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2.
Nat Commun ; 11(1): 6252, 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33288742

RESUMO

Biomarkers have revolutionized scientific research on neurodegenerative diseases, in particular Alzheimer's disease, transformed drug trial design, and are also increasingly improving patient management in clinical practice. A few key cerebrospinal fluid biomarkers have been robustly associated with neurodegenerative diseases. Several novel biomarkers are very promising, especially blood-based markers. However, many biomarker findings have had low reproducibility despite initial promising results. In this perspective, we identify possible sources for low reproducibility of studies on fluid biomarkers for neurodegenerative diseases, with a focus on Alzheimer's disease. We suggest guidelines for researchers and journal editors, with the aim to improve reproducibility of findings.


Assuntos
Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Humanos , Doenças Neurodegenerativas/diagnóstico , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano
3.
Med Sci Monit ; 26: e928996, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33177481

RESUMO

Since the initial reports of coronavirus disease 2019 (COVID-19) in China in late 2019, infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have spread rapidly, resulting in a global pandemic that has caused millions of deaths. Initially, the large number of infected people required the direction of global healthcare resources to provide supportive care for the acutely ill population in an attempt to reduce mortality. While clinical trials for safe and effective antiviral agents are ongoing, and vaccine development programs are being accelerated, long-term sequelae of SARS-CoV-2 infection have become increasingly recognized and concerning. Although the upper and lower respiratory tracts are the main sites of entry of SARS-CoV-2 into the body, resulting in COVID-19 pneumonia as the most common presentation, acute lung damage may be followed by pulmonary fibrosis and chronic impairment of lung function, with impaired quality of life. Also, increasing reports have shown that SARS-CoV-2 infection involves the central nervous system (CNS) and the peripheral nervous system (PNS) and directly or indirectly damages neurons, leading to long-term neurological sequelae. This review aims to provide an update on the mechanisms involved in the development of the long-term sequelae of SARS-CoV-2 infection in the 3 main areas of lung injury, neuronal injury, and neurodegenerative diseases, including Alzheimer disease, Parkinson disease, and multiple sclerosis, and highlights the need for patient monitoring following the acute stage of infection with SARS-CoV-2 to provide a rationale for the prevention, diagnosis, and management of these potential long-term sequelae.


Assuntos
/complicações , Lesão Pulmonar/epidemiologia , Doenças Neurodegenerativas/epidemiologia , Fibrose Pulmonar/epidemiologia , /patogenicidade , /epidemiologia , /virologia , Progressão da Doença , Humanos , Lesão Pulmonar/diagnóstico , Lesão Pulmonar/imunologia , Lesão Pulmonar/prevenção & controle , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/prevenção & controle , Pandemias , Fibrose Pulmonar/diagnóstico , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/prevenção & controle , Qualidade de Vida , Fatores de Tempo
5.
Zh Nevrol Psikhiatr Im S S Korsakova ; 120(10. Vyp. 2): 22-30, 2020.
Artigo em Russo | MEDLINE | ID: mdl-33205927

RESUMO

Tau-protein pathology is the basis of a great variety of neurodegenerative diseases. Misfolding tau-protein conformation structure is the key pathogenetic mechanism of development of such multisystem degenerations as progressive supranuclear palsy, corticobasal syndrome, and fronto-temporal degeneration, as well as relatively recently added primary age-associated tauopathies and others. This review presents current views on the pathogenesis of various forms of neurodegenerative pathology linked to tau-protein accumulation. Potential of clinical diagnosis and modern diagnostic criteria, as well as existing therapy approaches, are discussed.


