“…It has then to be noted that, between 1981 and the early 2000s, a number of reports can be traced that somehow paved the path to the full acknowledgment of the ALS-FTD spectrum occurred with the first, dedicated nosographic system by Strong et al [ 100 ]—as indexed by a number reviews that elegantly summarized evidence at that time available, among the most remarkable being those by Strong et al [ 101 ] and Neary et al [ 79 ], with some other, relevant reports between 1981 and the early 2000s being also more recently brought to the light by Alberti et al [ 2 ]. The present work also follows up to and completes the previous one by Bak and Hodges [ 7 ], who pioneeristically addressed certain of the historical records herewith described, and is complemented by an extremely recent, historical work by Carlos and Josephs [ 22 ] who focused on the centenary journey leading to the acknowledgment of the neuropathological basis of FTD-spectrum disorders. Fig.…”
Background
Among clinicians and researchers, it is common knowledge that, in ALS, cognitive and behavioral involvement within the spectrum of frontotemporal degenerations (FTDs) begun to be regarded as a fact in the late 1990s of the twentieth century. By contrast, a considerable body of evidence on cognitive/behavioral changes in ALS can be traced in the literature dating from the late nineteenth century.
Methods
Worldwide reports on cognitive/behavioral involvement in ALS dating from 1886 to 1981 were retrieved thanks to Biblioteca di Area Medica “Adolfo Ferrate,” Sistema Bibliotecario di Ateneo, University of Pavia, Pavia, Italy and qualitatively synthetized.
Results
One-hundred and seventy-four cases of ALS with co-occurring FTD-like cognitive/behavioral changes, described in Europe, America, and Asia, were detected. Neuropsychological phenotypes were consistent with the revised Strong et al.’s consensus criteria. Clinical observations were not infrequently supported by histopathological, post-mortem verifications of extra-motor, cortical/sub-cortical alterations, as well as by in vivo instrumental exams—i.e., assessments of brain morphology/physiology and psychometric testing. In this regard, as earlier as 1907, the notion of motor and cognitive/behavioral features in ALS yielding from the same underlying pathology was acknowledged. Hereditary occurrences of ALS with cognitive/behavioral dysfunctions were reported, as well as familial associations with ALS-unrelated brain disorders. Neuropsychological symptoms often occurred before motor ones. Bulbar involvement was at times acknowledged as a risk factor for cognitive/behavioral changes in ALS.
Discussion
Historical observations herewith delivered can be regarded as the antecedents of current knowledge on cognitive/behavioral impairment in the ALS-FTD spectrum.
“…It has then to be noted that, between 1981 and the early 2000s, a number of reports can be traced that somehow paved the path to the full acknowledgment of the ALS-FTD spectrum occurred with the first, dedicated nosographic system by Strong et al [ 100 ]—as indexed by a number reviews that elegantly summarized evidence at that time available, among the most remarkable being those by Strong et al [ 101 ] and Neary et al [ 79 ], with some other, relevant reports between 1981 and the early 2000s being also more recently brought to the light by Alberti et al [ 2 ]. The present work also follows up to and completes the previous one by Bak and Hodges [ 7 ], who pioneeristically addressed certain of the historical records herewith described, and is complemented by an extremely recent, historical work by Carlos and Josephs [ 22 ] who focused on the centenary journey leading to the acknowledgment of the neuropathological basis of FTD-spectrum disorders. Fig.…”
Background
Among clinicians and researchers, it is common knowledge that, in ALS, cognitive and behavioral involvement within the spectrum of frontotemporal degenerations (FTDs) begun to be regarded as a fact in the late 1990s of the twentieth century. By contrast, a considerable body of evidence on cognitive/behavioral changes in ALS can be traced in the literature dating from the late nineteenth century.
Methods
Worldwide reports on cognitive/behavioral involvement in ALS dating from 1886 to 1981 were retrieved thanks to Biblioteca di Area Medica “Adolfo Ferrate,” Sistema Bibliotecario di Ateneo, University of Pavia, Pavia, Italy and qualitatively synthetized.
Results
One-hundred and seventy-four cases of ALS with co-occurring FTD-like cognitive/behavioral changes, described in Europe, America, and Asia, were detected. Neuropsychological phenotypes were consistent with the revised Strong et al.’s consensus criteria. Clinical observations were not infrequently supported by histopathological, post-mortem verifications of extra-motor, cortical/sub-cortical alterations, as well as by in vivo instrumental exams—i.e., assessments of brain morphology/physiology and psychometric testing. In this regard, as earlier as 1907, the notion of motor and cognitive/behavioral features in ALS yielding from the same underlying pathology was acknowledged. Hereditary occurrences of ALS with cognitive/behavioral dysfunctions were reported, as well as familial associations with ALS-unrelated brain disorders. Neuropsychological symptoms often occurred before motor ones. Bulbar involvement was at times acknowledged as a risk factor for cognitive/behavioral changes in ALS.
