RESUMO
BACKGROUND: Brain MRI with volumetric quantification, MRI volumetry, can improve diagnostic delineation of patients with neurocognitive disorders by identifying brain atrophy that may not be evident on visual assessments. OBJECTIVE: To investigate diagnostic utility of MRI volumetry in traumatic brain injury (TBI), early-onset Alzheimer disease (EOAD), late-onset Alzheimer disease, and behavioral variant frontotemporal dementia (bvFTD). METHOD: We utilized 137 participants of TBI (n = 40), EOAD (n = 45), LOAD (n = 32), and bvFTD (n = 20). Participants had 3D T1 brain MRI imaging amendable to MRI volumetry. Scan volumes were analyzed with Neuroreader. One-way ANOVA compared brain volumes across diagnostic groups. Discriminant analysis was done with leave-one-out cross validation on Neuroreader metrics to determine diagnostic delineation across groups. RESULT: LOAD was the oldest compared to other groups (F = 27.5, p < .001). There were no statistically significant differences in sex (p = .58) with women comprising 54.7% of the entire cohort. EOAD and LOAD had the lowest Mini-Mental State Exam (MMSE) scores compared to TBI (p = .04 for EOAD and p = .01 for LOAD). LOAD had lowest hippocampal volumes (Left Hippocampus F = 13.1, Right Hippocampus F = 7.3, p < .001), low white matter volume in TBI (F = 5.9, p < .001), lower left parietal lobe volume in EOAD (F = 9.4, p < .001), and lower total gray matter volume in bvFTD (F = 32.8, p < .001) and caudate atrophy (F = 1737.5, p < .001). Areas under the curve ranged from 92.3 to 100%, sensitivity between 82.2 and 100%, specificity of 78.1-100%. TBI was the most accurately delineated diagnosis. Predictive features included caudate, frontal, parietal, temporal lobar and total white matter volumes. CONCLUSION: We identified the diagnostic utility of regional volumetric differences across multiple neurocognitive disorders. Brain MRI volumetry is widely available and can be applied in distinguishing these disorders.
Assuntos
Doença de Alzheimer , Lesões Encefálicas Traumáticas , Encéfalo , Demência Frontotemporal , Imageamento por Ressonância Magnética , Humanos , Feminino , Masculino , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/patologia , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/patologia , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Adulto , Atrofia/patologia , Diagnóstico DiferencialRESUMO
BACKGROUND AND OBJECTIVES: Behavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy. METHODS: We analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 (c9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT) gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms. RESULTS: A total of 522 participants were included: 221 c9orf72 (138 presymptomatic), 213 GRN (157 presymptomatic), and 88 MAPT (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In c9orf72 and GRN pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in MAPT pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum (p < 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms (p < 0.05). Particularly, in c9orf72 pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness. DISCUSSION: We identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.
Assuntos
Proteína C9orf72 , Demência Frontotemporal , Progranulinas , Proteínas tau , Humanos , Demência Frontotemporal/genética , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/patologia , Demência Frontotemporal/psicologia , Masculino , Feminino , Proteína C9orf72/genética , Pessoa de Meia-Idade , Progranulinas/genética , Proteínas tau/genética , Idoso , Estudos Longitudinais , Atrofia/patologia , Sintomas Comportamentais/etiologia , Sintomas Comportamentais/genética , Imageamento por Ressonância Magnética , Transtornos Mentais/genética , Estudos de Coortes , Fenótipo , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging and experimental studies indicate early changes in brain structure and connectivity in C9-ALS/FTD, even before symptom onset. Because these early disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, and controls. Our work revealed the presence of all three C9-HRE-related molecular pathologies and developmental stage-dependent size phenotypes in cerebral organoids from C9-ALS/FTD patients. In addition, single-cell RNA sequencing identified changes in cell type abundance and distribution in C9-ALS/FTD organoids, including a reduction in the number of deep layer cortical neurons and the distribution of neural progenitors. Further, molecular and cellular analyses and patch-clamp electrophysiology detected various changes in synapse structure and function. Intriguingly, organoids from all presymptomatic C9-HRE carriers displayed C9-HRE molecular pathology, whereas the extent to which more downstream cellular defects, as found in C9-ALS/FTD models, were detected varied for the different presymptomatic C9-HRE cases. Together, these results unveil early changes in 3D human brain tissue organization and synaptic connectivity in C9-ALS/FTD that likely constitute initial pathologies crucial for understanding disease onset and the design of therapeutic strategies.
