RESUMO
A major evolution from purely clinical diagnoses to biomarker supported clinical diagnosing has been occurring over the past years in neurology. High-throughput methods, such as next-generation sequencing and mass spectrometry-based proteomics along with improved neuroimaging methods, are accelerating this development. This calls for a consensus framework that is broadly applicable and provides a spot-on overview of the clinical validity of novel biomarkers. We propose a harmonized terminology and a uniform concept that stratifies biomarkers according to clinical context of use and evidence levels, adapted from existing frameworks in oncology with a strong focus on (epi)genetic markers and treatment context. We demonstrate that this framework allows for a consistent assessment of clinical validity across disease entities and that sufficient evidence for many clinical applications of protein biomarkers is lacking. Our framework may help to identify promising biomarker candidates and classify their applications by clinical context, aiming for routine clinical use of (protein) biomarkers in neurology.
Assuntos
Doenças do Sistema Nervoso , Humanos , Biomarcadores , Proteômica/métodos , Espectrometria de Massas , NeuroimagemRESUMO
BACKGROUND: In amyloid-positive individuals at risk for Alzheimer's disease (AD), high soluble 42-amino acid amyloid-ß (Aß42) levels are associated with normal cognition. It is unknown if this relationship applies longitudinally in a genetic cohort. OBJECTIVE: To test the hypothesis that high Aß42 preserves normal cognition in amyloid-positive individuals with Alzheimer's disease (AD)-causing mutations (APP, PSEN1, or PSEN2) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau). METHODS: Cognitive progression was defined as any increase in Clinical Dementia Rating (CDRâ=â0, normal cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression. RESULTS: Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8%) meeting criteria for progression after 3.3±2.0 years. Soluble Aß42 levels were higher among CDR non-progressors than CDR progressors. Higher Aß42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval [CI], 0.19-0.67; pâ=â0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68-0.96; pâ=â0.018). CSF Aß42 levels predicting lower risk of progression increased with higher SUVR levels. CONCLUSION: High CSF Aß42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.
Assuntos
Doença de Alzheimer , Amiloidose , Disfunção Cognitiva , Demência , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons/métodos , Demência/genética , Cognição , Mutação/genética , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Disfunção Cognitiva/líquido cefalorraquidianoRESUMO
Limited cleavage promotes the aggregation propensity of protein tau in neurodegenerative tauopathies. Cathepsin S (CatS) is overexpressed in brains of patients suffering from tauopathies such as Alzheimer's disease (AD). Furthermore, CatS serum levels correlate with survival in the elderly. The current study investigates whether limited cleavage by CatS promotes tau aggregation, and whether CatS serum levels may correlate with disease severity in tauopathies. Oligomer formation of fluorescently labeled protein tau was monitored by single particle fluorescence spectroscopy after coincubation with CatS. Tau cleavage patterns were investigated by SDS-PAGE. For serum analyses, samples were collected from 42 patients with probable progressive supranuclear palsy (PSP) according to NINDS-PSP criteria. Disease severity was assessed by PSP rating scale (PSP-RS), PSP staging system (PSP-S) and Schwab and England Activities of Daily Living (SEADL). CatS, cystatin C (CysC) and interleukin 6 (IL-6) serum levels were determined by ELISA, ECLIA and turbidimetry, respectively. SDS-PAGE demonstrated a distinct cleavage pattern of protein tau after coincubation with CatS. Furthermore, tau oligomer formation was increased 2.4-fold (p < 0.05) after limited cleavage. Serum CatS and CysC levels did not correlate with disease severity in PSP. Of note, IL-6 correlated with PSP-S (r = 0.41; 95% CI 0.11-0.65; p = 0.008), SEADL (r = -0.37; 95% CI -0.61 to -0.06; p = 0.017) and the history and gait/midline subdomains of the PSP-RS. While CatS facilitates tau aggregation in vitro, serum levels of CatS appear not to correlate with disease severity. The observed correlation of IL-6 with disease severity warrants further investigation of inflammatory markers in PSP.
