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Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.
Assuntos
Autopsia/métodos , COVID-19/mortalidade , COVID-19/virologia , Bulbo Olfatório/virologia , Mucosa Olfatória/virologia , Mucosa Respiratória/virologia , Idoso , Anosmia , COVID-19/fisiopatologia , Endoscopia/métodos , Feminino , Glucuronosiltransferase/biossíntese , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Transtornos do Olfato , Neurônios Receptores Olfatórios/metabolismo , Sistema Respiratório , SARS-CoV-2 , OlfatoRESUMO
The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE ε4-related sporadic AD and APOE ε4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD.
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Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Amiloide/metabolismo , Modelos Estatísticos , Doença de Alzheimer/psicologia , Neuropatias Amiloides/metabolismo , Neuropatias Amiloides/patologia , Peptídeos beta-Amiloides , Animais , Humanos , Proteínas tau/metabolismoRESUMO
Concomitant Alzheimer's disease (AD) pathology is a frequent event in the context of Lewy body disease (LBD), occurring in approximately half of all cases. Evidence shows that LBD patients with AD copathology show an accelerated disease course, a greater risk of cognitive decline and an overall poorer prognosis. However, LBD-AD cases may show heterogeneous motor and non-motor phenotypes with higher risk of dementia, and, consequently, be not rarely misdiagnosed. In this review, we summarize the state-of-the-art on LBD-AD by discussing the synergistic effects between AD neuropathological changes and Lewy pathology and their clinical relevance. Furthermore, we provide an extensive overview of neuroimaging and fluid biomarkers under assessment in LBD-AD and their possible diagnostic and prognostic value. AD pathology can be suspected in vivo by means of CSF, MRI and PET markers, whereas α-synuclein seed amplification assays (SAAs) represent to date the most promising technique to identify Lewy pathology in different biological tissues. Pathological imaging and CSF AD biomarkers are associated with a higher likelihood of cognitive decline in LBD but do not always mirror the neuropathological severity like in pure AD. The implementation of blood-based biomarkers of AD might allow the fast screening of LBD patients for AD copathology, thus improving the overall diagnostic sensitivity for LBD-AD. Finally, we discuss the literature on novel candidate biomarkers being exploited in LBD-AD to investigate other aspects of neurodegeneration, such as neuroaxonal injury, glial activation and synaptic dysfunction. The thorough characterization of AD copathology in LBD should be taken into account for the differential diagnosis of dementia syndromes, for the prognostic evaluation on an individual level and for guiding symptomatic and disease-modifying therapies.
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Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic congenital condition characterised by ocular, cutaneous and central nervous system involvement. Mosaic activating variants in FGFR1 and KRAS have been reported in several individuals with this syndrome. We report on a patient with neurofibromatosis type 1 (NF1) with a germline pathogenic variant in the NF1 gene and an ECCL phenotype, suggesting ECCL to be part of a spectrum of malformations associated with NF1 pathogenic variants. An anatomical hemispherectomy was performed for intractable epilepsy. Through genetic analysis of blood, cerebral tissue and giant cell lesions in both jaws, we identified the germline NF1 pathogenic variant in all samples and a second-hit pathogenic NF1 variant in cerebral tissue and both giant cell lesions. Both NF1 variants were located on different alleles resulting in somatic mosaicism for a biallelic NF1 inactivation originating in early embryogenesis (second-hit mosaicism or Happle type 2 mosaicism). The biallelic deficit in NF1 in the left hemicranium explains the severe localised, congenital abnormality in this patient. Identical first and second-hit variants in a giant cell lesion of both upper and lower jaws provide confirmatory evidence for an early embryonic second hit involving at least the neural crest. We suggest that the ECCL phenotype may be part of a spectrum of congenital problems associated with mosaic NF1 nullisomy originating during early embryogenesis. The biallelic NF1 inactivation during early embryogenesis mimics the severe activation of the RAS-MAPK pathway seen in ECCL caused by embryonic mosaic activating FGFR1 and KRAS variants in the cranial region. We propose that distinct mechanisms of mosaicism can cause the ECCL phenotype through convergence on the RAS-MAPK pathway.
