RESUMO
Sports concussion has recently assumed special importance because of the widely publicized entity of chronic traumatic encephalopathy (CTE). Identified primarily in former contact sports athletes with repeated mild traumatic brain injury (mTBI), CTE is a distinct tauopathy that can only be diagnosed postmortem and for which no specific treatment is available. Although the hazards of repeated mTBI are generally acknowledged, a spirited controversy has developed because a firm link between sports concussion and CTE has been questioned. We briefly review the history of CTE, discuss areas of uncertainty, and offer suggestions to assist neurologists confronting these issues and advance understanding of this vexing problem. ANN NEUROL 2023;93:222-225.
Assuntos
Concussão Encefálica , Encefalopatia Traumática Crônica , Tauopatias , Humanos , Encefalopatia Traumática Crônica/diagnóstico , Concussão Encefálica/complicações , Concussão Encefálica/diagnóstico , Tauopatias/complicações , Atletas , AutopsiaRESUMO
BACKGROUND: Bradykinesia is a cardinal feature in parkinsonisms. No study has assessed the differential features of bradykinesia in patients with pathology-proven synucleinopathies and tauopathies. OBJECTIVE: We examined whether bradykinesia features (speed, amplitude, rhythm, and sequence effect) may differ between pathology-proven synucleinopathies and tauopathies. METHODS: Forty-two cases who underwent autopsy were included and divided into synucleinopathies (Parkinson's disease and dementia with Lewy bodies) and tauopathies (progressive supranuclear palsy). Two raters blinded to the diagnosis retrospectively scored the Movement Disorders Society-Unified Parkinson's Disease Rating Scale Part III and Modified Bradykinesia Rating Scale on standardized videotaped neurological examinations. Bradykinesia scores were compared using the Mann-Whitney test and logistic regression models to adjust for disease duration. RESULTS: Demographic and clinical parameters were similar between synucleinopathies and tauopathies. There were no differences between speed, amplitude, rhythm, and sequence effect in synucleinopathies and tauopathies in unadjusted comparisons and adjusted models (all P > 0.05). CONCLUSIONS: Clinical bradykinesia features do not distinguish the underlying neuropathology in neurodegenerative parkinsonisms. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Hipocinesia , Doença de Parkinson , Sinucleinopatias , Tauopatias , Gravação em Vídeo , Humanos , Hipocinesia/complicações , Hipocinesia/fisiopatologia , Modelos Logísticos , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Estudos Retrospectivos , Estatísticas não Paramétricas , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/patologia , Paralisia Supranuclear Progressiva/fisiopatologia , Sinucleinopatias/complicações , Sinucleinopatias/patologia , Sinucleinopatias/fisiopatologia , Tauopatias/complicações , Tauopatias/patologia , Tauopatias/fisiopatologia , Autopsia , Masculino , Feminino , Pessoa de Meia-Idade , IdosoRESUMO
Tauopathies, including Alzheimer's disease and primary age-related tauopathy (PART), present heterogeneous clinico-pathological phenotypes that include dementia, aphasia, motor neuron diseases, and psychiatric symptoms. PART is neuropathologically characterized by the presence of neurofibrillary tangles in limbic regions without significant Aß deposition, but its clinical features have not yet been fully established. Here, we present two patients with distinct psychosis and behavioral symptoms. At autopsy, these patients showed tau pathologies that could not be classified as typical PART, although PART-like neurofibrillary tangles were present in limbic regions. Clinically, both patients were admitted to mental hospitals due to severe delusions or other neuropsychiatric/behavioral symptoms. The first case presented with hallucination, delusion, and apathy at age 70, and died of pancreatic cancer at age 75. He had neuronal cytoplasmic inclusions with selective accumulation of 3Rtau in the striatum and thorn-shaped astrocytes in the amygdala. The second case, who presented with abnormal behaviors such as wandering, agitation and disinhibition, exhibited limbic neurodegeneration with massive 4R tau-positive oligodendroglial inclusions in the medial temporal white matter. His age at onset was 73, and the duration of disease was 15 years. These findings support the notion that distinct limbic tau pathology with concomitant degeneration of the related neural circuits might induce specific psychosis and behavioral symptoms. This underlines the importance of neuropathological evaluation for both clinical education and practice in the fields of neuropathology and neuropsychiatry.