Assuntos
Esclerose Lateral Amiotrófica , Proteína C9orf72 , Demência Frontotemporal , Células-Tronco Pluripotentes Induzidas , Organoides , Sinapses , Humanos , Organoides/patologia , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Proteína C9orf72/genética , Células-Tronco Pluripotentes Induzidas/patologia , Sinapses/patologia , Sinapses/genética , Masculino , Feminino , Córtex Cerebral/patologia , Expansão das Repetições de DNA/genéticaRESUMO
Hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion results in multiple dipeptide repeat proteins, among which arginine-rich poly-GR proteins are highly toxic to neurons and decrease the rate of protein synthesis. We investigated whether the effect on protein synthesis contributes to neuronal dysfunction and degeneration. We found that the expression of poly-GR proteins inhibited global translation by perturbing translation elongation. In iPSC-differentiated neurons, the translation of transcripts with relatively slow elongation rates was further slowed, and stalled, by poly-GR. Elongation stalling increased ribosome collisions and induced a ribotoxic stress response (RSR) mediated by ZAKα that increased the phosphorylation of the kinase p38 and promoted cell death. Knockdown of ZAKα or pharmacological inhibition of p38 ameliorated poly-GR-induced toxicity and improved the survival of iPSC-derived neurons from patients with C9ORF72-ALS/FTD. Our findings suggest that targeting the RSR may be neuroprotective in patients with ALS/FTD caused by repeat expansion in C9ORF72.
Assuntos
Esclerose Lateral Amiotrófica , Proteína C9orf72 , Expansão das Repetições de DNA , Demência Frontotemporal , Células-Tronco Pluripotentes Induzidas , Neurônios , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Humanos , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Neurônios/metabolismo , Neurônios/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Expansão das Repetições de DNA/genética , Elongação Traducional da Cadeia Peptídica , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Estresse Fisiológico/genética , Ribossomos/metabolismo , Ribossomos/genéticaRESUMO
Lysosomes play a pivotal role in coordinating macromolecule degradation and regulating cell growth and metabolism. Despite substantial progress in identifying lysosomal signaling proteins, understanding the pathways that synchronize lysosome functions with changing cellular demands remains incomplete. This study uncovers a role for TANK-binding kinase 1 (TBK1), well known for its role in innate immunity and organelle quality control, in modulating lysosomal responsiveness to nutrients. Specifically, we identify a pool of TBK1 that is recruited to lysosomes in response to elevated amino acid levels. This lysosomal TBK1 phosphorylates Rab7 on serine 72. This is critical for alleviating Rab7-mediated inhibition of amino acid-dependent mTORC1 activation. Furthermore, a TBK1 mutant (E696K) associated with amyotrophic lateral sclerosis and frontotemporal dementia constitutively accumulates at lysosomes, resulting in elevated Rab7 phosphorylation and increased mTORC1 activation. This data establishes the lysosome as a site of amino acid regulated TBK1 signaling that is crucial for efficient mTORC1 activation. This lysosomal pool of TBK1 has broader implications for lysosome homeostasis, and its dysregulation could contribute to the pathogenesis of ALS-FTD.