Assuntos
Lipomatose , Mosaicismo , Síndromes Neurocutâneas , Neurofibromina 1 , Fenótipo , Humanos , Lipomatose/genética , Lipomatose/patologia , Síndromes Neurocutâneas/genética , Síndromes Neurocutâneas/patologia , Neurofibromina 1/genética , Alelos , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Feminino , Masculino , Mutação em Linhagem Germinativa/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , OftalmopatiasRESUMO
Despite considerable research efforts, it is still not clear which mechanisms underlie neuronal cell death in neurodegenerative diseases. During the last 20 years, multiple pathways have been identified that can execute regulated cell death (RCD). Among these RCD pathways, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-related cell death, and lysosome-dependent cell death have been intensively investigated. Although RCD consists of numerous individual pathways, multiple common proteins have been identified that allow shifting from one cell death pathway to another. Another layer of complexity is added by mechanisms such as the endosomal machinery, able to regulate the activation of some RCD pathways, preventing cell death. In addition, restricted axonal degeneration and synaptic pruning can occur as a result of RCD activation without loss of the cell body. RCD plays a complex role in neurodegenerative processes, varying across different disorders. It has been shown that RCD is differentially involved in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), among the most common neurodegenerative diseases. In AD, neuronal loss is associated with the activation of not only necroptosis, but also pyroptosis. In ALS, on the other hand, motor neuron death is not linked to canonical necroptosis, whereas pyroptosis pathway activation is seen in white matter microglia. Despite these differences in the activation of RCD pathways in AD and ALS, the accumulation of protein aggregates immunoreactive for p62/SQSTM1 (sequestosome 1) is a common event in both diseases and many other neurodegenerative disorders. In this review, we describe the major RCD pathways with clear activation in AD and ALS, the main interactions between these pathways, as well as their differential and similar involvement in these disorders. Finally, we will discuss targeting RCD as an innovative therapeutic concept for neurodegenerative diseases, such as AD and ALS. Considering that the execution of RCD or "cellular suicide" represents the final stage in neurodegeneration, it seems crucial to prevent neuronal death in patients by targeting RCD. This would offer valuable time to address upstream events in the pathological cascade by keeping the neurons alive.
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Doença de Alzheimer , Esclerose Lateral Amiotrófica , Morte Celular Regulada , Humanos , Morte Celular , Neurônios MotoresRESUMO
Antimicrobial peptides (AMPs) are major components of the innate immune defense. Accumulating evidence suggests that the antibacterial activity of many AMPs is dependent on the formation of amyloid-like fibrils. To identify novel fibril forming AMPs, we generated a spleen-derived peptide library and screened it for the presence of amyloidogenic peptides. This approach led to the identification of a C-terminal 32-mer fragment of alpha-hemoglobin, termed HBA(111-142). The non-fibrillar peptide has membranolytic activity against various bacterial species, while the HBA(111-142) fibrils aggregated bacteria to promote their phagocytotic clearance. Further, HBA(111-142) fibrils selectively inhibited measles and herpes viruses (HSV-1, HSV-2, HCMV), but not SARS-CoV-2, ZIKV and IAV. HBA(111-142) is released from its precursor by ubiquitous aspartic proteases under acidic conditions characteristic at sites of infection and inflammation. Thus, HBA(111-142) is an amyloidogenic AMP that may specifically be generated from a highly abundant precursor during bacterial or viral infection and may play an important role in innate antimicrobial immune responses.