Assuntos
Doença de Alzheimer , Transtornos Psicóticos , Tauopatias , Masculino , Humanos , Proteínas tau , Autopsia , Tauopatias/complicações , Tauopatias/patologia , Doença de Alzheimer/patologia , Emaranhados Neurofibrilares/patologia , Transtornos Psicóticos/patologiaRESUMO
AIMS: Accumulating evidence suggests that patients with frontotemporal lobar degeneration (FTLD) can have pathologic accumulation of multiple proteins, including tau and TDP-43. This study aimed to determine the frequency and characteristics of concurrent tau pathology in FTLD with TDP-43 pathology (FTLD-TDP). METHODS: The study included 146 autopsy-confirmed cases of FTLD-TDP and 55 cases of FTLD-TDP with motor neuron disease (FTLD-MND). Sections from the basal forebrain were screened for tau pathology with phosphorylated-tau immunohistochemistry. For cases with tau pathology on the screening section, additional brain sections were studied to establish a diagnosis. Genetic analysis of C9orf72, GRN and MAPT was performed on select cases. RESULTS: We found 72 cases (36%) with primary age-related tauopathy (PART), 85 (42%) with ageing-related tau astrogliopathy (ARTAG), 45 (22%) with argyrophilic grain disease (AGD) and 2 cases (1%) with corticobasal degeneration (CBD). Patients with ARTAG or AGD were significantly older than those without these comorbidities. One of the patients with FTLD-TDP and CBD had C9orf72 mutation and relatively mild tau pathology, consistent with incidental CBD. CONCLUSION: The coexistence of TDP-43 and tau pathologies was relatively common, particularly PART and ARTAG. Although rare, patients with FTLD can have multiple neurodegenerative proteinopathies. The absence of TDP-43-positive astrocytic plaques may suggest that CBD and FTLD-TDP were independent disease processes in the two patients with both tau and TDP-43 pathologies. It remains to be determined if mixed cases represent a unique disease process or two concurrent disease processes in an individual.
Assuntos
Encéfalo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Degeneração Lobar Frontotemporal/complicações , Neurônios/metabolismo , Tauopatias/complicações , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Feminino , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/patologia , Tauopatias/metabolismo , Tauopatias/patologiaRESUMO
OBJECTIVE: Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease, with the ε4 allele increasing risk in a dose-dependent fashion. In addition to ApoE4 playing a crucial role in amyloid-ß deposition, recent evidence suggests that it also plays an important role in tau pathology and tau-mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau-mediated neurodegeneration. METHODS: Herein, we used antisense oligonucleotides (ASOs) against human APOE to reduce ApoE4 levels in the P301S/ApoE4 mouse model of tauopathy. We treated P301S/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 and 7.5 months of age and performed brain pathological assessments at 9 months of age. RESULTS: Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by ~50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO-treated mice. INTERPRETATION: We conclude that reducing ApoE4 levels should be explored further as a therapeutic approach for APOE4 carriers with tauopathy including Alzheimer's disease. ANN NEUROL 2021;89:952-966.
Assuntos
Apolipoproteína E4/antagonistas & inibidores , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/etiologia , Oligonucleotídeos Antissenso/uso terapêutico , Tauopatias/complicações , Tauopatias/tratamento farmacológico , Animais , Apolipoproteína E4/sangue , Apolipoproteína E4/genética , Colesterol/metabolismo , Giro Denteado/patologia , Encefalite/prevenção & controle , Técnicas de Introdução de Genes , Injeções Intraventriculares , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Neurofilamentos/metabolismo , Oligonucleotídeos Antissenso/administração & dosagem , Sinapses/efeitos dos fármacos , Sinapses/patologia , Proteínas tau/metabolismoRESUMO
BACKGROUND AND PURPOSE: Globular glial tauopathies (GGTs) have heterogeneous presentations; little evidence regarding typical clinical and magnetic resonance imaging (MRI) presentations are available. METHODS: We retrospectively assessed MRIs from three postmortem-confirmed GGT cases, in two patients with atypical progressive aphasia and one with corticobasal syndrome. RESULTS: We suggest that four principal concomitant MRI findings characterize GGT type I: a sagittal callosal hyperintense band, marked focal callosal atrophy suggesting white matter degeneration originating in cortical areas responsible for symptoms (anterior atrophy in predominantly language manifestations and posterior atrophy in predominantly apraxia), periventricular white matter lesions, and mild-to-moderate brain stem atrophy. CONCLUSIONS: We observed four concomitant MRI abnormalities in patients with atypical dementia, parkinsonism, and late incomplete supranuclear gaze palsy. Two patients had atypical progressive aphasia and one had corticobasal syndrome.