Assuntos
Aminoácidos , Lisossomos , Alvo Mecanístico do Complexo 1 de Rapamicina , Proteínas Serina-Treonina Quinases , proteínas de unión al GTP Rab7 , Humanos , Aminoácidos/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Demência Frontotemporal/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Células HEK293 , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab de Ligação ao GTP/genética , Transdução de SinaisRESUMO
BACKGROUND: Several variants of sequestosome 1 (SQSTM1) were screened in patients with amyotrophic lateral sclerosis (ALS), while the pathogenicity and genotype-phenotype correlation remains unclear. METHODS: We screened variants of SQSTM1 gene in 2011 Chinese patients with ALS and performed a burden analysis focusing on the rare variants. Furthermore, we conducted a comprehensive analysis of patients with variants of SQSTM1 gene in patients with ALS from our cohort and published studies. RESULTS: In our cohort, we identified 32 patients with 25 different SQSTM1 variants with a mutant frequency of 1.6%. Notably, 26% (5/19) of the patients with ALS with SQSTM1 variant in our cohort had comorbid cognitive impairment and 43% (3/7) of them had behavioural variant frontotemporal dementia (FTD). Our meta-analysis found a total frequency of SQSTM1 variants in 7183 patients with ALS was 2.4%; burden analysis indicated that patients with ALS had enrichment of ultra-rare (minor allele frequency<0.01%) probably pathogenic variants in SQSTM1. Most variants were missense variants and distributed in various domains of p62 protein, some of which might be related to comorbidities of Paget's disease of bone and FTD. CONCLUSION: Our study established the largest cohort of patients with ALS with SQSTM1 variants, expanded the mutation spectrum and investigated the genotype-phenotype correlations of SQSTM1 variants.
Assuntos
Esclerose Lateral Amiotrófica , Estudos de Associação Genética , Proteína Sequestossoma-1 , Humanos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/epidemiologia , Proteína Sequestossoma-1/genética , Feminino , Masculino , Pessoa de Meia-Idade , Frequência do Gene , Predisposição Genética para Doença , Mutação , Idoso , Adulto , Fenótipo , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , GenótipoRESUMO
Diminished basal parasympathetic nervous system activity is a feature of frontotemporal dementia that relates to left frontoinsula dysfunction and empathy impairment. Individuals with a pathogenic expansion of the hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis, provide a unique opportunity to examine whether parasympathetic activity is disrupted in genetic forms of frontotemporal dementia and to investigate when parasympathetic deficits manifest in the pathophysiological cascade. We measured baseline respiratory sinus arrhythmia, a parasympathetic measure of heart rate variability, over two minutes in a sample of 102 participants that included 19 asymptomatic expansion carriers (C9+ asymp), 14 expansion carriers with mild cognitive impairment (C9+ MCI), 16 symptomatic expansion carriers with frontotemporal dementia (C9+ FTD), and 53 expansion-negative healthy controls (C9- HC) who also underwent structural magnetic resonance imaging. In follow-up analyses, we compared baseline respiratory sinus arrhythmia in the C9+ FTD group with an independent age-, sex-, and clinical severity-matched group of 26 people with sporadic behavioral variant frontotemporal dementia. The Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating-Sum of Boxes score was used to quantify behavioral symptom severity, and informant ratings on the Interpersonal Reactivity Index provided measures of participants' current emotional (empathic concern) and cognitive (perspective-taking) empathy. Results indicated that the C9+ FTD group had lower baseline respiratory sinus arrhythmia than the C9+ MCI, C9+ asymp, and C9- HC groups, a deficit that was comparable to that of sporadic behavioral variant frontotemporal dementia. Linear regression analyses indicated that lower baseline respiratory sinus arrhythmia was associated with worse behavioral symptom severity and lower empathic concern and perspective-taking across the C9orf72 expansion carrier clinical spectrum. Whole-brain voxel-based morphometry analyses in participants with C9orf72 pathogenic expansions found that lower baseline respiratory sinus arrhythmia correlated with smaller gray matter volume in the left frontoinsula and bilateral thalamus, key structures that support parasympathetic function, and in the bilateral parietal lobes, occipital lobes, and cerebellum, regions that are also vulnerable in individuals with C9orf72 expansions. This study provides novel evidence that basal parasympathetic functioning is diminished in FTD due to C9orf72 expansions and suggests that baseline respiratory sinus arrhythmia may be a potential non-invasive biomarker that is sensitive to behavioral symptoms in the early stages of disease.