Assuntos
Doenças Neurodegenerativas , Paralisia Supranuclear Progressiva , Tauopatias , Encéfalo/metabolismo , Humanos , Doenças Neurodegenerativas/diagnóstico , Paralisia Supranuclear Progressiva/diagnóstico , Tauopatias/diagnóstico , Tauopatias/tratamento farmacológico , Proteínas tau/metabolismo
6.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 5831-5837, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33019300

RESUMO

Clinicians often use speech to characterize neurodegenerative disorders. Such characterizations require clinical judgment, which is subjective and can require extensive training. Quantitative Production Analysis (QPA) can be used to obtain objective quantifiable assessments of patient functioning. However, such human-based analyses of speech are costly and time consuming. Inexpensive off-the-shelf technologies such as speech recognition and part of speech taggers may avoid these problems. This study evaluates the ability of an automatic speech to text transcription system and a part of speech tagger to assist with measuring pronoun and verb ratios, measures based on QPA. Five participant groups provided spontaneous speech samples. One group consisted of healthy controls, while the remaining groups represented four subtypes of frontotemporal dementia. Findings indicated measurement of pronoun and verb ratio was robust despite errors introduced by automatic transcription and the tagger and despite these off-the-shelf products not having been trained on the language obtained from speech of the included population.


Assuntos
Demência Frontotemporal , Doenças Neurodegenerativas , Doença de Pick , Demência Frontotemporal/diagnóstico , Humanos , Doenças Neurodegenerativas/diagnóstico , Fala , Termômetros
7.
JAMA Netw Open ; 3(10): e2018777, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33006621

RESUMO

Importance: Cigarette smoking has been associated with risk of neurodegenerative disorders, such as Alzheimer disease. The association between smoking and biomarkers of changes in human cerebrospinal fluid (CSF) is not fully understood. Objective: To investigate the association of cigarette smoking with CSF biomarkers of neurodegeneration, neuroinflammation, oxidation, and neuroprotection. Design, Setting, and Participants: In this case-control study of 191 adult men in China, biomarkers in the CSF of participants with and without significant cigarette exposure were examined. Participants who did not smoke and had no history of substance use disorder or dependence were assigned to the nonsmoking group. The active smoking group included participants who consumed at least 10 cigarettes per day for 1 year. Five-milliliter samples of CSF were obtained from routine lumbar puncture conducted before anterior cruciate ligament reconstruction surgery. Data collection took place from September 2014 to January 2016, and analysis took place from January to February 2016. Exposures: Cigarette smoking. Main Outcomes and Measures: CSF levels of ß-amyloid 42 (Aß42), which has diagnostic specificity for Alzheimer disease, tumor necrosis factor alpha (TNFα), brain-derived neurotrophic factor (BDNF), total superoxide dismutase (SOD), and nitric oxide synthase (NOS) were measured. Sociodemographic data and history of smoking were obtained. Results: Of 191 participants, 87 (45.5%) were included in the active smoking group and 104 (54.4%) in the nonsmoking group. Compared with the active smoking group, the nonsmoking group was younger (mean [SD] age, 34.4 [10.5] years vs 29.6 [9.5] years; P = .01), had more education (mean [SD] duration of education, 11.9 [3.1] years vs 13.2 [2.6] years; P = .001), and had lower body mass index (mean [SD], 25.9 [3.6] vs 24.9 [4.0]; P = .005). Comparing the nonsmoking group with the smoking group, mean (SD) CSF levels of Aß42 (38.0 [25.9] pg/mL vs 52.8 [16.5] pg/mL; P < .001) and TNFα (23.0 [2.5] pg/mL vs 28.0 [2.0] pg/mL; P < .001) were significantly lower, while BDNF (23.1 [3.9] pg/mL vs 13.8 [2.7] pg/mL; P < .001), total SOD (15.7 [2.6] U/L vs 13.9 [2.4] U/L; P < .001), total NOS (28.3 [7.2] U/L vs 14.7 [5.6] U/L; P < .001), inducible NOS (16.0 [5.4] U/L vs 10.3 [2.7] U/L; P < .001), and constitutive NOS (12.4 [6.9] U/mL vs 4.4 [3.9] U/mL) were higher. In addition, in participants in the smoking group who were aged 40 years or older, total SOD levels were negatively correlated with Aß42 levels (r = -0.57; P = .02). In those who smoked at least 20 cigarettes per day, TNFα levels were positively correlated with Aß42 levels (r = 0.51; P = .006). The association of TNFα with Aß42 production was stronger than that of total SOD with Aß42 production (z = -4.38; P < .001). Conclusions and Relevance: This case-control study found that cigarette smoking was associated with at-risk biomarkers for Alzheimer disease, as indicated by higher Aß42 levels, excessive oxidative stress, neuroinflammation, and impaired neuroprotection found in the CSF of participants in the active smoking group.


Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/diagnóstico , Biomarcadores/química , Líquido Cefalorraquidiano/química , Fumar Cigarros/efeitos adversos , Disfunção Cognitiva/induzido quimicamente , Inflamação/induzido quimicamente , Doenças Neurodegenerativas/induzido quimicamente , Adulto , Fatores Etários , Doença de Alzheimer/epidemiologia , Estudos de Casos e Controles , China/epidemiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Humanos , Inflamação/diagnóstico , Inflamação/epidemiologia , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/epidemiologia , Neuroproteção/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Adulto Jovem
8.
Neurol Sci ; 41(11): 3063-3065, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32965525

RESUMO

BACKGROUND: Fahr's syndrome (or Fahr's disease) is a rare, neurological disorder characterized by bilateral calcification in the cerebellum, thalamus, basal ganglia, and cerebral cortex as a result of calcium and phosphorus metabolism disorder. The patients may be asymptomatic and clinical symptoms represent a wide range of neurologic manifestations and nonspecific neuropsychiatric disorders. We report an unusual case of Fahr's syndrome which was asymptomatic and incidentally diagnosed by generalized tonic-clonic seizure in a patient with SARS-CoV-2 (COVID-19) pneumonia. CASE PRESENTATION: The patient was a 68-year-old female and admitted to our emergency department suffering from cough and fatigue. After thorax computed tomography (CT) and SARS-CoV-2 PCR test, she was diagnosed as COVID-19 pneumonia. In the intensive care unit, the patient had a tonic-clonic convulsion starting from the left arm and spreading to the whole body. Fahr's syndrome was diagnosed after a cranial CT scan and blood metabolic panel test. CONCLUSIONS: As a result of the clinical, radiological, and biochemical evaluations, the patient was diagnosed incidentally as Fahr's syndrome associated with hypoparathyroidism. Seizures could be induced by hydroxychloroquine that was in the COVID-19 treatment or the inflammation caused by COVID-19 pneumonia. The association between the mortality of COVID-19 pneumonia and Fahr's syndrome is unknown which needs further research.


Assuntos
Doenças dos Gânglios da Base/diagnóstico , Calcinose/diagnóstico , Infecções por Coronavirus/complicações , Doenças Neurodegenerativas/diagnóstico , Pneumonia Viral/complicações , Convulsões/etiologia , Idoso , Doenças dos Gânglios da Base/complicações , Betacoronavirus , Calcinose/complicações , Evolução Fatal , Feminino , Humanos , Achados Incidentais , Doenças Neurodegenerativas/complicações , Pandemias , Pneumonia Viral/virologia
9.
BMC Neurol ; 20(1): 356, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32967628

RESUMO

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a chronic progressive neurodegenerative disease that is characterized by the discovery of eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous systems and visceral organs. In this paper, we report a case of an adult-onset neuronal intranuclear inclusion disease presenting with mental abnormality in China. CASE PRESENTATION: A 62-year-old woman presented with mental abnormality and forgetfulness for 3 months before she was admitted to our hospital. There were prodromal symptoms of fever before she had the mental disorder. Encephalitis was first suspected, and the patient underwent lumbar puncture and brain magnetic resonance imaging (MRI). A cerebrospinal fluid (CSF) examination indicated normal pressure, a normal white blood cell count, and slightly elevated protein and glucose levels. Coxsackie B virus, enterovirus, and cytomegalovirus tests showed normal results. Bacterial culture and Cryptococcus neoformans test results were negative. The contrast-enhanced MRI of the brain was normal. The brain diffusion-weighted imaging (DWI) showed a symmetrically distributed strip-shaped hyperintensity signal of the corticomedullary junction in the bilateral frontal, parietal, and temporal lobes. We considered the diagnosis of the NIID, and therefore, skin biopsy was performed. The electron microscopy revealed that intranuclear inclusions in the nucleus of fibrocytes existed and were composed of filaments. CONCLUSIONS: NIID is a rare neurodegenerative disease with diverse clinical manifestations. In clinical work, when a patient presents with abnormal mental behavior and exhibits hyperintensity signals on DWI images of the corticomedullary junction, it is crucial to consider the diagnosis of NIID.