Assuntos
Corpo Caloso , Tauopatias , Atrofia/patologia , Corpo Caloso/patologia , Humanos , Neuroimagem , Estudos Retrospectivos , Tauopatias/complicações , Tauopatias/diagnóstico por imagemRESUMO
BACKGROUND: Obesity leads to low-grade inflammation in the adipose tissue and liver and neuroinflammation in the brain. Obesity-induced insulin resistance (IR) and neuroinflammation seem to intensify neurodegeneration including Alzheimer's disease. In this study, the impact of high-fat (HF) diet-induced obesity on potential neuroinflammation and peripheral IR was tested separately in males and females of THY-Tau22 mice, a model of tau pathology expressing mutated human tau protein. METHODS: Three-, 7-, and 11-month-old THY-Tau22 and wild-type males and females were tested for mobility, anxiety-like behavior, and short-term spatial memory in open-field and Y-maze tests. Plasma insulin, free fatty acid, cholesterol, and leptin were evaluated with commercial assays. Liver was stained with hematoxylin and eosin for histology. Brain sections were 3',3'-diaminobenzidine (DAB) and/or fluorescently detected for ionized calcium-binding adapter molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), and tau phosphorylated at T231 (pTau (T231)), and analyzed. Insulin signaling cascade, pTau, extracellular signal-regulated kinase 1/2 (ERK1/2), and protein phosphatase 2A (PP2A) were quantified by western blotting of hippocampi of 11-month-old mice. Data are mean ± SEM and were subjected to Mann-Whitney t test within age and sex and mixed-effects analysis and Bonferroni's post hoc test for age comparison. RESULTS: Increased age most potently decreased mobility and increased anxiety in all mice. THY-Tau22 males showed impaired short-term spatial memory. HF diet increased body, fat, and liver weights and peripheral IR. HF diet-fed THY-Tau22 males showed massive Iba1+ microgliosis and GFAP+ astrocytosis in the hippocampus and amygdala. Activated astrocytes colocalized with pTau (T231) in THY-Tau22, although no significant difference in hippocampal tau phosphorylation was observed between 11-month-old HF and standard diet-fed THY-Tau22 mice. Eleven-month-old THY-Tau22 females, but not males, on both diets showed decreased synaptic and postsynaptic plasticity. CONCLUSIONS: Significant sex differences in neurodegenerative signs were found in THY-Tau22. Impaired short-term spatial memory was observed in 11-month-old THY-tau22 males but not females, which corresponded to increased neuroinflammation colocalized with pTau(T231) in the hippocampi and amygdalae of THY-Tau22 males. A robust decrease in synaptic and postsynaptic plasticity was observed in 11-month-old females but not males. HF diet caused peripheral but not central IR in mice of both sexes.
Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Obesidade/complicações , Tauopatias/complicações , Animais , Modelos Animais de Doenças , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Hipocampo/metabolismo , Inflamação , Masculino , Memória de Curto Prazo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Limitação da Mobilidade , Obesidade/etiologia , Fosforilação , Fatores Sexuais , Tauopatias/genética , Proteínas tauRESUMO
In Alzheimer's disease, the tauopathy is known as a major mechanism responsible for the development of cognitive deficits. Early biomarkers of such affectations for diagnosis/stratification are crucial in Alzheimer's disease research, and brain connectome studies increasingly show their potential establishing pathology fingerprints at the network level. In this context, we conducted an in vivo multimodal MRI study on young Thy-Tau22 transgenic mice expressing tauopathy, performing resting state functional MRI and structural brain imaging to identify early connectome signatures of the pathology, relating with histological and behavioural investigations. In the prodromal phase of tauopathy, before the emergence of cognitive impairments, Thy-Tau22 mice displayed selective modifications of brain functional connectivity involving three main centres: hippocampus (HIP), amygdala (AMG) and the isocortical areas, notably the somatosensory (SS) cortex. Each of these regions showed differential histopathological profiles. Disrupted ventral HIP-AMG functional pathway and altered dynamic functional connectivity were consistent with high pathological tau deposition and astrogliosis in both hippocampus and amygdala, and significant microglial reactivity in amygdalar nuclei. These patterns were concurrent with widespread functional hyperconnectivity of memory-related circuits of dorsal hippocampus-encompassing dorsal HIP-SS communication-in the absence of significant cortical histopathological markers. These findings suggest the coexistence of two intermingled mechanisms of response at the functional connectome level in the early phases of pathology: a maladaptive and a likely compensatory response. Captured in the connectivity patterns, such first responses to pathology could further be used in translational investigations as a lead towards an early biomarker of tauopathy as well as new targets for future treatments.
Assuntos
Transtornos da Memória/patologia , Transtornos da Memória/psicologia , Rede Nervosa/patologia , Tauopatias/patologia , Tauopatias/psicologia , Animais , Astrócitos/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/psicologia , Conectoma , Progressão da Doença , Gliose/patologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Transtornos da Memória/etiologia , Camundongos , Camundongos Transgênicos , Rede Nervosa/diagnóstico por imagem , Tauopatias/complicações , Tauopatias/diagnóstico por imagem , Proteínas tau/metabolismoRESUMO
Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer's disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term 'cistauosis', appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer's disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Lesões Encefálicas/patologia , Lesões Encefálicas/prevenção & controle , Tauopatias/prevenção & controle , Proteínas tau/antagonistas & inibidores , Proteínas tau/química , Doença de Alzheimer/complicações , Doença de Alzheimer/prevenção & controle , Animais , Anticorpos Monoclonais/uso terapêutico , Afinidade de Anticorpos , Axônios/metabolismo , Axônios/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas/complicações , Lesões Encefálicas/metabolismo , Modelos Animais de Doenças , Epitopos/química , Epitopos/imunologia , Feminino , Humanos , Masculino , Camundongos , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/biossíntese , Fosfoproteínas/imunologia , Fosfoproteínas/toxicidade , Estresse Fisiológico , Tauopatias/complicações , Tauopatias/metabolismo , Tauopatias/patologia , Proteínas tau/biossíntese , Proteínas tau/imunologia , Proteínas tau/toxicidadeRESUMO
BACKGROUND AND PURPOSE: Argyrophilic grain disease (AGD) is a limbic-predominant 4R-tauopathy. AGD is thought to be an age-related disorder and is frequently detected as a concomitant pathology with other neurodegenerative conditions. There is a paucity of data on the clinical phenotype of pure AGD. In elderly patients, however, AGD pathology frequently associates with cognitive decline, personality changes, urine incontinence and cachexia. In this study, clinicopathological findings were analysed in individuals younger than 75. METHODS: Patients were identified retrospectively based on neuropathological examinations during 2006-2017 and selected when AGD was the primary and dominant pathological finding. Clinical data were obtained retrospectively through medical records. RESULTS: In all, 55 patients (2% of all examinations performed during that period) with AGD were identified. In seven cases (13%) AGD was the primary neuropathological diagnosis without significant concomitant pathologies. Two patients were female, median age at the time of death was 64 years (range 51-74) and the median duration of disease was 3 months (range 0.5-36). The most frequent symptoms were progressive cognitive decline, urinary incontinence, seizures and psychiatric symptoms. Brain magnetic resonance imaging revealed mild temporal atrophy. CONCLUSIONS: Argyrophilic grain disease is a rarely recognized limbic tauopathy in younger individuals. Widening the clinicopathological spectrum of tauopathies may allow identification of further patients who could benefit from tau-based therapeutic strategies.
