages = {124113},
doi = {10.1016/j.watres.2025.124113},
pmid = {40614501},
issn = {1879-2448},
abstract = {Selective lithium (Li) recovery from seawater-based resources is challenged by low Li concentrations and the presence of competing ions such as Na[+], K[+], Mg[2+], and Ca[2+]. This study presents an innovative approach by integrating capacitive deionization (CDI) with a titanium-based lithium-ion sieve (LIS) membrane-coated cathode and an anion exchange membrane (AEM)-coated anode for enhanced Li recovery from seawater desalination brine (SWDB). The cathode was fabricated using Li2TiO3 (LTO) adsorbent through rolling pressing and dip coating methods. Characterization confirmed the successful fabrication of the LTO membrane-coated electrode. The performance of the LTO-AEM-CDI system was evaluated using simulated SWDB through an adsorption-rinsing-desorption operational mode. The results indicated that the rinsing stage plays a crucial role in significantly enhancing Li selectivity. A 10-cycle stability test demonstrated the system's reliability, maintaining the active Li selectivity (ALS) consistently above 100 across all cycles. This research highlights the potential of combining LIS, membrane technologies, and CDI for effective Li extraction from seawater-based resources.},
}

@article {pmid40614474,
year = {2025},
author = {Montenegro, MF and Morales, JMN and Morán Vieyra, FE and Borsarelli, CD},
title = {Eco-friendly synthesis of a silver nanohybrid with carbon dots derived from Quebracho Colorado leaves and its application in the colorimetric detection of Al[3].},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {343},
number = {},
pages = {126628},
doi = {10.1016/j.saa.2025.126628},
pmid = {40614474},
issn = {1873-3557},
abstract = {The Schinopsis lorentzii tree leaves were utilized for the first time in the production of carbon dots (CDs) with a diameter of 6 nm through hydrothermal carbonization at 200 °C. The heating of AgNO3 aqueous solutions up to 70 °C in the presence of CDs results in the formation of silver nanohybrids (AgNP@CDs), with a zeta potential of -48 mV, a diameter of 33 nm, and a surface plasmon resonance (SPR) absorption band centered at 440 nm. Among the various cations examined, only the incorporation of Al[3+] in the AgNP@CDs solution induced a color shift from yellow to brown, leading to the formation of colloidal aggregates with an approximate diameter of 550 nm. The formation of AgNP@CDs nanohybrids and aggregates in the absence and presence of Al[3+], respectively, was modeled by combining UV-vis absorption spectra with multivariate curve resolution-alternating least squares (MCR-ALS) analysis. For the AgNP@CDs, a sequential nucleation-aggregation mechanism was observed, with a global activation energy of 28 kJ/mol. In the presence of Al[3+], a four-species sequential mechanism describes the progressive formation of larger aggregates, with dose-response curves that are characteristic of highly cooperative binding equilibriums with an average global binding constant of 7 × 10[4] M[-1]. The analytical performance of the AgNP@CDs resulted in a sensitivity of 0.03 μM, a linear range between 10 and 20 μM, and a limit of detection of 3.5 μM. These parameters are consistent with those previously reported for the colorimetric determination of Al[3+] using AgNPs capped with different molecules.},
}

@article {pmid40613930,
year = {2025},
author = {Qi, Y and Xu, J and Wang, Y and Gao, Y and Sun, Z and Deng, Z and Shao, Y and Li, P and Nieland, JDV},
title = {Changes of Sonic Hedgehog mediated FAK/ERK pathway proteins in amyotrophic lateral sclerosis model mice.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {40613930},
issn = {1432-2072},
support = {202303021221206//Shanxi Provincial Key Research and Development Project/ ; 2024-148//Shanxi Provincial Education Department/ ; 2024ZYY2B050//Health Commission of Shanxi Province/ ; },
}

@article {pmid40613809,
year = {2025},
author = {Veenstra, J and Ozog, D and Ghosh, S},
title = {Response to Yang et al's "A Disproportionality Analysis on Benzoyl Peroxide and Its Risk of Malignancy Using the FDA Adverse Event Reporting System".},
journal = {The Journal of investigative dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jid.2025.05.025},
pmid = {40613809},
issn = {1523-1747},
}

