Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder.
Ontology highlight
ABSTRACT:
SUBMITTER: De Marchi F
PROVIDER: S-EPMC10295684 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
Publications
Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder.
De Marchi Fabiola F Franjkic Toni T Schito Paride P Russo Tommaso T Nimac Jerneja J Chami Anna A AA Mele Angelica A Vidatic Lea L Kriz Jasna J Julien Jean-Pierre JP Apic Gordana G Russell Robert B RB Russell Robert B RB Rogelj Boris B Cannon Jason R JR Baralle Marco M Agosta Federica F Hecimovic Silva S Mazzini Letizia L Buratti Emanuele E Munitic Ivana I
Biomedicines 20230531 6
Proteinopathy and neuroinflammation are two main hallmarks of neurodegenerative diseases. They also represent rare common events in an exceptionally broad landscape of genetic, environmental, neuropathologic, and clinical heterogeneity present in patients. Here, we aim to recount the emerging trends in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorder. Our review will predominantly focus on neuroinflammation and systemic immune imbalance in ALS and FTD, ...[more]
Similar Datasets
Project description:Nuclear clearance and cytoplasmic mislocalization of the essential RNA binding protein, TDP-43, is a pathologic hallmark of amyotrophic lateral sclerosis, frontotemporal dementia, and related neurodegenerative disorders collectively termed "TDP-43 proteinopathies." TDP-43 mislocalization causes neurodegeneration through both loss and gain of function mechanisms. Loss of TDP-43 nuclear RNA processing function destabilizes the transcriptome by multiple mechanisms including disruption of pre-mRNA splicing, the failure of repression of cryptic exons, and retrotransposon activation. The accumulation of cytoplasmic TDP-43, which is prone to aberrant liquid-liquid phase separation and aggregation, traps TDP-43 in the cytoplasm and disrupts a host of downstream processes including the trafficking of RNA granules, local translation within axons, and mitochondrial function. In this review, we will discuss the TDP-43 therapy development pipeline, beginning with therapies in current and upcoming clinical trials, which are primarily focused on accelerating the clearance of TDP-43 aggregates. Then, we will look ahead to emerging strategies from preclinical studies, first from high-throughput genetic and pharmacologic screens, and finally from mechanistic studies focused on the upstream cause(s) of TDP-43 disruption in ALS/FTD. These include modulation of stress granule dynamics, TDP-43 nucleocytoplasmic shuttling, RNA metabolism, and correction of aberrant splicing events.
| S-EPMC9587158 | biostudies-literature
Project description:There is an increasing interest in the study of the relation between alterations in systemic lipid metabolism and neurodegenerative disorders, in particular in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). In ALS these alterations are well described and evident not only with the progression of the disease but also years before diagnosis. Still, there are some discrepancies in findings relating to the causal nature of lipid metabolic alterations, partly due to the great clinical heterogeneity in ALS. ALS presentation is within a disorder spectrum with Frontotemporal Dementia (FTD), and many patients present mixed forms of ALS and FTD, thus increasing the variability. Lipid metabolic and other systemic metabolic alterations have not been well studied in FTD, or in ALS-FTD mixed forms, as has been in pure ALS. With the recent development in lipidomics and the integration with other -omics platforms, there is now emerging data that not only facilitates the identification of biomarkers but also enables understanding of the underlying pathological mechanisms. Here, we reviewed the recent literature to compile lipid metabolic alterations in ALS, FTD, and intermediate mixed forms, with a view to appraising key commonalities or differences within the spectrum.
| S-EPMC9138405 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprise a spectrum of neurodegenerative diseases linked to TDP-43 proteinopathy, which at the cellular level, is characterized by loss of nuclear TDP-43 and accumulation of cytoplasmic TDP-43 inclusions that ultimately cause RNA processing defects including dysregulation of splicing, mRNA transport and translation. Complementing our previous work in motor neurons, here we report a novel model of TDP-43 proteinopathy based on overexpression of TDP-43 in a subset of Drosophila Kenyon cells of the mushroom body (MB), a circuit with structural characteristics reminiscent of vertebrate cortical networks. This model recapitulates several aspects of dementia-relevant pathological features including age-dependent neuronal loss, nuclear depletion and cytoplasmic accumulation of TDP-43, and behavioral deficits in working memory and sleep that occur prior to axonal degeneration. RNA immunoprecipitations identify several candidate mRNA targets of TDP-43 in MBs, some of which are unique to the MB circuit and others that are shared with motor neurons. Among the latter is the glypican Dally-like-protein (Dlp), which exhibits significant TDP-43 associated reduction in expression during aging. Using genetic interactions we show that overexpression of Dlp in MBs mitigates TDP-43 dependent working memory deficits, conistent with Dlp acting as a mediator of TDP-43 toxicity. Substantiating our findings in the fly model, we find that the expression of GPC6 mRNA, a human ortholog of dlp, is specifically altered in neurons exhibiting the molecular signature of TDP-43 pathology in FTD patient brains. These findings suggest that circuit-specific Drosophila models provide a platform for uncovering shared or disease-specific molecular mechanisms and vulnerabilities across the spectrum of TDP-43 proteinopathies.