Assuntos
Proteína C9orf72 , Disfunção Cognitiva , Expansão das Repetições de DNA , Empatia , Demência Frontotemporal , Imageamento por Ressonância Magnética , Sistema Nervoso Parassimpático , Tálamo , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Proteína C9orf72/genética , Idoso , Empatia/fisiologia , Demência Frontotemporal/genética , Demência Frontotemporal/fisiopatologia , Demência Frontotemporal/patologia , Demência Frontotemporal/diagnóstico por imagem , Expansão das Repetições de DNA/genética , Imageamento por Ressonância Magnética/métodos , Sistema Nervoso Parassimpático/fisiopatologia , Tálamo/diagnóstico por imagem , Tálamo/fisiopatologia , Tálamo/patologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Heterozigoto , Arritmia Sinusal Respiratória/fisiologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiopatologia , Córtex Cerebral/patologiaRESUMO
AIMS: Mutations in the MAPT gene encoding tau protein can cause autosomal dominant neurodegenerative tauopathies including frontotemporal dementia (often with Parkinsonism). In Alzheimer's disease, the most common tauopathy, synapse loss is the strongest pathological correlate of cognitive decline. Recently, Positron Emission Tomography (PET) imaging with synaptic tracers revealed clinically relevant loss of synapses in primary tauopathies; however, the molecular mechanisms leading to synapse degeneration in primary tauopathies remain largely unknown. In this study, we examined post-mortem brain tissue from people who died with frontotemporal dementia with tau pathology (FTDtau) caused by the MAPT intronic exon 10 + 16 mutation, which increases splice variants containing exon 10 resulting in higher levels of tau with four microtubule-binding domains. METHODS: We used RNA sequencing and histopathology to examine temporal cortex and visual cortex, to look for molecular phenotypes compared to age, sex and RNA integrity matched participants who died without neurological disease (n = 12 FTDtau10 + 16 and 13 controls). RESULTS: Bulk tissue RNA sequencing reveals substantial downregulation of gene expression associated with synaptic function. Upregulated biological pathways in human MAPT 10 + 16 brain included those involved in transcriptional regulation, DNA damage response and neuroinflammation. Histopathology confirmed increased pathological tau accumulation in FTDtau10 + 16 cortex as well as a loss of presynaptic protein staining and region-specific increased colocalization of phospho-tau with synapses in temporal cortex. CONCLUSIONS: Our data indicate that synaptic pathology likely contributes to pathogenesis in FTDtau10 + 16 caused by the MAPT 10 + 16 mutation.
Assuntos
Demência Frontotemporal , Mutação , Sinapses , Proteínas tau , Humanos , Proteínas tau/genética , Proteínas tau/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Masculino , Feminino , Sinapses/patologia , Sinapses/metabolismo , Idoso , Pessoa de Meia-Idade , Expressão Gênica/genética , Encéfalo/patologia , Encéfalo/metabolismo , Tauopatias/genética , Tauopatias/patologia , Tauopatias/metabolismoRESUMO
INTRODUCTION: First reports associated mutations in triggering receptors expressed on myeloid cells 2 (TREM2) with autosomal recessive Nasu-Hakola disease characterized by painful bone cysts and progressive presenile dementia with psychotic symptoms; however, recent TREM2 biallelic rare variants are suggested to be causative also for the behavioral variant of frontotemporal dementia (bvFTD) without bone involvement. MATERIAL AND METHODS: Clinical data of three unrelated bvFTD patients carrying TREM2 biallelic variants were evaluated. All patients underwent neurological, psychiatric, and cognitive evaluation and neuroimaging. A full neuropsychological assessment was performed in two cases. RESULTS: Two patients carried compound heterozygous TREM2 variants, p.R62C and p.T66M, and one carried the homozygous p.D87N variant. Based on all obtained clinical and neuroimaging data, a behavioral variant of frontotemporal dementia was diagnosed in all cases. Their clinical manifestation was typical with neuropsychiatric and cognitive features, without bone abnormalities. CONCLUSIONS: Despite all three subjects partially resembling clinical manifestations of Nasu-Hakola disease with TREM2 mutations, we reveal some distinct features, including age of onset, neuroimaging findings, or disease course.