@article {pmid40612333,
year = {2025},
author = {Rossip, MG and Hastings, J and Burwinkel, H and Lavrova, E and Steinbrenner, R and Bensaid, N and Cooke, DL and Pantanelli, SM},
title = {Relative Behavior of Modern Intraocular Lens Power Calculation Formulas Across a Realistic Range of Biometry Values.},
journal = {Clinical ophthalmology (Auckland, N.Z.)},
volume = {19},
number = {},
pages = {2037-2045},
pmid = {40612333},
issn = {1177-5467},
abstract = {PURPOSE: To investigate the relative performance of modern intraocular lens (IOL) power calculation formulas over a wide range of biometric parameters.

PATIENTS AND METHODS: Through the concept of emmetropization there exists a mean keratometry, anterior chamber depth, lens thickness, and white-to-white for a given axial length (AL). Using a database of biometric values from 2721 surgery naïve eyes, these relationships were modeled and used to create an artificial dataset of 170 eyes with an anatomically realistic distribution of biometric parameters. Biometric values for each artificial eye were entered into the ESCRS IOL power calculation website. The emmetropic IOL power was calculated for Barrett Universal II, Cooke K6, Kane, PEARL-DGS, HofferQST, EVO v2.0, and Hill-RBF v3.0. Separately, emmetropic IOL powers were calculated for the Zeiss AI formula. The disparity between the formulas was evaluated to determine the ALs at which they diverged.

RESULTS: For eyes with ALs between 22.5 and 28.1 mm, emmetropic IOL powers and spherical equivalent predictions differed by less than 0.25 D. Outside this range, spherical equivalent predictions differed by 0.25 D or more. At ALs < 19.5 mm the difference in emmetropic IOL power across the formulas exceeded 1.0 D.

CONCLUSION: This work helped to identify an implementation error in Pearl-DGS, which was corrected in collaboration with the formula's author. Cataract surgeons should consider that formula choice still has a clinically meaningful impact on refractive outcomes in eyes with axial lengths of <22.5 mm and >28.1 mm. We estimate that this may represent more than 10% of the population.},
}

@article {pmid40612293,
year = {2025},
author = {Bayleyegn Derso, T and Mengistu, BA and Demessie, Y and Fenta, MD and Getnet, K},
title = {Neural stem cells in adult neurogenesis and their therapeutic applications in neurodegenerative disorders: a concise review.},
journal = {Frontiers in molecular medicine},
volume = {5},
number = {},
pages = {1569717},
pmid = {40612293},
issn = {2674-0095},
abstract = {The idea of using stem cell therapy to treat neurodegenerative diseases has undergone significant change over the years and has made significant progress recently. Neurotrophins, growth factors, and transcription factors regulate neural stem cell proliferation and differentiation. Disruption of these regulatory mechanisms, including negative feedback, can contribute to neurodegenerative diseases. Contemporary research highlights a growing global concern regarding diverse neurodegenerative disorders affecting both humans and animals. These conditions arise from neuronal cell death, axonal regeneration failure, and impairment of neuronal structure. Current pharmacological treatments primarily offer symptomatic relief without altering disease progression. Consequently, researchers are investigating innovative therapeutic strategies, with neural stem cell therapy emerging as a promising avenue. Adult neural stem cells, embryonic neural stem cells, and induced pluripotent stem cells represent potential cell sources, although challenges such as ethical considerations and technical limitations remain. The therapeutic application of neural stem cells holds significant promise for addressing neurodegenerative diseases, including Alzheimer's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, and multiple sclerosis. Neural stem cell therapy aims to replenish lost neurons and promote neural regeneration in these conditions. While clinical trials have demonstrated some success in improving cognitive and motor functions in individuals with neurodegenerative impairments, challenges such as immunological rejection, the identification of compatible cell sources, ethical concerns, treatment efficacy, and potential side effects necessitate thorough investigation before widespread clinical implementation. Despite these challenges, neural stem cell-based therapy offers substantial potential for revolutionizing the treatment of neurodegenerative diseases and central nervous system injuries. This paper, therefore, explores adult neurogenesis and the therapeutic potential of neural stem cells within the dynamic field of neurodegenerative disorders.},
}