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COVID-19 , Infecção por Zika virus , Zika virus , Humanos , Peptídeos , Amiloide/química , Antibacterianos/farmacologia , HemoglobinasRESUMO
There is emerging evidence that amyloid beta protein (Aß) and tau-related lesions in the retina are associated with Alzheimer's disease (AD). Aß and hyperphosphorylated (p)-tau deposits have been described in the retina and were associated with small amyloid spots visualized by in vivo imaging techniques as well as degeneration of the retina. These changes correlate with brain amyloid deposition as determined by histological quantification, positron emission tomography (PET) or clinical diagnosis of AD. However, the literature is not coherent on these histopathological and in vivo imaging findings. One important reason for this is the variability in the methods and the interpretation of findings across different studies. In this perspective, we indicate the critical methodological deviations among different groups and suggest a roadmap moving forward on how to harmonize (i) histopathologic examination of retinal tissue; (ii) in vivo imaging among different methods, devices, and interpretation algorithms; and (iii) inclusion/exclusion criteria for studies aiming at retinal biomarker validation.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Retina/diagnóstico por imagem , Biomarcadores/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/patologiaRESUMO
BACKGROUND: Phosphorylated tau (p-tau) accumulation, a hallmark of Alzheimer's disease (AD), can also be found in the retina. However, it is uncertain whether it is linked to AD or another tauopathy. METHODS: Retinas from 164 individuals, with and without AD, were analyzed for p-tau accumulation and its relationship with age, dementia, and vision impairment. RESULTS: Retinal p-tau pathology showed a consistent pattern with four stages and a molecular composition distinct from that of cerebral tauopathies. The stage of retinal p-tau pathology correlated with age (r = 0.176, P = 0.024) and was associated with AD (odds ratio [OR] 3.193; P = 0.001), and inflammation (OR = 2.605; P = 0.001). Vision impairment was associated with underlying eye diseases (ß = 0.292; P = 0.001) and the stage of retinal p-tau pathology (ß = 0.192; P = 0.030) in a linear regression model. CONCLUSIONS: The results show the presence of a primary retinal tauopathy that is distinct from cerebral tauopathies.
Assuntos
Doença de Alzheimer , Tauopatias , Humanos , Tauopatias/patologia , Proteínas tau , Doença de Alzheimer/patologia , RetinaRESUMO
The major neuropathological hallmarks of Alzheimer's disease (AD) are amyloid ß (Aß) plaques and neurofibrillary tangles (NFT), accompanied by neuroinflammation and neuronal loss. Increasing evidence is emerging for the activation of the canonical NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome in AD. However, the mechanisms leading to neuronal loss in AD and the involvement of glial cells in these processes are still not clear. The aim of this study was to investigate the contribution of pyroptosis, a pro-inflammatory mechanism of cell death downstream of the inflammasome, to neurodegeneration in AD. Immunohistochemistry and biochemical analysis of protein levels were performed on human post-mortem brain tissue. We investigated the presence of cleaved gasdermin D (GSDMD), the pyroptosis effector protein, as well as the NLRP3 inflammasome-forming proteins, in the medial temporal lobe of 23 symptomatic AD, 25 pathologically defined preclinical AD (p-preAD) and 21 non-demented control cases. Cleaved GSDMD was detected in microglia, but also in astrocytes and in few pyramidal neurons in the first sector of the cornu ammonis (CA1) of the hippocampus and the temporal cortex of Brodmann area 36. Only microglia expressed all NLRP3 inflammasome-forming proteins (i.e., ASC, NLRP3, caspase-1). Cleaved GSDMD-positive astrocytes and neurons exhibited caspase-8 and non-canonical inflammasome protein caspase-4, respectively, potentially indicating alternative pathways for GSDMD cleavage. Brains of AD patients exhibited increased numbers of cleaved GSDMD-positive cells. Cleaved GSDMD-positive microglia and astrocytes were found in close proximity to Aß plaques, while cleaved GSDMD-positive neurons were devoid of NFTs. In CA1, NLRP3-positive microglia and cleaved GSDMD-positive neurons were associated with local neuronal loss, indicating a possible contribution of NLRP3 inflammasome and pyroptosis activation to AD-related neurodegeneration. Taken together, our results suggest cell type-specific activation of pyroptosis in AD and extend the current knowledge about the contribution of neuroinflammation to the neurodegenerative process in AD via a direct link to neuron death by pyroptosis.