Assuntos
Transtornos Cognitivos/etiologia , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/diagnóstico , China , Feminino , Humanos , Corpos de Inclusão Intranuclear/patologia , Pessoa de Meia-Idade , Doenças Neurodegenerativas/patologia
10.
Rinsho Shinkeigaku ; 60(10): 653-662, 2020 Oct 24.
Artigo em Japonês | MEDLINE | ID: mdl-32893241

RESUMO

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that had been diagnosed by autopsy until recently, but the number of cases has increased since skin biopsy was reported to be useful in 2011. In 2019, the genetical cause of NIID was identified as the extension of the GGC repeat sequence on the NOTCH2NLC gene, and genetic diagnosis became possible. In NIID, there are two groups: a group onset with cognitive dysfunction, and with leukoencephalopathy on head MRI and a high intensity signal at the corticomedurally junction on DWI, and a group with limb weakness. It is necessary to include NIID in the differential diagnosis of leukoencephalopathy and neuropathy, and it is necessary to combine skin biopsy and genetic testing to accurately diagnose of NIID and promote pathological elucidation.


Assuntos
Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Adolescente , Adulto , Idade de Início , Biópsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Diagnóstico Diferencial , Imagem de Difusão por Ressonância Magnética , Feminino , Testes Genéticos , Humanos , Corpos de Inclusão Intranuclear/genética , Corpos de Inclusão Intranuclear/patologia , Leucoencefalopatias , Masculino , Debilidade Muscular , Doenças Neurodegenerativas/patologia , Receptor Notch2/genética , Pele/patologia , Repetições de Trinucleotídeos , Adulto Jovem
11.
Neurology ; 95(22): e3026-e3035, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32973122

RESUMO

OBJECTIVE: To investigate whether tau phosphorylated at Thr217 (p-tau T217) assay in CSF can distinguish patients with Alzheimer disease (AD) from patients with other dementias and healthy controls. METHODS: We developed and validated a novel Simoa immunoassay to detect p-tau T217 in CSF. There was a total of 190 participants from 3 cohorts with AD (n = 77) and other neurodegenerative diseases (n = 69) as well as healthy participants (n = 44). RESULTS: The p-tau T217 assay (cutoff 242 pg/mL) identified patients with AD with accuracy of 90%, with 78% positive predictive value (PPV), 97% negative predictive value (NPV), 93% sensitivity, and 88% specificity, compared favorably with p-tau T181 ELISA (52 pg/mL), showing 78% accuracy, 58% PPV, 98% NPV, 71% specificity, and 97% sensitivity. The assay distinguished patients with AD from age-matched healthy controls (cutoff 163 pg/mL, 98% sensitivity, 93% specificity), similarly to p-tau T181 ELISA (cutoff 60 pg/mL, 96% sensitivity, 86% specificity). In patients with AD, we found a strong correlation between p-tau T217 and p-tau T181, total tau and ß-amyloid 40, but not ß-amyloid 42. CONCLUSIONS: This study demonstrates that p-tau T217 displayed better diagnostic accuracy than p-tau T181. The data suggest that the new p-tau T217 assay has potential as an AD diagnostic test in clinical evaluation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a CSF immunoassay for p-tau T217 distinguishes patients with AD from patients with other dementias and healthy controls.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Imunoensaio/normas , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico , Tauopatias/líquido cefalorraquidiano , Tauopatias/diagnóstico , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Afasia Primária Progressiva/líquido cefalorraquidiano , Afasia Primária Progressiva/diagnóstico , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Demência Frontotemporal/líquido cefalorraquidiano , Demência Frontotemporal/diagnóstico , Humanos , Imunoensaio/métodos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Paralisia Supranuclear Progressiva/líquido cefalorraquidiano , Paralisia Supranuclear Progressiva/diagnóstico
12.
Nat Commun ; 11(1): 3861, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737316

RESUMO

Integrating results from genome-wide association studies (GWASs) and gene expression studies through transcriptome-wide association study (TWAS) has the potential to shed light on the causal molecular mechanisms underlying disease etiology. Here, we present a probabilistic Mendelian randomization (MR) method, PMR-Egger, for TWAS applications. PMR-Egger relies on a MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and is scalable to hundreds of thousands of individuals. In simulations, PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust under various types of model misspecifications, is more powerful than existing TWAS/MR approaches, and can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank.