@article {pmid40611592,
year = {2025},
author = {DuVal, MG and Noga, T and Beecher, G},
title = {Long-term tofersen and cerebrospinal fluid macrophage inclusions in superoxide dismutase 1 amyotrophic lateral sclerosis.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-7},
doi = {10.1017/cjn.2025.10351},
pmid = {40611592},
issn = {0317-1671},
}

@article {pmid40610342,
year = {2025},
author = {Trubshaw, M and Yoganathan, K and Gohil, C and Stagg, CJ and Nobre, AC and Talbot, K and Woolrich, M and Thompson, AG and Turner, MR},
title = {Gamma activation spread reflects disease activity in amyotrophic lateral sclerosis.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {},
number = {},
pages = {2110823},
doi = {10.1016/j.clinph.2025.2110823},
pmid = {40610342},
issn = {1872-8952},
abstract = {OBJECTIVE: A non-invasive measure of cerebral motor system dysfunction would be valuable as a biomarker in amyotrophic lateral sclerosis (ALS). Task-based magnetoencephalography (tMEG) measures the magnetic fields generated by cortical neuronal oscillatory activity during task performance. Gamma activations are periods of high-power and high-frequency cortical oscillations integral to motor control.

METHODS: tMEG was undertaken during 60 bilateral isometric hand grip exercises in ALS (n = 42) and compared with healthy controls (HC, n = 33). Gamma activation spread (GAS) was estimated by calculating the number of activated regions during each 100 ms time-bin and compared statistically between groups. Gamma activation patterns were visualised by plotting each participant's brain activity separately as a 2-dimensional video.

RESULTS: There was no difference in grip strength between groups. GAS was greatly increased in the ALS group compared to HC (p < 0.001) and correlated positively with rate of ALSFRS-R progression (t = 1.35, p = 0.023) and a fine motor sub-score (t = -1.18, p = 0.047).

CONCLUSIONS: ALS was associated with a marked increase in regional spread of gamma frequency activation, greater in those with higher disease progression rates.

SIGNIFICANCE: The regional spread of gamma activity may reflect disease activity in ALS, with potential application as an experimental medicine readout.},
}

@article {pmid40610146,
year = {2025},
author = {Olivieri, AC},
title = {Hazards of using multivariate curve resolution for processing first-order spectral data. A rotational ambiguity analysis.},
journal = {Analytica chimica acta},
volume = {1367},
number = {},
pages = {344304},
doi = {10.1016/j.aca.2025.344304},
pmid = {40610146},
issn = {1873-4324},
abstract = {BACKGROUND: A growing number of reports are discussing the use of multivariate curve resolution - alternating least-squares (MCR-ALS) to process matrices built with first-order data, e.g., spectra. Although the results are promising, almost no complementary analysis of the impact of rotational ambiguity on the obtained solutions has been reported.

RESULTS: Several experimental data sets involving spectra (near infrared, UV-visible absorption, fluorescence emission) were processed with MCR-ALS, and then analyzed with channel-wise N-BANDS regarding the presence of rotational ambiguity. In cases of low spectral overlapping, almost unique profiles were found in the retrieved analyte concentration profiles. In cases of high spectral overlapping, however, substantial ambiguity was estimated in the analyte concentration profiles, making the analytical results less reliable. This is even more pronounced when uncalibrated components occur in the test samples. Channel-wise N-BANDS calculations agreed with the results from randomly initialized MCR-ALS models.

SIGNIFICANCE: Researchers using MCR-ALS in multivariate calibration protocols based on first-order data should always accompany the decomposition results with a rotational ambiguity analysis. This would provide insight into the reliability of the retrieved profiles, the estimation of the analyte concentrations and the qualitative interpretation of the spectra.},
}