Assuntos
Demência Frontotemporal , Glicoproteínas de Membrana , Receptores Imunológicos , Humanos , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Receptores Imunológicos/genética , Glicoproteínas de Membrana/genética , Masculino , Feminino , Pessoa de Meia-Idade , Mutação/genética , Panencefalite Esclerosante Subaguda/genética , Adulto , Osteocondrodisplasias/genética , Lipodistrofia/genéticaRESUMO
INTRODUCTION: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases. METHODS: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative. RESULTS: PVS was significantly associated with sEF (c = -0.125 ± 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH. DISCUSSION: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia. HIGHLIGHTS: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease.
Assuntos
Biomarcadores , Função Executiva , Proteína Glial Fibrilar Ácida , Sistema Glinfático , Imageamento por Ressonância Magnética , Doenças Neurodegenerativas , Substância Branca , Humanos , Proteína Glial Fibrilar Ácida/sangue , Feminino , Masculino , Idoso , Função Executiva/fisiologia , Doenças Neurodegenerativas/sangue , Biomarcadores/sangue , Sistema Glinfático/patologia , Sistema Glinfático/diagnóstico por imagem , Substância Branca/patologia , Substância Branca/diagnóstico por imagem , Disfunção Cognitiva/sangue , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Demência Frontotemporal/sangue , Demência Frontotemporal/patologia , Demência Frontotemporal/diagnóstico por imagem , Transtornos Cerebrovasculares/sangue , Transtornos Cerebrovasculares/diagnóstico por imagem , Transtornos Cerebrovasculares/patologia , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Estudos de Coortes , Pessoa de Meia-IdadeRESUMO
Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) are the two major neurodegenerative diseases with distinct clinical and neuropathological profiles. The aim of this report is to conduct a population-based investigation in well-characterized APP, PSEN1, PSEN2, MAPT, GRN, and C9orf72 mutation carriers/pedigrees from the north, the center, and the south of Italy. We retrospectively analyzed the data of 467 Italian individuals. We identified 21 different GRN mutations, 20 PSEN1, 11 MAPT, 9 PSEN2, and 4 APP. Moreover, we observed geographical variability in mutation frequencies by looking at each cohort of participants, and we observed a significant difference in age at onset among the genetic groups. Our study provides evidence that age at onset is influenced by the genetic group. Further work in identifying both genetic and environmental factors that modify the phenotypes in all groups is needed. Our study reveals Italian regional differences among the most relevant AD/FTD causative genes and emphasizes how the collaborative studies in rare diseases can provide new insights to expand knowledge on genetic/epigenetic modulators of age at onset.
Assuntos
Doença de Alzheimer , Demência Frontotemporal , Mutação , Proteínas tau , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/epidemiologia , Itália/epidemiologia , Demência Frontotemporal/genética , Demência Frontotemporal/epidemiologia , Demência Frontotemporal/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Proteínas tau/genética , Idade de Início , Proteína C9orf72/genética , Presenilina-2/genética , Estudos Retrospectivos , Precursor de Proteína beta-Amiloide/genética , Presenilina-1/genética , Progranulinas/genética , Adulto , Idoso de 80 Anos ou mais , Predisposição Genética para DoençaRESUMO
INTRODUCTION: Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization. METHODS: We described the clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S's effect on ANXA11 function and TDP-43 biology was characterized in induced pluripotent stem cell-derived neurons alongside multiomic neuronal and microglial profiling. RESULTS: ANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways. DISCUSSION: This study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity. HIGHLIGHTS: ANXA11 P93S is a pathogenic variant. Corticobasal syndrome is part of the ANXA11 phenotypic spectrum. Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP-43-related loss of splicing regulation. Microglial ANXA11 and related immune pathways are important drivers of disease. Cellular models are powerful tools for adjudicating variants of uncertain significance.