Assuntos
Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Análise da Randomização Mendeliana/estatística & dados numéricos , Modelos Genéticos , Transcriptoma , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Simulação por Computador , Bases de Dados Factuais , Gastroenteropatias/diagnóstico , Gastroenteropatias/genética , Gastroenteropatias/patologia , Humanos , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Funções Verossimilhança , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Herança Multifatorial , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia
14.
Nat Biomed Eng ; 4(8): 787-800, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32747831

RESUMO

The prevalence of concomitant proteinopathies and heterogeneous clinical symptoms in neurodegenerative diseases hinders the identification of individuals who might be candidates for a particular intervention. Here, by applying an unsupervised clustering algorithm to post-mortem histopathological data from 895 patients with degeneration in the central nervous system, we show that six non-overlapping disease clusters can simultaneously account for tau neurofibrillary tangles, α-synuclein inclusions, neuritic plaques, inclusions of the transcriptional repressor TDP-43, angiopathy, neuron loss and gliosis. We also show that membership to the six transdiagnostic disease clusters, which explains more variance in cognitive phenotypes than can be explained by individual diagnoses, can be accurately predicted from scores of the Mini-Mental Status Exam, protein levels in cerebrospinal fluid, and genotype at the APOE and MAPT loci, via cross-validated multiple logistic regression. This combination of unsupervised and supervised data-driven tools provides a framework that could be used to identify latent disease subtypes in other areas of medicine.


Assuntos
Doenças Neurodegenerativas/classificação , Doenças Neurodegenerativas/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Encéfalo/metabolismo , Encéfalo/patologia , Análise por Conglomerados , Genótipo , Humanos , Aprendizado de Máquina , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Fenótipo , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia
15.
Pediatrics ; 146(Suppl 1): S66-S69, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32737235

RESUMO

In all of medicine, there is perhaps nothing so distressing as bearing witness to a patient's suffering, especially if that patient is a child. We want to do everything that we can to avoid or alleviate a child's suffering, yet what do clinicians, ethicists, lawyers, or family members mean when they use the term "suffering," and how should these claims of suffering factor into pediatric decision-making? This question of suffering and what to do about it has played a key role in several prominent pediatric cases over the past decade, including the cases of Charlie Gard, Alfie Evans, and Baby Joseph. These cases have become seminal cases precisely because there is no clear resolution, and the "suffering child" continues to challenge our moral ideals of what it means to live a good life. In this article, I explore the various ways in which the concept of suffering is used in these cases, and I offer new ways in which parents, providers, and all those who work with sick children can approach the suffering child.


Assuntos
Tomada de Decisão Clínica/ética , Doença de Leigh , Encefalomiopatias Mitocondriais , Doenças Neurodegenerativas , Terminologia como Assunto , Suspensão de Tratamento/ética , História do Século XXI , Humanos , Lactente , Doença de Leigh/diagnóstico , Doença de Leigh/psicologia , Doença de Leigh/terapia , Masculino , Encefalomiopatias Mitocondriais/terapia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/psicologia , Doenças Neurodegenerativas/terapia , Ontário , Pais/psicologia , Estado Vegetativo Persistente/psicologia , Estado Vegetativo Persistente/terapia , Qualidade de Vida , Respiração Artificial/ética , Estresse Psicológico/diagnóstico , Estresse Psicológico/psicologia , Estresse Psicológico/terapia , Traqueostomia/psicologia , Reino Unido , Suspensão de Tratamento/legislação & jurisprudência
16.
JAMA ; 324(8): 772-781, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32722745

RESUMO

Importance: There are limitations in current diagnostic testing approaches for Alzheimer disease (AD). Objective: To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD. Design, Setting, and Participants: Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017). Exposures: Plasma P-tau217. Main Outcomes and Measures: Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]). Results: Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), ß-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aß42:Aß40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22). Conclusions and Relevance: Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.


