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International Journal of Molecular... Jul 2023Frontotemporal dementia (FTD) is a neurodegenerative disease of growing interest, since it accounts for up to 10% of middle-age-onset dementias and entails a social,... (Review)
Review
Frontotemporal dementia (FTD) is a neurodegenerative disease of growing interest, since it accounts for up to 10% of middle-age-onset dementias and entails a social, economic, and emotional burden for the patients and caregivers. It is characterised by a (at least initially) selective degeneration of the frontal and/or temporal lobe, generally leading to behavioural alterations, speech disorders, and psychiatric symptoms. Despite the recent advances, given its extreme heterogeneity, an overview that can bring together all the data currently available is still lacking. Here, we aim to provide a state of the art on the pathogenesis of this disease, starting with established findings and integrating them with more recent ones. In particular, advances in the genetics field will be examined, assessing them in relation to both the clinical manifestations and histopathological findings, as well as considering the link with other diseases, such as amyotrophic lateral sclerosis (ALS). Furthermore, the current diagnostic criteria will be explored, including neuroimaging methods, nuclear medicine investigations, and biomarkers on biological fluids. Of note, the promising information provided by neurophysiological investigations, i.e., electroencephalography and non-invasive brain stimulation techniques, concerning the alterations in brain networks and neurotransmitter systems will be reviewed. Finally, current and experimental therapies will be considered.
Topics: Middle Aged; Humans; Frontotemporal Dementia; Neurodegenerative Diseases; Pick Disease of the Brain; Amyotrophic Lateral Sclerosis; Temporal Lobe
PubMed: 37511491
DOI: 10.3390/ijms241411732 -
Cell Stem Cell Oct 2023Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy. One-third of patients have drug-refractory seizures and are left with suboptimal therapeutic...
Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy. One-third of patients have drug-refractory seizures and are left with suboptimal therapeutic options such as brain tissue-destructive surgery. Here, we report the development and characterization of a cell therapy alternative for drug-resistant MTLE, which is derived from a human embryonic stem cell line and comprises cryopreserved, post-mitotic, medial ganglionic eminence (MGE) pallial-type GABAergic interneurons. Single-dose intrahippocampal delivery of the interneurons in a mouse model of chronic MTLE resulted in consistent mesiotemporal seizure suppression, with most animals becoming seizure-free and surviving longer. The grafted interneurons dispersed locally, functionally integrated, persisted long term, and significantly reduced dentate granule cell dispersion, a pathological hallmark of MTLE. These disease-modifying effects were dose-dependent, with a broad therapeutic range. No adverse effects were observed. These findings support an ongoing phase 1/2 clinical trial (NCT05135091) for drug-resistant MTLE.
Topics: Mice; Animals; Humans; Hippocampus; Epilepsy, Temporal Lobe; Seizures; Interneurons; Brain
PubMed: 37802038
DOI: 10.1016/j.stem.2023.08.013 -
Science (New York, N.Y.) Oct 2023The cognitive abilities of humans are distinctive among primates, but their molecular and cellular substrates are poorly understood. We used comparative single-nucleus...
The cognitive abilities of humans are distinctive among primates, but their molecular and cellular substrates are poorly understood. We used comparative single-nucleus transcriptomics to analyze samples of the middle temporal gyrus (MTG) from adult humans, chimpanzees, gorillas, rhesus macaques, and common marmosets to understand human-specific features of the neocortex. Human, chimpanzee, and gorilla MTG showed highly similar cell-type composition and laminar organization as well as a large shift in proportions of deep-layer intratelencephalic-projecting neurons compared with macaque and marmoset MTG. Microglia, astrocytes, and oligodendrocytes had more-divergent expression across species compared with neurons or oligodendrocyte precursor cells, and neuronal expression diverged more rapidly on the human lineage. Only a few hundred genes showed human-specific patterning, suggesting that relatively few cellular and molecular changes distinctively define adult human cortical structure.
Topics: Animals; Humans; Gene Expression Profiling; Gorilla gorilla; Hominidae; Macaca mulatta; Pan troglodytes; Phylogeny; Transcriptome; Neocortex; Species Specificity; Temporal Lobe; Cognition
PubMed: 37824638
DOI: 10.1126/science.ade9516 -
Journal of Neuroinflammation Jul 2023Impaired activation and regulation of the extinction of inflammatory cells and molecules in injured neuronal tissues are key factors in the development of epilepsy....
Impaired activation and regulation of the extinction of inflammatory cells and molecules in injured neuronal tissues are key factors in the development of epilepsy. SerpinA3N is mainly associated with the acute phase response and inflammatory response. In our current study, transcriptomics analysis, proteomics analysis, and Western blotting showed that the expression level of Serpin clade A member 3N (SerpinA3N) is significantly increased in the hippocampus of mice with kainic acid (KA)-induced temporal lobe epilepsy, and this molecule is mainly expressed in astrocytes. Notably, in vivo studies using gain- and loss-of-function approaches revealed that SerpinA3N in astrocytes promoted the release of proinflammatory factors and aggravated seizures. Mechanistically, RNA sequencing and Western blotting showed that SerpinA3N promoted KA-induced neuroinflammation by activating the NF-κB signaling pathway. In addition, co-immunoprecipitation revealed that SerpinA3N interacts with ryanodine receptor type 2 (RYR2) and promotes RYR2 phosphorylation. Overall, our study reveals a novel SerpinA3N-mediated mechanism in seizure-induced neuroinflammation and provides a new target for developing neuroinflammation-based strategies to reduce seizure-induced brain injury.
Topics: Animals; Mice; Astrocytes; Epilepsy, Temporal Lobe; Hippocampus; Kainic Acid; Neuroinflammatory Diseases; NF-kappa B; Ryanodine Receptor Calcium Release Channel; Seizures; Signal Transduction; Serpins
PubMed: 37422673
DOI: 10.1186/s12974-023-02840-8 -
Nature Jan 2024Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated...
Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.
Topics: Humans; Amyloid; Brain Stem; Cryoelectron Microscopy; Frontotemporal Dementia; Frontotemporal Lobar Degeneration; Motor Cortex; Motor Neurons; Prefrontal Cortex; TATA-Binding Protein Associated Factors; Temporal Lobe
PubMed: 38057661
DOI: 10.1038/s41586-023-06801-2 -
PLoS Biology Aug 2023Music is core to human experience, yet the precise neural dynamics underlying music perception remain unknown. We analyzed a unique intracranial electroencephalography...
Music is core to human experience, yet the precise neural dynamics underlying music perception remain unknown. We analyzed a unique intracranial electroencephalography (iEEG) dataset of 29 patients who listened to a Pink Floyd song and applied a stimulus reconstruction approach previously used in the speech domain. We successfully reconstructed a recognizable song from direct neural recordings and quantified the impact of different factors on decoding accuracy. Combining encoding and decoding analyses, we found a right-hemisphere dominance for music perception with a primary role of the superior temporal gyrus (STG), evidenced a new STG subregion tuned to musical rhythm, and defined an anterior-posterior STG organization exhibiting sustained and onset responses to musical elements. Our findings show the feasibility of applying predictive modeling on short datasets acquired in single patients, paving the way for adding musical elements to brain-computer interface (BCI) applications.
Topics: Humans; Auditory Cortex; Music; Brain Mapping; Auditory Perception; Temporal Lobe; Acoustic Stimulation
PubMed: 37582062
DOI: 10.1371/journal.pbio.3002176