Assuntos
Anexinas , Proteínas de Ligação a DNA , Humanos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Anexinas/genética , Masculino , Mutação/genética , Feminino , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Neurônios/metabolismo , Neurônios/patologia , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Pessoa de Meia-Idade , IdosoAssuntos
Esclerose Lateral Amiotrófica , Biomarcadores , Vesículas Extracelulares , Demência Frontotemporal , Humanos , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Biomarcadores/sangue , Demência Frontotemporal/genética , Demência Frontotemporal/sangue , Demência Frontotemporal/patologia , Patologia MolecularRESUMO
RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.
Assuntos
Progressão da Doença , Demência Frontotemporal , Camundongos Transgênicos , Proteína FUS de Ligação a RNA , Animais , Humanos , Camundongos , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Demência Frontotemporal/patologia , Demência Frontotemporal/metabolismo , Demência Frontotemporal/genética , Agregação Patológica de Proteínas/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Proteína FUS de Ligação a RNA/genéticaRESUMO
GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this genetic mutation leads to neurodegeneration remains largely unknown. Using CRISPR-Cas9 technology, we deleted EXOC2, which encodes an essential exocyst subunit, in induced pluripotent stem cells (iPSCs) derived from C9ORF72-ALS/FTD patients. These cells are viable owing to the presence of truncated EXOC2, suggesting that exocyst function is partially maintained. Several disease-relevant cellular phenotypes in C9ORF72 iPSC-derived motor neurons are rescued due to, surprisingly, the decreased levels of dipeptide repeat (DPR) proteins and expanded G4C2 repeats-containing RNA. The treatment of fully differentiated C9ORF72 neurons with EXOC2 antisense oligonucleotides also decreases expanded G4C2 repeats-containing RNA and partially rescued disease phenotypes. These results indicate that EXOC2 directly or indirectly regulates the level of G4C2 repeats-containing RNA, making it a potential therapeutic target in C9ORF72-ALS/FTD.
Assuntos
Esclerose Lateral Amiotrófica , Proteína C9orf72 , Expansão das Repetições de DNA , Demência Frontotemporal , Células-Tronco Pluripotentes Induzidas , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Humanos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Demência Frontotemporal/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Expansão das Repetições de DNA/genética , Neurônios Motores/metabolismo , Neurônios Motores/patologiaRESUMO
Semantic dementia is a kind of neurodegenerative disorder, characterized by prominent semantic impairments and anterior temporal lobe atrophy. Since 2010, more studies have devoted to this rare disorder, revealing that it is more complex than we think. Clinical advances include more specific findings of semantic impairments and other higher order cognitive deficits. Neuroimaging techniques can help revealing the different brain networks affected (both structurally and functionally) in this condition. Pathological and genetic studies have also found more complex situations of semantic dementia, which might explain the huge variance existing in semantic dementia. Moreover, the current diagnosis criteria mainly focus on semantic dementia's classical prototype. We further delineated the features of three subtypes of semantic dementia based on atrophy lateralization with three severity stages. In a broader background, as a part of the continuum of neurodegenerative disorders, semantic dementia is commonly compared with other resembling conditions. Therefore, we summarized the differential diagnosis between semantic dementia and them. Finally, we introduced the challenges and achievements of its diagnosis, treatment, care and cross cultural comparison. By providing a comprehensive picture of semantic dementia on different aspects of advances, we hope to deepen the understanding of semantic dementia and promote more inspirations on both clinical and theoretical studies about it.
Assuntos
Demência Frontotemporal , Neuroimagem , Humanos , Neuroimagem/métodos , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/patologia , Demência Frontotemporal/psicologia , Demência Frontotemporal/fisiopatologia , Demência Frontotemporal/diagnóstico , Neuropsicologia/tendências , Neuropsicologia/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/fisiopatologiaAssuntos
Demência Frontotemporal , Proteínas tau , Animais , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Demência Frontotemporal/metabolismo , Camundongos , Humanos , Proteínas tau/genética , Proteínas tau/metabolismo , Mutação , Genótipo , Linhagem Celular , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologiaRESUMO
Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.