Assuntos
Doença de Alzheimer , Inflamassomos , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doença de Alzheimer/patologia , Piroptose , Microglia/patologia , Peptídeos beta-Amiloides , Astrócitos/patologia , Doenças Neuroinflamatórias , Neurônios/patologiaRESUMO
Amyotrophic lateral sclerosis (ALS) is associated with impaired energy metabolism, including weight loss and decreased appetite which are negatively correlated with survival. Neural mechanisms underlying metabolic impairment in ALS remain unknown. ALS patients and presymptomatic gene carriers have early hypothalamic atrophy. The lateral hypothalamic area (LHA) controls metabolic homeostasis through the secretion of neuropeptides such as orexin/hypocretin and melanin-concentrating hormone (MCH). Here, we show loss of MCH-positive neurons in three mouse models of ALS based on SOD1 or FUS mutations. Supplementation with MCH (1.2 µg/d) through continuous intracerebroventricular delivery led to weight gain in male mutant Sod1G86R mice. MCH supplementation increased food intake, rescued expression of the key appetite-related neuropeptide AgRP (agouti-related protein) and modified respiratory exchange ratio, suggesting increased carbohydrate usage during the inactive phase. Importantly, we document pTDP-43 pathology and neurodegeneration in the LHA of sporadic ALS patients. Neuronal cell loss was associated with pTDP-43-positive inclusions and signs of neurodegeneration in MCH-positive neurons. These results suggest that hypothalamic MCH is lost in ALS and contributes to the metabolic changes, including weight loss and decreased appetite.
Assuntos
Esclerose Lateral Amiotrófica , Neuropeptídeos , Masculino , Camundongos , Animais , Superóxido Dismutase-1 , Neuropeptídeos/metabolismo , Orexinas , Ingestão de Alimentos , Redução de PesoRESUMO
The retina is a potential source of biomarkers for the detection of neurodegenerative diseases. Accumulation of phosphorylated tau (p-tau) in the brain is a pathological feature characteristic for Alzheimer's disease (AD) and primary tauopathies. In this study the presence of p-tau in the retina in relation to tau pathology in the brain was assessed. Post-mortem eyes and brains were collected through the Netherlands Brain Bank from donors with AD (n = 17), primary tauopathies (n = 8), α-synucleinopathies (n = 13), other neurodegenerative diseases including non-tau frontotemporal lobar degeneration (FTLD) (n = 9), and controls (n = 15). Retina cross-sections were assessed by immunohistochemistry using antibodies directed against total tau (HT7), 3R and 4R tau isoforms (RD3, RD4), and phospho-epitopes Ser202/Thr205 (AT8), Thr217 (anti-T217), Thr212/Ser214 (AT100), Thr181 (AT270), Ser396 (anti-pS396) and Ser422 (anti-pS422). Retinal tau load was compared to p-tau Ser202/Thr205 and p-tau Thr217 load in various brain regions. Total tau, 3R and 4R tau isoforms were most prominently present in the inner plexiform layer (IPL) and outer plexiform layer (OPL) of the retina and were detected in all cases and controls as a diffuse and somatodendritic signal. Total tau, p-tau Ser202/Thr205 and p-tau Thr217 was observed in amacrine and horizontal cells of the inner nuclear layer (INL). Various antibodies directed against phospho-epitopes of tau showed immunoreactivity in the IPL, OPL, and INL. P-tau Ser202/Thr205 and Thr217 showed significant discrimination between AD and other tauopathies, and non-tauopathy cases including controls. Whilst immunopositivity was observed for p-tau Thr212/Ser214, Thr181 and Ser396, there were no group differences. P-tau Ser422 did not show any immunoreactivity in the retina. The presence of retinal p-tau Ser202/Thr205 and Thr217 correlated with Braak stage for NFTs and with the presence of p-tau Ser202/Thr205 in hippocampus and cortical brain regions. Depending on the phospho-epitope, p-tau in the retina is a potential biomarker for AD and primary tauopathies.
Assuntos
Doença de Alzheimer , Tauopatias , Humanos , Doença de Alzheimer/patologia , Fosforilação , Proteínas tau/metabolismo , Tauopatias/patologia , Encéfalo/patologia , Retina/patologia , EpitoposRESUMO
An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.