Assuntos
Doenças Neurodegenerativas , Tauopatias , Idoso , Atrofia/patologia , Encéfalo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tauopatias/complicações , Tauopatias/epidemiologia , Proteínas tau/metabolismoRESUMO
Globular glial tauopathy (GGT) is a rare 4-repeat tauopathy characterized by the accumulation of tau globular inclusions in astrocytes and oligodendrocytes. Several clinical phenotypes have been associated with GGT, making the prediction of this rare pathological entity difficult. We report the case of a patient with eye-movement abnormalities and gait instability, reminiscent of progressive supranuclear palsy-Richardson's syndrome (PSP-RS), who later developed upper motor neuron symptoms suggestive of primary lateral sclerosis (PLS). Neuropathological assessment revealed GGT type III pathology. A theoretical framework is proposed to help clinicians predict GGT in subjects with coexistent features of PSP-RS and PLS.
Assuntos
Demência Frontotemporal/diagnóstico , Doença dos Neurônios Motores/diagnóstico , Neuroglia/patologia , Tauopatias/diagnóstico , Idoso de 80 Anos ou mais , Evolução Fatal , Demência Frontotemporal/complicações , Demência Frontotemporal/patologia , Demência Frontotemporal/fisiopatologia , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Humanos , Masculino , Doença dos Neurônios Motores/complicações , Doença dos Neurônios Motores/patologia , Doença dos Neurônios Motores/fisiopatologia , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/etiologia , Transtornos da Motilidade Ocular/fisiopatologia , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/diagnóstico , Paralisia Supranuclear Progressiva/patologia , Paralisia Supranuclear Progressiva/fisiopatologia , Tauopatias/complicações , Tauopatias/patologia , Tauopatias/fisiopatologiaRESUMO
AIMS: Amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) is characterized by the presence of inclusions containing TDP-43 within motor neurones. In rare cases, ALS/MND may be associated with inclusions containing other proteins, such as fused in sarcoma (FUS), while motor system pathology may rarely be a feature of other neurodegenerative disorders. We here have investigated the association of FUS and tau pathology. METHODS: We report a case with an ALS/MND-plus clinical syndrome which pathologically demonstrated both FUS pathology and an atypical tauopathy. RESULTS: Clinical motor involvement was predominantly present in the upper motor neurone, and was accompanied by extrapyramidal features and sensory involvement, but with only minimal cognitive impairment. The presentation was sporadic and gene mutation screening was negative. Post mortem study demonstrated inclusions positive for FUS, including basophilic inclusion bodies. This was associated with 4R-tauopathy, largely as non-fibrillary diffuse phospho-tau in neurones, with granulovacuolar degeneration in a more restricted distribution. Double-staining revealed that neurones contained both types of protein pathology. CONCLUSION: FUS-positive basophilic inclusion body disease is a rare cause of ALS/MND, but in this case was associated with an unusual atypical tauopathy. The coexistence of two such rare neuropathologies raises the question of a pathogenic interaction.
Assuntos
Esclerose Lateral Amiotrófica/complicações , Corpos de Inclusão/patologia , Tauopatias/complicações , Adulto , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Progressão da Doença , Evolução Fatal , Humanos , Corpos de Inclusão/metabolismo , Masculino , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Proteína FUS de Ligação a RNA/metabolismo , Tauopatias/metabolismo , Tauopatias/patologiaRESUMO
PURPOSE: Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) have emerged as independent risk factors for an earlier onset of Alzheimer's disease (AD), although the pathophysiology underlying this risk is unclear. Postmortem studies have revealed extensive cerebral accumulation of tau following multiple and single TBI incidents. We hypothesized that a history of TBI and/or PTSD may induce an AD-like pattern of tau accumulation in the brain of nondemented war veterans. METHODS: Vietnam War veterans (mean age 71.4 years) with a history of war-related TBI and/or PTSD underwent [18F]AV145 PET as part of the US Department of Defense Alzheimer's Disease Neuroimaging Initiative. Subjects were classified into the following four groups: healthy controls (n = 21), TBI (n = 10), PTSD (n = 32), and TBI+PTSD (n = 17). [18F]AV1451 reference tissue-normalized standardized uptake value (SUVr) maps, scaled to the cerebellar grey matter, were tested for differences in tau accumulation between groups using voxel-wise and region of interest approaches, and the SUVr results were correlated with neuropsychological test scores. RESULTS: Compared to healthy controls, all groups showed widespread tau accumulation in neocortical regions overlapping with typical and atypical patterns of AD-like tau distribution. The TBI group showed higher tau accumulation than the other clinical groups. The extent of tauopathy was positively correlated with the neuropsychological deficit scores in the TBI+PTSD and PTSD groups. CONCLUSION: A history of TBI and/or PTSD may manifest in neurocognitive deficits in association with increased tau deposition in the brain of nondemented war veterans decades after their trauma. Further investigation is required to establish the burden of increased risk of dementia imparted by earlier TBI and/or PTSD.