Assuntos
Doença de Alzheimer/diagnóstico , Doenças Neurodegenerativas/diagnóstico , Proteínas tau/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Peptídeos beta-Amiloides , Área Sob a Curva , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Doenças Neurodegenerativas/sangue , Placa Amiloide/sangue , Tomografia por Emissão de Pósitrons , Presenilina-1/genética
17.
Fortschr Neurol Psychiatr ; 88(8): 528-531, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32634845

RESUMO

Posterior cortical atrophy (PCA) is a rare neurodegenerative disease, which manifests with complex visual disturbances. PCA can present in isolation ('PCA-pure') or in association with other neurodegenerative disorders ('PCA-plus'). Diagnosis is nevertheless frequently delayed, as PCA is a less known disease entity and initially a primary ocular disease is taken into consideration.


Assuntos
Atrofia/patologia , Córtex Cerebral/patologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/patologia , Transtornos da Visão/diagnóstico , Diagnóstico Tardio , Humanos , Doenças Raras/diagnóstico , Doenças Raras/patologia , Síndrome , Transtornos da Visão/patologia
18.
BMC Med ; 18(1): 140, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32552681

RESUMO

BACKGROUND: Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. METHODS: We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months. RESULTS: CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2-4 months in N = 29 participants and over 10-20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma. CONCLUSIONS: CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for prion disease advance, "secondary prevention" based on prodromal pathology may prove challenging; instead, "primary prevention" trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.


Assuntos
Biomarcadores/metabolismo , Doenças Neurodegenerativas/diagnóstico , Doenças Priônicas/diagnóstico , Adulto , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Priônicas/sangue , Doenças Priônicas/líquido cefalorraquidiano , Reprodutibilidade dos Testes , Fatores de Risco
19.
J Clin Neurosci ; 77: 17-24, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32389547

RESUMO

Social cognition (SC) is the set of socio-cognitive processes that guide automatic and voluntary behaviors by modulating behavioral responses, it includes both cognitive (Theory of the mind - ToM) and affective aspects (Empathy). SC also includes representations of internal somatic states, self-knowledge, perception of others, communication with others and interpersonal motivations. SC is relevant in daily life and reflects the neural complexity of social processing. The purpose of this scoping review is to evaluate the role of SC in neurological disorders, also considering the pathophysiological mechanisms underlying SC and potential assessment tools. The included studies were carried out between 2010 and 2019 and were found on PubMed, Scopus, Cochrane, and Web of Sciences databases, using the combined terms "social cognition"; "dementia"; "multiple sclerosis"; "parkinson", "amyotrophic lateral sclerosis", "neurodegenerative disease". Our review has shown that different SC domains are affected by several neurological conditions, with regards to dementia and amyotrophic lateral sclerosis. Further studies are needed to investigate the association between cognitive and social deficits, for a better management of patients with neurological disorders.


Assuntos
Cognição/fisiologia , Doenças Neurodegenerativas/psicologia , Comportamento Social , Teoria da Mente/fisiologia , Esclerose Amiotrófica Lateral/complicações , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/psicologia , Empatia/fisiologia , Feminino , Humanos , Masculino , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/psicologia , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/diagnóstico , Testes Neuropsicológicos , Autoimagem
20.
Ageing Res Rev ; 61: 101069, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32416267

RESUMO

Treatment options for many neurodegenerative diseases are limited due to the lack of early diagnostic procedures that allow timely delivery of therapeutic agents to affected neurons prior to cell death. While notable advances have been made in neurodegenerative disease biomarkers, whether or not the biomarkers discovered to date are useful for early diagnosis remains an open question. Additionally, the reliability of these biomarkers has been disappointing, due in part to the large dissimilarities between the tissues traditionally used to source biomarkers and primarily diseased neurons. In this article, we review the potential viability of atypical epigenetic and/or consequent transcriptional alterations (ETAs) as biomarkers of early-stage neurodegenerative disease, and present our perspectives on the discovery and practical use of such biomarkers in patient-derived neural samples using single-cell level analyses, thereby greatly enhancing the reliability of biomarker application.


Assuntos
Epigenômica , Doenças Neurodegenerativas , Biomarcadores , Diagnóstico Precoce , Humanos , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Reprodutibilidade dos Testes
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