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Doença de Alzheimer , Esclerose Lateral Amiotrófica , Demência Frontotemporal , Humanos , Doença de Alzheimer/patologia , Demência Frontotemporal/patologia , Esclerose Lateral Amiotrófica/patologia , Proteínas de Ligação a DNA/genéticaRESUMO
BACKGROUND: Uveal melanoma is an orphan malignancy with very limited data on treatment options in metastatic setting. METHODS: In this single-center retrospective study, we describe real-world epidemiological and survival data on 121 metastatic uveal melanoma (MUM) patients registered in our institution. As a large tertiary referral center, almost 30% of all diagnoses in the Flemish region of Belgium were covered. Primarily, we determined whether introduction of immune checkpoint inhibitors (ICI) led to improved overall survival (OS) in MUM patients. Secondarily, response rates to ICI were assessed and we evaluated whether first-line ICI could be a valid alternative to liver-directed therapy (LDT) in liver-only disease. RESULTS: The initially perceived 10.8 months survival benefit from treatment with ICI disappeared after correction for immortality bias. By analyzing treatment type as time-varying covariate on OS, no significant benefit of ICI over other systemic therapies (HR = 0.771) or best supportive care (BSC) (HR = 0.780) was found. Also comparison of the pre-ICI versus ICI era showed no OS improvement after introduction of ICI in our center (p = 0.7994). Only liver-directed and local oligometastatic approaches were associated with a lower chance of mortality when compared to ICI (p = 0.0025), other systemic therapies (p = 0.0001) and BSC (p = 0.0003), yet without correction for selection bias. We reported overall response rates on ICI ranging from 8-15% and we found some support for neoadjuvant strategies with ICI resulting in remission or downsizing, allowing oligometastatic approaches later on. In first-line liver-only disease, median real-world progression-free survival and OS did not significantly differ between patients treated with LDT or ICI upfront (p = 0.2930 and p = 0.5461 respectively). CONCLUSION: Although we documented responses to ICI, our analyses do not demonstrate an OS benefit of ICI over alternative treatment strategies for MUM. However, local treatment options, whether liver-directed or for oligometastatic disease, may be beneficial and should be considered.
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Melanoma , Neoplasias Uveais , Humanos , Estudos Retrospectivos , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/patologia , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/patologiaRESUMO
Alzheimer's disease is neuropathologically characterized by the deposition of the amyloid ß-peptide (Aß) as amyloid plaques. Aß plaque pathology starts in the neocortex before it propagates into further brain regions. Moreover, Aß aggregates undergo maturation indicated by the occurrence of post-translational modifications. Here, we show that propagation of Aß plaques is led by presumably non-modified Aß followed by Aß aggregate maturation. This sequence was seen neuropathologically in human brains and in amyloid precursor protein transgenic mice receiving intracerebral injections of human brain homogenates from cases varying in Aß phase, Aß load and Aß maturation stage. The speed of propagation after seeding in mice was best related to the Aß phase of the donor, the progression speed of maturation to the stage of Aß aggregate maturation. Thus, different forms of Aß can trigger propagation/maturation of Aß aggregates, which may explain the lack of success when therapeutically targeting only specific forms of Aß.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Animais , Humanos , Camundongos , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Placa Amiloide/metabolismo , Camundongos Transgênicos , Encéfalo/patologia , Modelos Animais de DoençasRESUMO
Cerebral amyloid angiopathy (CAA) is the most frequent cause of lobar hemorrhages in the brains of elderly individuals. It is characterized by the deposition of amyloidogenic proteins in the vessel wall of leptomeningeal and/or intracerebral blood vessels. Different proteins can cause CAA. Most frequently, the amyloid ß protein (Aß) is found to be deposited in CAA and indicates a link to Alzheimer's disease, because Aß is known to be deposited in amyloid plaques characteristic of Alzheimer's disease. Among other proteins that can also cause CAA, transthyretin (TTR) is the most important one because TTR amyloidosis can be successfully treated. Therefore, it is essential to diagnose TTR-related CAA even in biopsies taken in the context of cerebral hematoma evacuations if possible. The current "Boston criteria version 2.0" for the diagnosis of CAA highlight the importance of autopsy for the definite diagnosis of CAA and biopsies for the diagnosis of probable CAA. Here, we discuss the implications of Aß-related and non-Aß-related forms of CAA for their current diagnostic relevance also in the context of neurodegenerative diseases as well as the implications of the Boston criteria version 2.0 for neuropathological diagnosis.