@article {pmid40610071,
year = {2025},
author = {Selvaraj, C and Vijayalakshmi, P and Desai, D and Manoharan, J},
title = {Proteostasis imbalance: Unraveling protein aggregation in neurodegenerative diseases and emerging therapeutic strategies.},
journal = {Advances in protein chemistry and structural biology},
volume = {146},
number = {},
pages = {1-34},
doi = {10.1016/bs.apcsb.2024.11.008},
pmid = {40610071},
issn = {1876-1631},
mesh = {Humans ; *Proteostasis ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; Autophagy ; *Protein Aggregation, Pathological/metabolism/therapy/pathology ; *Protein Aggregates ; },
abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are defined by the accumulation of misfolded and aggregated proteins, which impair cellular function and result in progressive neuronal death. This chapter examines the critical function of proteostasis-cellular protein homeostasis-in sustaining neuronal health and its disruption as a key factor in disease progression. Proteostasis is upheld by a complex array of mechanisms, which encompass molecular chaperones, the ubiquitin-proteasome system, autophagy-lysosomal pathways, and mitochondrial quality control. Impairment of these systems leads to protein misfolding and aggregation, resulting in toxic cellular environments that promote neurodegeneration. Novel therapeutic approaches focus on restoring proteostasis through the enhancement of cellular protein folding, degradation, and clearance mechanisms. This encompasses small molecule chaperones, gene therapy, RNA-based treatments, immunotherapy, autophagy inducers, and stem cell-based approaches, each addressing distinct components of the proteostasis network to mitigate or prevent disease progression. While these therapies show potential, challenges persist, such as possible side effects, selective targeting, and the efficacy of blood-brain barrier penetration. Personalized medicine and combination therapies customized to specific disease profiles are increasingly recognized for their potential to improve efficacy and safety. This chapter consolidates recent developments in therapies aimed at proteostasis, addresses the challenges encountered in clinical applications, and outlines potential future directions for transformative treatments. Ongoing research indicates that proteostasis modulation may significantly alter the course of neurodegenerative disease treatment, potentially enhancing patient outcomes and quality of life.},
}

Humans
*Proteostasis
*Neurodegenerative Diseases/metabolism/therapy/pathology
Animals
Autophagy
*Protein Aggregation, Pathological/metabolism/therapy/pathology
*Protein Aggregates

@article {pmid40609634,
year = {2025},
author = {Lukianenko, N and Kang, DM and Bekci, A and Kim, YK and Lim, S},
title = {Nucleocytoplasmic HDAC inhibition drives acetylation-dependent TDP-43 mislocalization and disulfide-linked oligomerization.},
journal = {Journal of molecular biology},
volume = {},
number = {},
pages = {169318},
doi = {10.1016/j.jmb.2025.169318},
pmid = {40609634},
issn = {1089-8638},
abstract = {TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), are characterized by aberrant cytoplasmic mislocalization and aggregation of TDP-43. Here, we established a live-cell TDP43-BiFC model to visualize TDP-43 oligomerization in real time and screened diverse cellular stressors. Histone deacetylase (HDAC) inhibition emerged as the most potent trigger of TDP-43 oligomerization. In particular, selective inhibition of the shuttling HDAC4/5 with LMK-235 induced an early and robust formation of cytoplasmic TDP-43 oligomers, comparable to or even exceeding the effect of the pan-HDAC inhibitor apicidin. In contrast, nuclear-restricted HDAC1/3 inhibition by MS-275 prolonged TDP-43 retention in the nucleus with minimal cytoplasmic mislocalization or oligomerization, underscoring distinct roles for nuclear versus nucleocytoplasmic HDACs. Inhibition of cytoplasmic HDAC6 (tubastatin A) had no significant effect. Notably, both shuttling and pan-HDAC inhibition increased TDP-43 acetylation and promoted the accumulation of stable, disulfide-linked TDP-43 oligomers. These findings identify lysine acetylation as a key regulator of disulfide bond-dependent TDP-43 oligomerization and suggest that targeting nucleocytoplasmic HDACs could be a novel therapeutic strategy in TDP-43 proteinopathies.},
}

@article {pmid40609398,
year = {2025},
author = {Yazdanian, T and Azimi, P and Babu, S},
title = {Cervical spinal cord MRI in ALS individuals: a systematic review and meta-analysis.},
journal = {NeuroImage. Clinical},
volume = {47},
number = {},
pages = {103832},
doi = {10.1016/j.nicl.2025.103832},
pmid = {40609398},
issn = {2213-1582},
abstract = {BACKGROUND: Disease tracking and prognostication of amyotrophic lateral sclerosis (ALS) can be quite challenging in people living with ALS, due to the complexity of central nervous system disease biology. This systematic review and meta-analysis aim to summarize cervical spinal cord quantitative MRI (qMRI) biomarker changes in individuals with ALS.