| S-EPMC10588218 | biostudies-literature
Project description:ObjectiveThe aims of this study were to (i) explore psychotic experiences across the entire amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum from a clinical and genetic perspective, (ii) determine the rate of abnormal perceptual experiences across the five sensory modalities and (iii) explore the neurobiological factors that lead to psychosis vulnerability in ALS-FTD.MethodsIn a prospective case-controlled study design, 100 participants were enrolled including ALS (n = 37, 24% satisfied criteria for ALS-Plus), ALS-FTD (n = 11), bvFTD (n = 27) and healthy controls (n = 25). Psychotic experiences, perceptual abnormalities and psychosocial factors were determined by means of the clinical interview and carer and patient reports. Voxel-based morphometry analyses determined atrophy patterns in patients experiencing psychosis-like experiences and other perceptual abnormalities.ResultsThe rates of psychotic experiences and abnormalities of perception in each sensory modality were high across the entire ALS-FTD continuum. The rate was highest in those with C9orf72 expansions. Rates were also high in patients with pure ALS including psychosis measured by carer-based reports (18%) and self-report measures of psychotic-like experiences (21%). In an ENTER regression model, social anxiety and ACE-III scores were the best predictors of psychosis proneness, accounting for 44% of the score variance. Psychosis-like experiences and perceptual abnormalities were associated with a predominantly frontal and temporal pattern of atrophy that extended to the cerebellum and centred on the anterior thalamus.InterpretationThe model for psychosis proneness in ALS-FTD likely includes complex interactions between cognitive, social and neurobiological factors that determine vulnerability to psychosis and that may have relevance for individualised patient management.
| S-EPMC8351398 | biostudies-literature
Project description:IntroductionFrontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two phenotypes of the same neurodegenerative disease, the FTD-ALS spectrum. What determines the development of one rather than the other phenotype is still unknown. Based on the clinical observation that patients' personality seems to differ between the two phenotypes, i.e., ALS patients tend to display kind, prosocial behaviors whereas FTD patients tend to present anti-social behaviors, and that these traits are often reported as pre-existing the disease onset by caregivers, we set up to study experimentally patients' personality in their premorbid life.MethodsWe first tested for differences between groups, then tested the association between premorbid personality and current functional organization of the brain. Premorbid personality of a cohort of forty patients, 27 FTD and 13 ALS, was explored through the NEO Personality Inventory 3 (NEO-PI-3), which analyses the five main personality factors, completed by the caregiver with reference to patient's personality 20 years before symptoms onset (premorbid). A subgroup of patients underwent a brain MRI including structural and resting-state functional MRI (rsfMRI).ResultsA significant difference between FTD and ALS in premorbid personality emerged in the Openness (133.92 FTD vs. 149.84 ALS, p = 0.01) and Extraversion (136.55 FTD vs. 150.53 ALS, p = 0.04) factors. This suggests that ALS patients had been, in their premorbid life, more open to new experiences, more sociable and optimistic than FTD patients. They also showed greater functional connectivity than both FTD and a control group in the Salience resting state network, over and above differences in gray matter atrophy. Finally, there was a positive correlation between premorbid Openness and functional connectivity in the Salience network across all patients, suggesting a possible association between premorbid personality and current functional organization of the brain, irrespective of the degree of atrophy.DiscussionOur proof-of-concept results suggest that premorbid personality may eventually predispose to the development of one, rather than the other, phenotype in the FTD-ALS spectrum.
| S-EPMC10582748 | biostudies-literature
Project description:BackgroundTDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS-FTD spectrum.MethodsWe used a data-driven procedure to identify 13 anatomic clusters of brain volume for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS-FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS-FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease.ResultsSuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy in either prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 types B, E and C. In contrast, the prefrontal/somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS-FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. The overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King's stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology.ConclusionsOur findings suggest distinct neurodegenerative subtypes of disease along the ALS-FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns.
| S-EPMC10701950 | biostudies-literature
Project description:BackgroundTDP-43 proteinopathies represents a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS-FTD spectrum.MethodsWe used a data-driven procedure to identify 13 anatomic clusters of brain volumes for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS-FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS-FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease.ResultsSuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy either in prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The Limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 type B, E and C. In contrast, the Prefrontal/Somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS-FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. Overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King's stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology.ConclusionsOur findings suggest distinct neurodegenerative subtypes of disease along the ALS-FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns.