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Doença de Alzheimer , Amiloidose , Angiopatia Amiloide Cerebral , Humanos , Idoso , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/metabolismo , Angiopatia Amiloide Cerebral/diagnóstico , Angiopatia Amiloide Cerebral/etiologia , Encéfalo/patologia , Amiloidose/patologia , Hemorragia Cerebral/etiologiaRESUMO
Alexander disease is a leukodystrophy caused by mutations in the GFAP gene, primarily affecting the astrocytes. This report describes the prenatal and post-mortem neuroimaging findings in a case of genetically confirmed, fetal-onset Alexander disease with pathological correlation after termination of pregnancy. The additional value of fetal brain magnetic resonance imaging in the third trimester as a complementary evaluation tool to neurosonography is shown for suspected cases of fetal-onset Alexander disease. Diffuse signal abnormalities of the periventricular white matter in association with thickening of the fornix and optic chiasm can point towards the diagnosis. Furthermore, the presence of atypical imaging findings such as microcephaly and cortical folding abnormalities in this case broadens our understanding of the phenotypic variability of Alexander disease.
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Doença de Alexander , Gravidez , Feminino , Humanos , Doença de Alexander/diagnóstico por imagem , Doença de Alexander/genética , Doença de Alexander/patologia , Proteína Glial Fibrilar Ácida/genética , Ventrículos Cerebrais/patologia , Radiografia , Mutação , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Postmortem fetal magnetic resonance imaging (MRI) has been on the rise since it was proven to be a good alternative to conventional autopsy. Since the fetal brain is sensitive to postmortem changes, extensive tissue fixation is required for macroscopic and microscopic assessment. Estimation of brain maceration on MRI, before autopsy, may optimize histopathological resources. OBJECTIVE: The aim of the study is to develop an MRI-based postmortem fetal brain maceration score and to correlate it with brain maceration as assessed by autopsy. MATERIALS AND METHODS: This retrospective single-center study includes 79 fetuses who had postmortem MRI followed by autopsy. Maceration was scored on MRI on a numerical severity scale, based on our brain-specific maceration score and the whole-body score of Montaldo. Additionally, maceration was scored on histopathology with a semiquantitative severity scale. Both the brain-specific and the whole-body maceration imaging scores were correlated with the histopathological maceration score. Intra- and interobserver agreements were tested for the brain-specific maceration score. RESULTS: The proposed brain-specific maceration score correlates well with fetal brain maceration assessed by autopsy (τ = 0.690), compared to a poorer correlation of the whole-body method (τ = 0.452). The intra- and interobserver agreement was excellent (correlation coefficients of 0.943 and 0.864, respectively). CONCLUSION: We present a brain-specific postmortem MRI maceration score that correlates well with the degree of fetal brain maceration seen at histopathological exam. The score is reliably reproduced by different observers with different experience.
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Morte Fetal , Mudanças Depois da Morte , Feminino , Humanos , Autopsia/métodos , Estudos Retrospectivos , Feto/diagnóstico por imagem , Feto/patologia , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagemRESUMO
INTRODUCTION: Imaging studies indicated basal forebrain reduction in primary progressive aphasia (PPA), which might be a candidate marker for cholinergic treatment. Nucleus basalis of Meynert (nbM) neuronal loss has been reported, but a systematic quantitative neuropathological assessment including the three clinical PPA variants is lacking. METHODS: Quantitative assessment of neuronal density and pathology was performed on nbM tissue of 47 cases: 15 PPA, constituting the different clinicopathological phenotypes, 14 Alzheimer's disease (AD), and 18 cognitively normals. RESULTS: Group-wise, reduced nbM neuronal density was restricted to AD. At the individual level, semantic variant PPA with underlying AD neuropathological change (ADNC) had lower neuronal densities, while those with frontotemporal lobar degeneration (FTLD) transactive response DNA binding protein 43 kDa (TDP-43) type C pathology were unaffected. Higher Braak stages and increased numbers of nbM-related pretangles were associated with nbM neuronal loss. DISCUSSION: nbM neuronal loss in PPA is related to ADNC. This study cautions against overinterpreting MRI-based basal forebrain volumes in non-AD PPA as neuronal loss.