METHODS: PubMed, Scopus, Cochrane Library, and Web of Science databases were searched up to August 2023. The terms used were "ALS", "cervical spinal cord", "MRI"," diffusion tensor imaging (DTI)", " fractional anisotropy (FA)", " mean diffusivity (MD) "," magnetization transfer ratio (MTR)", " cross-sectional area (CSA)", " radial diffusivity (RD) ", and " atrophy ". The Newcastle-Ottawa scale (NOS) was used to assess study quality. We calculated the pooled: 1) Standardized mean difference (SMD) and 95% CIs for comparative assessment of qMRI parameters in ALS individuals and the healthy population. 2) Estimate the mean of qMRI parameters for normative values in two groups by CMA software. Heterogeneity and publication bias were determined by the I-squared statistic and funnel plots.

RESULTS: Thirty studies, with 1817 participants (35.9 % female) were included in this review, and 29 had a NOS ≥ 5 which indicates high-quality of data overall. The SMD analysis showed (a) significant decrease in CSA along the whole length of cervical cord (C1-C7) (p value < 0.0001), with a preferential thinning of the cervical enlargement region (C4-C6 region) (p value < 0.0001) (b) significant decrease in FA (p value < 0.0001), particularly FA left lateral corticospinal tract (p value < 0.0001) and (c) a significant increase in MD (p value < 0.0001) in ALS individuals compared to controls. The pooled analysis reveals that the mean (SD) values for ALS individuals versus controls for (a) CSA (in mm[2]) were C1 [73.4 (0.75), 78.5 (0.67), 6.9 % difference]; C2 [70.6 (3.1), 71.5 (3.5), 1.2 % difference]; C3 [69.8(1.5), 74.9 (1.9), 7.3 % difference]; C4 [71.9 (1.8), 77.6 (2.8), 7.9 % difference]; C5 [71.8 (2.5), 79.5 (3.3), 10.7 % difference]; C6 [66.8 (2.7), 73.7 (3.7), 10.3 % difference]; C7 [56.7 (F2.2), 62.1 (2.5), 9.5 % difference]; (b) FA [0.54 (0.03), 0.56 (0.03)]; (c) MD[1.11 (0.18), 0.88(0)]; and (d) FA LLCST [ 0.65 (0.04), 0.77 (0.04)], respectively. The mean (SD) value of the MTR and RD for ALS individuals was 40.3 (2.3), and 0.70 (0.0).

CONCLUSIONS: qMRI metrics of spinal cord show discriminatory potential between ALS and healthy controls. The selective atrophy of the cervical enlargement (C4-C6) is replicable across multiple studies as seen in this metanalysis and hence is a potential imaging marker for quantifying and tracking lower motor neuron degeneration in ALS.},
}