Assuntos
Catepsinas/sangue , Interleucina-6/metabolismo , Paralisia Supranuclear Progressiva/sangue , Tauopatias/sangue , Proteínas tau/metabolismo , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/psicologia , Tauopatias/complicaçõesRESUMO
BACKGROUND: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are characterized by rapid deterioration and a fatal outcome. OBJECTIVES: Admission triggers, treatment efficacy, and care patterns. METHODS: Retrospective analysis of patients with PSP/CBD admitted to an inpatient specialized palliative care service. RESULTS: In 38 patients, there were 63 admissions for swallowing difficulties, falls, pain, impaired communication, cognitive/mood disturbances, respiratory symptoms, and infection. Mean length of stay was 11.6 days. Treatment response was variable. In 68%, of admission episodes there was stabilization or improvement, 75% were discharged home. In case of readmission, the mean interval has been 9.7 months. Time since diagnosis and admission triggers were not associated with outcome or death. CONCLUSION: Patients showed high symptom load contrasting with discharge rates and subsequent health care utilization. Brief multidisciplinary interventions might be helpful to preserve autonomy.
Assuntos
Doenças dos Gânglios da Base/complicações , Cuidados Paliativos , Admissão do Paciente/estatística & dados numéricos , Paralisia Supranuclear Progressiva/complicações , Acidentes por Quedas , Idoso , Idoso de 80 Anos ou mais , Transtornos de Deglutição/etiologia , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Estudos RetrospectivosRESUMO
The causes of death in patients with neurodegenerative diseases are important information for patients and relatives because misleading information causes additional burdens. Early and frank discussion about disease progression, the causes of death, and end-of-life decisions might support the patient's and family's acceptance of the dying process and also helps physicians to frame treatment goals more explicitly. These goals include the place of death as well as medication administered at the end of life. The Liverpool Care Pathway provides a useful tool to standardize the care at the end of life that contributes to individual decisions and care plans. The prescription of medication at the end of life in various neurodegenerative diseases differs from treatment during the earlier phases of the diseases, not only because of swallowing difficulties but also in terms of symptom control.
Assuntos
Doenças do Sistema Nervoso/terapia , Neurologia/métodos , Cuidados Paliativos/métodos , HumanosRESUMO
Patients with chronic neurologic disorders suffer from the burden of disease progression without the hope for a cure. Therefore, symptom management and palliative care approaches should be included from the beginning of the illness. Palliative care aims at improving a patient's quality of life by alleviating suffering due to physical, psychosocial, and spiritual factors. Since no curative and only limited life-prolonging treatment options are available for most chronic neurologic disorders, a palliative care approach can help to create a treatment plan that considers all aspects of the disease. We have provided palliative care approaches for the most common neurodegenerative disorders like dementia, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. A palliative approach to neurologic disorders does not simply mean limiting treatment and focusing on pain. Instead, the whole unit of care, consisting of the patient, relatives, and caregivers, should be perceived with all their needs.
Assuntos
Doenças do Sistema Nervoso/terapia , Cuidados Paliativos/métodos , Doença Crônica , HumanosAssuntos
Cuidados Paliativos/métodos , Síndrome das Pernas Inquietas/epidemiologia , Idoso , Agonistas de Dopamina/uso terapêutico , Feminino , Unidades Hospitalares , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/terapia , Estudos Prospectivos , Síndrome das Pernas Inquietas/diagnóstico , Síndrome das Pernas Inquietas/terapia , Tetra-Hidronaftalenos/uso terapêutico , Tiofenos/uso terapêuticoRESUMO
BACKGROUND: Fibrillar amyloid-like deposits and co-deposits of tau and α-synuclein are found in several common neurodegenerative diseases. Recent evidence indicates that small oligomers are the most relevant toxic aggregate species. While tau fibril formation is well-characterized, factors influencing tau oligomerization and molecular interactions of tau and α-synuclein are not well understood. RESULTS: We used a novel approach applying confocal single-particle fluorescence to investigate the influence of tau phosphorylation and metal ions on tau oligomer formation and its coaggregation with α-synuclein at the level of individual oligomers. We show that Al3+ at physiologically relevant concentrations and tau phosphorylation by GSK-3ß exert synergistic effects on the formation of a distinct SDS-resistant tau oligomer species even at nanomolar protein concentration. Moreover, tau phosphorylation and Al3+ as well as Fe3+ enhanced both formation of mixed oligomers and recruitment of α-synuclein in pre-formed tau oligomers. CONCLUSIONS: Our findings provide a new perspective on interactions of tau phosphorylation, metal ions, and the formation of potentially toxic oligomer species, and elucidate molecular crosstalks between different aggregation pathways involved in neurodegeneration.