Assuntos
Doença de Alzheimer , Afasia Primária Progressiva , Degeneração Lobar Frontotemporal , Humanos , Doença de Alzheimer/patologia , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/patologia , Degeneração Lobar Frontotemporal/patologia , Neurônios/metabolismo , Afasia Primária Progressiva/diagnóstico por imagem , Afasia Primária Progressiva/patologiaRESUMO
INTRODUCTION: The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are hexanucleotide repeats in chromosome 9 open reading frame 72 (C9orf72). These repeats produce dipeptide repeat proteins with poly(PR) being the most toxic one. METHODS: We performed a kinome-wide CRISPR/Cas9 knock-out screen in human induced pluripotent stem cell (iPSC) -derived cortical neurons to identify modifiers of poly(PR) toxicity, and validated the role of candidate modifiers using in vitro, in vivo, and ex-vivo studies. RESULTS: Knock-down of NIMA-related kinase 6 (NEK6) prevented neuronal toxicity caused by poly(PR). Knock-down of nek6 also ameliorated the poly(PR)-induced axonopathy in zebrafish and NEK6 was aberrantly expressed in C9orf72 patients. Suppression of NEK6 expression and NEK6 activity inhibition rescued axonal transport defects in cortical neurons from C9orf72 patient iPSCs, at least partially by reversing p53-related DNA damage. DISCUSSION: We identified NEK6, which regulates poly(PR)-mediated p53-related DNA damage, as a novel therapeutic target for C9orf72 FTD/ALS.
Assuntos
Esclerose Lateral Amiotrófica , Demência Frontotemporal , Células-Tronco Pluripotentes Induzidas , Animais , Humanos , Esclerose Lateral Amiotrófica/genética , Demência Frontotemporal/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteína C9orf72/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Sistemas CRISPR-Cas , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Neurônios/metabolismo , Expansão das Repetições de DNA/genética , Quinases Relacionadas a NIMA/genética , Quinases Relacionadas a NIMA/metabolismoRESUMO
Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of motor neurons in the motor cortex, brainstem, and spinal cord. Although ALS is considered a motor neuron disorder, neuroinflammation also plays an important role. Recent evidence in ALS disease models indicates activation of the inflammasome and subsequent initiation of pyroptosis, an inflammatory type of cell death. In this study, we determined the expression and distribution of the inflammasome and pyroptosis effector proteins in post-mortem brain and spinal cord from ALS patients (n = 25) and controls (n = 19), as well as in symptomatic and asymptomatic TDP-43A315T transgenic and wild-type mice. Furthermore, we evaluated its correlation with the presence of TDP-43 pathological proteins and neuronal loss. Expression of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, pyroptosis effector protein cleaved Gasdermin D (GSDMD), and IL-18 was detected in microglia in human ALS motor cortex and spinal cord, indicative of canonical inflammasome-triggered pyroptosis activation. The number of cleaved GSDMD-positive precentral white matter microglia was increased compared to controls and correlated with a decreased neuronal density in human ALS motor cortex. Neither of this was observed in the spinal cord. Similar results were obtained in TDP-43A315T mice, where microglial pyroptosis activation was significantly increased in the motor cortex upon symptom onset, and correlated with neuronal loss. There was no significant correlation with the presence of TDP-43 pathological proteins both in human and mouse tissue. Our findings emphasize the importance of microglial NLRP3 inflammasome-mediated pyroptosis activation for neuronal degeneration in ALS and pave the way for new therapeutic strategies counteracting motor neuron degeneration in ALS by inhibiting microglial inflammasome/pyroptosis activation.