@article {pmid40608189,
year = {2025},
author = {Sharma, VK},
title = {Dysbiosis and Neurodegeneration in ALS: Unraveling the Gut-Brain Axis.},
journal = {Neuromolecular medicine},
volume = {27},
number = {1},
pages = {50},
pmid = {40608189},
issn = {1559-1174},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/microbiology/therapy ; *Dysbiosis/complications/physiopathology/therapy ; *Gastrointestinal Microbiome/physiology ; Animals ; *Brain-Gut Axis/physiology ; *Brain/physiopathology ; },
abstract = {Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disorder marked by the progressive degeneration of motor neurons in the brain and spinal cord. Despite decades of research, ALS remains incurable, diagnostically elusive, and is accompanied by rapid clinical decline, morbidity, and mortality. Its pathophysiology involves a complex interplay of genetic mutations (SOD1, C9/f72), environmental triggers, oxidative stress, neuroinflammation, and the accumulation of misfolded proteins, such as TDP-43 and SOD1. These factors disrupt cellular homeostasis aggravates excitotoxicity and neuronal death. Existing treatments, such as riluzole (a glutamate release modulator) and edaravone (a free radical scavenger), offer limited benefits, modestly prolonging survival or slowing functional decline without halting progression. Investigational approaches include antisense oligonucleotides targeting mutant SOD1 or C9orf72 genes, stem cell-based motor neuron replacement, and biomarker discovery to enable earlier diagnosis and progression monitoring. ALS patients frequently exhibit gastrointestinal (GI) symptoms, including dysphagia, sialorrhea, constipation, delayed gastric emptying, and pancreatic/parotid deficiencies. These observations underscore a close association between GI dysfunction and ALS pathogenesis. Also, recent studies implicate the gut-brain-microbiota axis in disease evolution, with microbial metabolites influencing neuroimmune interactions, synaptic plasticity, myelination, and skeletal muscle function. These studies indicate that dysbiosis-an imbalance in gut microbiota-may have a crucial role in ALS progression by impairing intestinal barrier integrity, promoting endotoxemia, and driving systemic inflammation. Conversely, ALS progression itself worsens dysbiosis, creating a vicious cycle of neuroinflammation and neurodegeneration. Preclinical and clinical evidence suggests that interventions targeting gut microbiota-such as prebiotics, probiotics, antibiotics, or phage therapy-could alleviate symptoms and slow disease progression and specific probiotic strains have also shown promise in reducing oxidative stress and inflammation in animal models. These findings highlight the urgent need to elucidate the functional role of gut microbiota in ALS to unlock novel diagnostic and therapeutic avenues. This review synthesizes current knowledge on the pathophysiology of ALS, with a focus on the emerging role of the gut-brain-microbiota axis. It highlights how dysbiosis influences diverse disease markers and neurodegenerative mechanisms, offering insights into potential therapeutic strategies and identifying key research gaps and future directions.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/physiopathology/microbiology/therapy
*Dysbiosis/complications/physiopathology/therapy
*Gastrointestinal Microbiome/physiology
Animals
*Brain-Gut Axis/physiology
*Brain/physiopathology

@article {pmid40608121,
year = {2025},
author = {Ruzi, Z and Zha, W and Yuan, HY and Liu, J},
title = {RNA G-quadruplexes: emerging regulators of gene expression and therapeutic targets.},
journal = {Functional & integrative genomics},
volume = {25},
number = {1},
pages = {143},
pmid = {40608121},
issn = {1438-7948},
support = {22262002//National Natural Science Foundation of China/ ; },
mesh = {*G-Quadruplexes ; Humans ; *Gene Expression Regulation ; *RNA/chemistry/genetics/metabolism ; Animals ; Neoplasms/genetics ; SARS-CoV-2 ; Neurodegenerative Diseases/genetics ; Alternative Splicing ; },
abstract = {RNA G-quadruplexes (rG4s) are non-canonical, four-stranded secondary structures formed by guanine-rich RNA sequences. These dynamic elements have garnered significant attention for their critical roles in regulating gene expression, including translation, alternative splicing, mRNA localization, and stability. This review synthesizes recent progress in understanding the structural determinants and formation dynamics of rG4s, highlighting the contributions of sequence motifs, ionic conditions, and RNA-binding proteins to their stability and function. Functional studies reveal that rG4s modulate key oncogenic transcripts (e.g., MYC, BCL2), contribute to splicing regulation, and influence intracellular RNA trafficking. In pathological contexts, rG4s have been implicated in the molecular etiology of cancers, neurodegenerative diseases such as amyotrophic lateral sclerosis and Fragile X syndrome, and viral replication mechanisms in pathogens including HIV and SARS-CoV-2. Advances in high-throughput techniques, such as G4-seq, rG4-seq, and live-cell imaging, have facilitated the global identification and characterization of rG4s in physiological and disease settings. Moreover, the therapeutic targeting of rG4s using small molecules holds promise for selective gene regulation and biomarker development. Comparative analyses across in vitro, in vivo, and clinical studies underscore the cell-type-specific and context-dependent roles of rG4s, especially in mediating stress responses and apoptosis. Despite methodological limitations and challenges in achieving targeted delivery, rG4s represent a compelling frontier for precision medicine. This review outlines current insights and future directions toward harnessing rG4 biology for therapeutic innovation.},
}

*G-Quadruplexes
Humans
*Gene Expression Regulation
*RNA/chemistry/genetics/metabolism
Animals
Neoplasms/genetics
SARS-CoV-2
Neurodegenerative Diseases/genetics
Alternative Splicing