Discussion
Historical observations herewith delivered can be regarded as the antecedents of current knowledge on cognitive/behavioral impairment in the ALS-FTD spectrum.
“…Landmark proteomics studies on post-mortem brain extracts from FTLD and ALS patients in 2006 uncovered TDP-43 as a key protein associated with FTLD, specifically ubiquitin-positive but tau- and alpha-synuclein negative FTLD ( Arai et al, 2006 ; Neumann et al, 2006 ). This predominantly nuclear protein that was known to bind the TAR element of the human immunodeficiency virus has since been implicated in the pathogenesis of multiple neurodegenerative diseases collectively known as TDP-43 proteinopathies ( de Boer et al, 2020 ; Huang et al, 2020 ; Carlos and Josephs, 2022 ). Early studies observed TDP-43 cytoplasmic inclusions in ALS and AD ( Arai et al, 2006 ; Igaz et al, 2008 ).…”
Section: Transactivation Response Element Dna-binding Protein 43 Prot...mentioning
Understanding and ameliorating neurodegenerative diseases represents a key challenge for supporting the health span of the aging population. Diverse protein aggregates have been implicated in such neurodegenerative disorders, including amyloid-β, α-synuclein, tau, fused in sarcoma (FUS), and transactivation response element (TAR) DNA-binding protein 43 (TDP-43). Recent years have seen significant growth in our mechanistic knowledge of relationships between these proteins and some of the membrane-less nuclear structures that fulfill key roles in the cell function. These include the nucleolus, nuclear speckles, and paraspeckles. The ability of macromolecular protein:RNA complexes to partition these nuclear condensates through biophysical processes that involve liquid–liquid phase separation (LLPS) has also gained attention recently. The paraspeckle, which is scaffolded by the architectural long-non-coding RNA nuclear enriched abundant transcript 1 (NEAT1) plays central roles in RNA processing and metabolism and has been linked dynamically to TDP-43. In this mini-review, we outline essential early and recent insights in relation to TDP-43 proteinopathies. We then appraise the relationships between TDP-43 and NEAT1 in the context of neuronal paraspeckles and neuronal stress. We highlight key areas for investigation based on recent advances in our understanding of how TDP-43 affects neuronal function, especially in relation to messenger ribosomal nucleic acid (mRNA) splicing. Finally, we offer perspectives that should be considered for translational pipelines in order to improve health outcomes for the management of neurodegenerative diseases.
“…It might at least in part lead to neurodegeneration via inappropriate necroptosis of neurons (Dobson-Stone et al, 2020a,b). The pathogenesis of FTD is associated with changes in the TAR DNAbinding protein 43 (Carlos and Josephs, 2022). It has been shown that in this type of dementia, TDP-43 undergoes additional ubiquitination (Arai et al, 2006).…”
In the last few years, necroptosis, a recently described type of cell death, has been reported to play an important role in the development of various brain pathologies. Necroptosis is a cell death mechanism that has morphological characteristics similar to necrosis but is mediated by fundamentally different molecular pathways. Necroptosis is initiated by signaling through the interaction of RIP1/RIP3/MLKL proteins (receptor-interacting protein kinase 1/receptor-interacting protein kinase 3/mixed lineage kinase domain-like protein). RIPK1 kinase is usually inactive under physiological conditions. It is activated by stimulation of death receptors (TNFR1, TNFR2, TLR3, and 4, Fas-ligand) by external signals. Phosphorylation of RIPK1 results in the formation of its complex with death receptors. Further, complexes with the second member of the RIP3 and MLKL cascade appear, and the necroptosome is formed. There is enough evidence that necroptosis plays an important role in the pathogenesis of brain ischemia and neurodegenerative diseases. In recent years, a point of view that both neurons and glial cells can play a key role in the development of the central nervous system (CNS) pathologies finds more and more confirmation. Astrocytes play complex roles during neurodegeneration and ischemic brain damage initiating both impair and protective processes. However, the cellular and molecular mechanisms that induce pathogenic activity of astrocytes remain veiled. In this review, we consider these processes in terms of the initiation of necroptosis. On the other hand, it is important to remember that like other types of programmed cell death, necroptosis plays an important role for the organism, as it induces a strong immune response and is involved in the control of cancerogenesis. In this review, we provide an overview of the complex role of necroptosis as an important pathogenetic component of neuronal and astrocyte death in neurodegenerative diseases, epileptogenesis, and ischemic brain damage.
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