Assuntos
Esclerose Lateral Amiotrófica , Biomarcadores , Proteínas de Ligação a DNA , Vesículas Extracelulares , Demência Frontotemporal , Proteínas tau , Humanos , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/genética , Proteínas tau/sangue , Proteínas tau/metabolismo , Vesículas Extracelulares/metabolismo , Demência Frontotemporal/sangue , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Biomarcadores/sangue , Proteínas de Ligação a DNA/sangue , Proteínas de Ligação a DNA/genética , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Paralisia Supranuclear Progressiva/sangue , Paralisia Supranuclear Progressiva/diagnóstico , Isoformas de Proteínas/sangueRESUMO
Tau pathologies are detected in the brains of some of the most common neurodegenerative diseases including Alzheimer's disease (AD), Lewy body dementia (LBD), chronic traumatic encephalopathy (CTE), and frontotemporal dementia (FTD). Tau proteins are expressed in six isoforms with either three or four microtubule-binding repeats (3R tau or 4R tau) due to alternative RNA splicing. AD, LBD, and CTE brains contain pathological deposits of both 3R and 4R tau. FTD patients can exhibit either 4R tau pathologies in most cases or 3R tau pathologies less commonly in Pick's disease, which is a subfamily of FTD. Here, we report the isoform-specific roles of tau in FTD. The P301L mutation, linked to familial 4R tau FTD, induces mislocalization of 4R tau to dendritic spines in primary hippocampal cultures that were prepared from neonatal rat pups of both sexes. Contrastingly, the G272V mutation, linked to familial Pick's disease, induces phosphorylation-dependent mislocalization of 3R tau but not 4R tau proteins to dendritic spines. The overexpression of G272V 3R tau but not 4R tau proteins leads to the reduction of dendritic spine density and suppression of mEPSCs in 5-week-old primary rat hippocampal cultures. The decrease in mEPSC amplitude caused by G272V 3R tau is dynamin-dependent whereas that caused by P301L 4R tau is dynamin-independent, indicating that the two tau isoforms activate different signaling pathways responsible for excitatory synaptic dysfunction. Our 3R and 4R tau studies here will shed new light on diverse mechanisms underlying FTD, AD, LBD, and CTE.
Assuntos
Espinhas Dendríticas , Demência Frontotemporal , Mutação , Isoformas de Proteínas , Proteínas tau , Proteínas tau/metabolismo , Proteínas tau/genética , Animais , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Ratos , Masculino , Humanos , Feminino , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Sinapses/metabolismo , Sinapses/patologia , Ratos Sprague-Dawley , Hipocampo/metabolismo , Hipocampo/patologia , Células CultivadasRESUMO
Epigenetics, a potential underlying pathogenic mechanism of neurodegenerative diseases, has been in the scope of several studies performed so far. However, there is a gap in regard to analyzing different forms of early-onset dementia and the use of Lymphoblastoid cell lines (LCLs). We performed a genome-wide DNA methylation analysis on sixty-four samples (from the prefrontal cortex and LCLs) including those taken from patients with early-onset forms of Alzheimer's disease (AD) and frontotemporal dementia (FTD) and healthy controls. A beta regression model and adjusted p-values were used to obtain differentially methylated positions (DMPs) via pairwise comparisons. A correlation analysis of DMP levels with Clariom D array gene expression data from the same cohort was also performed. The results showed hypermethylation as the most frequent finding in both tissues studied in the patient groups. Biological significance analysis revealed common pathways altered in AD and FTD patients, affecting neuron development, metabolism, signal transduction, and immune system pathways. These alterations were also found in LCL samples, suggesting the epigenetic changes might not be limited to the central nervous system. In the brain, CpG methylation presented an inverse correlation with gene expression, while in LCLs, we observed mainly a positive correlation. This study enhances our understanding of the biological pathways that are associated with neurodegeneration, describes differential methylation patterns, and suggests LCLs are a potential cell model for studying neurodegenerative diseases in earlier clinical phases than brain tissue.