Assuntos
Lesões Encefálicas Traumáticas/complicações , Transtornos de Estresse Pós-Traumáticos/complicações , Tauopatias/complicações , Veteranos/estatística & dados numéricos , Idoso , Doença Crônica , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Tauopatias/diagnóstico por imagemRESUMO
BACKGROUND AND PURPOSE: AV-1451 (18 F-AV-1451, flortaucipir) positron emission tomography was performed in C9orf72 expansion carriers to assess tau accumulation and disease manifestation. METHODS: Nine clinically characterized C9orf72 expansion carriers and 18 age- and gender- matched cognitively normal individuals were psychometrically evaluated and underwent tau positron emission tomography imaging. The regional AV-1451 standard uptake value ratios from multiple brain regions were analyzed. Spearman correlation was performed to relate the AV-1451 standard uptake value ratio to clinical, psychometric and cerebrospinal fluid measures. RESULTS: C9orf72 expansion carriers had increased AV-1451 binding in the entorhinal cortex compared to controls. Primary age-related tauopathy was observed postmortem in one patient. AV-1451 uptake did not correlate with clinical severity, disease duration, psychometric performance or cerebrospinal fluid markers. CONCLUSION: C9orf72 expansion carriers exhibited increased AV-1451 uptake in entorhinal cortex compared to cognitively normal controls, suggesting a propensity for primary age-related tauopathy. However, AV-1451 accumulation was not associated with psychometric performance in our cohort.
Assuntos
Proteína C9orf72/genética , Disfunção Cognitiva/metabolismo , Córtex Entorrinal/metabolismo , Tomografia por Emissão de Pósitrons , Tauopatias/metabolismo , Proteínas tau/metabolismo , Idoso , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Estudos de Coortes , Expansão das Repetições de DNA , Córtex Entorrinal/diagnóstico por imagem , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Tauopatias/complicações , Tauopatias/diagnóstico por imagemRESUMO
See Josephs (doi:10.1093/brain/awx367) for a scientific commentary on this article.In many neurodegenerative disorders, familial forms have provided important insights into the pathogenesis of their corresponding sporadic forms. The first mutations associated with frontotemporal lobar degeneration (FTLD) were found in the microtubule-associated protein tau (MAPT) gene on chromosome 17 in families with frontotemporal degeneration and parkinsonism (FTDP-17). However, it was soon discovered that 50% of these families had a nearby mutation in progranulin. Regardless, the original FTDP-17 nomenclature has been retained for patients with MAPT mutations, with such patients currently classified independently from the different sporadic forms of FTLD with tau-immunoreactive inclusions (FTLD-tau). The separate classification of familial FTLD with MAPT mutations implies that familial forms cannot inform on the pathogenesis of the different sporadic forms of FTLD-tau. To test this assumption, this study pathologically assessed all FTLD-tau cases with a known MAPT mutation held by the Sydney and Cambridge Brain Banks, and compared them to four cases of four subtypes of sporadic FTLD-tau, in addition to published case reports. Ten FTLD-tau cases with a MAPT mutation (K257T, S305S, P301L, IVS10+16, R406W) were screened for the core differentiating neuropathological features used to diagnose the different sporadic FTLD-tau subtypes to determine whether the categorical separation of MAPT mutations from sporadic FTLD-tau is valid. Compared with sporadic cases, FTLD-tau cases with MAPT mutations had similar mean disease duration but were younger at age of symptom onset (55 ± 4 years versus 70 ± 6 years). Interestingly, FTLD-tau cases with MAPT mutations had similar patterns and severity of neuropathological features to sporadic FTLD-tau subtypes and could be classified into: Pick's disease (K257T), corticobasal degeneration (S305S, IVS10+16, R406W), progressive supranuclear palsy (S305S) or globular glial tauopathy (P301L, IVS10+16). The finding that the S305S mutation could be classified into two tauopathies suggests additional modifying factors. Assessment of our cases and previous reports suggests that distinct MAPT mutations result in particular FTLD-tau subtypes, supporting the concept that they are likely to inform on the varied cellular mechanisms involved in distinctive forms of sporadic FTLD-tau. As such, FTLD-tau cases with MAPT mutations should be considered familial forms of FTLD-tau subtypes rather than a separate FTDP-17 category, and continued research on the effects of different mutations more focused on modelling their impact to produce the very different sporadic FTLD-tau pathologies in animal and cellular models.