| S-EPMC10441467 | biostudies-literature
Project description:ObjectiveMutations in the gene encoding for optineurin (OPTN) have been reported in the context of different neurodegenerative diseases including the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. Based on single case reports, neuropathological data in OPTN mutation carriers have revealed transactive response DNA-binding protein 43 kDa (TDP-43) pathology, in addition to accumulations of tau and alpha-synuclein. Herein, we present two siblings from a consanguineous family with a homozygous frameshift mutation in the OPTN gene and different clinical presentations.MethodsBoth affected siblings underwent (i) clinical, (ii) neurophysiological, (iii) neuropsychological, (iv) radiological, and (v) laboratory examinations, and (vi) whole-exome sequencing (WES). Postmortem histopathological examination was conducted in the index patient, who deceased at the age of 41.ResultsThe index patient developed rapidly progressing clinical features of upper and lower motor neuron dysfunction as well as apathy and cognitive deterioration at the age of 41. Autopsy revealed an ALS-FTLD pattern associated with prominent neuronal and oligodendroglial TDP-43 pathology, and an atypical limbic 4-repeat tau pathology reminiscent of argyrophilic grain disease. The brother of the index patient exhibited behavioral changes and mnestic deficits at the age of 38 and was diagnosed with behavioral FTD 5 years later, without any evidence of motor neuron dysfunction. WES revealed a homozygous frameshift mutation in the OPTN gene in both siblings (NM_001008212.2: c.1078_1079del; p.Lys360ValfsTer18).InterpretationOPTN mutations can be associated with extensive TDP-43 pathology and limbic-predominant tauopathy and present with a heterogeneous clinical phenotype within the ALS-FTD spectrum within the same family.
| S-EPMC11187959 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of both upper and lower motor neurons (MNs) in the brain, brainstem and spinal cord. The neurodegenerative mechanisms leading to MN loss in ALS are not fully understood. Importantly, the reasons why MNs are specifically targeted in this disorder are unclear, when the proteins associated genetically or pathologically with ALS are expressed ubiquitously. Furthermore, MNs themselves are not affected equally; specific MNs subpopulations are more susceptible than others in both animal models and human patients. Corticospinal MNs and lower somatic MNs, which innervate voluntary muscles, degenerate more readily than specific subgroups of lower MNs, which remain resistant to degeneration, reflecting the clinical manifestations of ALS. In this review, we discuss the possible factors intrinsic to MNs that render them uniquely susceptible to neurodegeneration in ALS. We also speculate why some MN subpopulations are more vulnerable than others, focusing on both their molecular and physiological properties. Finally, we review the anatomical network and neuronal microenvironment as determinants of MN subtype vulnerability and hence the progression of ALS.
| S-EPMC6610326 | biostudies-literature
Project description:ObjectiveTo investigate cognitive impairments in amyotrophic lateral sclerosis (ALS), extending both within and beyond the established frontotemporal dementia (FTD) spectrum, using the Complementary Cognitive ALS Screen (C-CAS).MethodsThe C-CAS, designed to complement the Edinburgh cognitive and behavioural ALS screen (ECAS), explores cognitive (sub)domains not investigated by the ECAS. Normative data were collected, and models adjusted for age, sex, and education level were developed. Item scores below the 5th percentile in controls were considered abnormal. A sum score was constructed, and C-CAS impairments were compared between ALS patients and controls, and to ECAS impairments.ResultsData from 314 controls and 184 ALS patients were analyzed. The C-CAS is feasible, well-tolerated, and takes 15-20 min to complete. ALS patients performed worse across all 12 items. Within the FTD spectrum, impairments in social cognition, inhibition, and cognitive flexibility were identified in up to 16%, 14%, and 12% of ALS patients, respectively, with minimal overlap with ECAS impairments. Beyond the FTD spectrum, impairments were found in visuoconstruction, incidental non-verbal memory and body orientation (13% each), with minimal overlap with ECAS memory or visuospatial impairments. Overall, 24% of the ALS patients obtained an abnormal C-CAS sum score. Compared to the ECAS, the C-CAS detected additional impairments in 15% of ALS patients. Item-specific and sum score results based on normative data can be accessed at ( https://apps4mnd.com/ccas/ ).InterpretationWe identified cognitive impairments in ALS within and beyond the FTD spectrum not captured by existing screening tools. The C-CAS complements the ECAS, improving personalized counseling and research stratification in ALS.
| S-EPMC11903523 | biostudies-literature