Assuntos
Demência Frontotemporal/complicações , Demência Frontotemporal/genética , Mutação/genética , Tauopatias/complicações , Proteínas tau/genética , Idoso , Estudos de Coortes , Correlação de Dados , Feminino , Demência Frontotemporal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Tauopatias/genéticaRESUMO
Argyrophilic grain disease (AgD) is a frequent late-onset 4R tauopathy of old age characterized by the presence of profuse spindle-shaped argyrophilic grains (AGs). It is a neurodegenerative disorder that is clinically characterized by a slow progressive amnestic mild cognitive impairment similar to Alzheimer's disease. In rare instances, it is characterized as a behavioral-variant frontotemporal dementia (bv-FTD). In this study, we report a case with typical clinical and neuroimaging features of bv-FTD, who had autopsy findings consistent with a definitive diagnosis of AgD. We suggest that AgD might be included in the differential diagnosis of patients presenting with bv-FTD.â©.
Assuntos
Demência Frontotemporal/etiologia , Tauopatias/complicações , Idoso , Humanos , MasculinoRESUMO
Globular glial tauopathy (GGT) is a group of 4-repeat tauopathies characterized by widespread globular glial inclusions (GGIs). GGT is now classified into three subtypes based on the distribution and morphology of the GGIs. We report an autopsy case of GGT in an 85-year-old woman who presented with semantic dementia, a rare phenotype in GGT. Postmortem examination revealed marked atrophy of the frontotemporal and motor cortices and corticospinal tract degeneration with widespread occurrence of globular neurofibrillary tangles and GGIs. The distribution of the pathology was similar to that seen in GGT type III. However, the morphology of astrocytic inclusions in the present case differed from that in type III. Moreover, the tau burden in the primary motor area was more severe in the gray than in the white matter, and globular oligodendroglial inclusions were more numerous than astrocytic inclusions, corresponding to GGT type II. By contrast, the tau pathology in the temporal lobe was chiefly globular oligodendroglial inclusions in the white matter, corresponding to GGT type I. Thus, the present case exhibited a combination of GGT types I and II pathology. Our findings appear to extend the pathological heterogeneity of GGT.
Assuntos
Encéfalo/patologia , Neuroglia/patologia , Tauopatias/patologia , Idoso de 80 Anos ou mais , Astrócitos/patologia , Feminino , Demência Frontotemporal/etiologia , Demência Frontotemporal/patologia , Humanos , Corpos de Inclusão/patologia , Emaranhados Neurofibrilares/patologia , Oligodendroglia/patologia , Tauopatias/complicações , Proteínas tau/metabolismoRESUMO
Vascular risk factors, such as type 2 diabetes mellitus (T2DM), are associated with the increased risk of Alzheimer's disease. One of the common T2DM medications, dipeptidyl peptidase (DPP)-4 inhibitors, have a minimum risk for hypoglycemia and have recently been suggested to ameliorate ß-amyloid pathology. However, conflicting results have been reported regarding the effects of DPP-4 inhibition on cognitive function and tau pathology. Thus, we investigated whether inhibiting DPP-4 affects tau pathology and cognition in a mouse model of tauopathy with hyperglycemia. Male mice overexpressing the P301S mutant human microtubule-associated protein tau gene (PS19) were fed either a low or high-fat diet. PS19 mice were then administered either linagliptin, a DPP-4 inhibitor, or vehicle, from 6 weeks to 8 months of age. Linagliptin-treated mice exhibited higher levels of glucagon-like peptide-1 and decreased fasting blood glucose, compared with the vehicle-treated mice at 8 months. Linagliptin treatment significantly restored spatial reference memory and increased cerebral blood flow without affecting phosphorylation levels of tau or endothelial nitric oxide synthase (eNOS) in the brain. Linagliptin may ameliorate HFD-induced cognitive worsening in tauopathy, at least partially, by increasing cerebral perfusion via the eNOS-independent pathway.
Assuntos
Disfunção Cognitiva/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Linagliptina/uso terapêutico , Tauopatias/tratamento farmacológico , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Humanos , Hiperglicemia/complicações , Hiperglicemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tauopatias/complicações , Tauopatias/patologiaRESUMO
BACKGROUND: Fractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We have previously shown that Cx3cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX3CL1 is essential in regulating neuronal tau pathology. METHODS: We used transgenic mice lacking endogenous Cx3cl1 (Cx3cl1-/-) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX3CL1 (referred to as Cx3cl1105Δ mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. RESULTS: First, increased basal tau levels accompanied microglial activation in Cx3cl1105Δ mice compared to control groups. Second, increased CD45+ and F4/80+ neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx3cl1-/-, and hTau/Cx3cl1105Δ mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx3cl1105Δ mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx3cr1 deletion), which likely contributes to the elevated tau pathology. CONCLUSIONS: Collectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology.
Assuntos
Quimiocina CX3CL1/genética , Regulação da Expressão Gênica/genética , Microglia/metabolismo , Tauopatias/patologia , Animais , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Quimiocina CX3CL1/metabolismo , Transtornos Cognitivos/etiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , Mutação/genética , Tauopatias/complicações , Tauopatias/genética , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Corticobasal degeneration (CBD) is a clinically heterogeneous tauopathy, which has overlapping clinicopathologic and genetic characteristics with progressive supranuclear palsy (PSP). This study aimed to elucidate whether transactive response DNA-binding protein of 43 kDa (TDP-43) pathology contributes to clinicopathologic heterogeneity of CBD. Paraffin-embedded sections of the midbrain, pons, subthalamic nucleus, and basal forebrain from 187 autopsy-confirmed CBD cases were screened with immunohistochemistry for phospho-TDP-43. In cases with TDP-43 pathology, additional brain regions (i.e., precentral, cingulate, and superior frontal gyri, hippocampus, medulla, and cerebellum) were immunostained. Hierarchical clustering analysis was performed based on the topographical distribution and severity of TDP-43 pathology, and clinicopathologic and genetic features were compared between the clusters. TDP-43 pathology was observed in 45% of CBD cases, most frequently in midbrain tegmentum (80% of TDP-43-positive cases), followed by subthalamic nucleus (69%). TDP-43-positive CBD was divided into TDP-limited (52%) and TDP-severe (48%) by hierarchical clustering analysis. TDP-severe patients were more likely to have been diagnosed clinically as PSP compared to TDP-limited and TDP-negative patients (80 vs 32 vs 30%, P < 0.001). The presence of downward gaze palsy was the strongest factor for the antemortem diagnosis of PSP, and severe TDP-43 pathology in the midbrain tectum was strongly associated with downward gaze palsy. In addition, tau burden in the olivopontocerebellar system was significantly greater in TDP-positive than TDP-negative CBD. Genetic analyses revealed that MAPT H1/H1 genotype frequency was significantly lower in TDP-severe than in TDP-negative and TDP-limited CBD (65 vs 89 vs 91%, P < 0.001). The homozygous minor allele frequencies in GRN rs5848 and TMEM106B rs3173615 were not significantly different between the three groups. In conclusion, the present study indicates that CBD with severe TDP-43 pathology is a distinct clinicopathologic subtype of CBD, characterized by PSP-like clinical presentations, severe tau pathology in the olivopontocerebellar system, and low frequency of MAPT H1 haplotype.