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1.
J Neurol Sci ; 421: 117316, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33561753

RESUMEN

OBJECTIVE: We sought to review the literature on cerebrospinal fluid (CSF) testing in patients with COVID-19 for evidence of viral neuroinvasion by SARS-CoV-2. METHODS: We performed a systematic review of Medline and Embase between December 1, 2019 and November 18, 2020 to identify case reports or series of patients who had COVID-19 diagnosed based on positive SARS-CoV-2 polymerase chain reaction (PCR) or serologic testing and had CSF testing due to a neurologic symptom. RESULTS: We identified 242 relevant documents which included 430 patients with COVID-19 who had acute neurological symptoms prompting CSF testing. Of those, 321 (75%) patients had symptoms that localized to the central nervous system (CNS). Of 304 patients whose CSF was tested for SARS-CoV-2 PCR, there were 17 (6%) whose test was positive, all of whom had symptoms that localized to the central nervous system (CNS). The majority (13/17, 76%) of these patients were admitted to the hospital because of neurological symptoms. Of 58 patients whose CSF was tested for SARS-CoV-2 antibody, 7 (12%) had positive antibodies with evidence of intrathecal synthesis, all of whom had symptoms that localized to the CNS. Of 132 patients who had oligoclonal bands evaluated, 3 (2%) had evidence of intrathecal antibody synthesis. Of 77 patients tested for autoimmune antibodies in the CSF, 4 (5%) had positive findings. CONCLUSION: Detection of SARS-CoV-2 in CSF via PCR or evaluation for intrathecal antibody synthesis appears to be rare. Most neurological complications associated with SARS- CoV-2 are unlikely to be related to direct viral neuroinvasion.


Asunto(s)
/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso/diagnóstico , /metabolismo , Biomarcadores/líquido cefalorraquídeo , Humanos , Enfermedades del Sistema Nervioso/etiología , /aislamiento & purificación
2.
Cochrane Database Syst Rev ; 2: CD010945, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33566374

RESUMEN

BACKGROUND: Dementia is a syndrome that comprises many differing pathologies, including Alzheimer's disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta-amyloid (1-42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes. OBJECTIVES: To determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome. SEARCH METHODS: We searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies. SELECTION CRITERIA: We considered cross-sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype. DATA COLLECTION AND ANALYSIS: Seven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the 'Quality Assessment of Diagnostic Accuracy Studies' (QUADAS-2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross-tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta-analyses using bivariate, random-effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs). In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non-ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol-related cognitive disorder (ARCD), Creutzfeldt-Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test-positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42. MAIN RESULTS: We identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS-2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies). The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non-ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity. AUTHORS' CONCLUSIONS: Our review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non-ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/líquido cefalorraquídeo , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/líquido cefalorraquídeo , Alcoholismo/complicaciones , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Sesgo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/sangre , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Intervalos de Confianza , Síndrome de Creutzfeldt-Jakob/sangre , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquídeo , Síndrome de Creutzfeldt-Jakob/diagnóstico , Demencia Vascular/sangre , Demencia Vascular/líquido cefalorraquídeo , Demencia Vascular/diagnóstico , Diagnóstico Diferencial , Demencia Frontotemporal/sangre , Demencia Frontotemporal/líquido cefalorraquídeo , Demencia Frontotemporal/diagnóstico , Humanos , Hidrocéfalo Normotenso/sangre , Hidrocéfalo Normotenso/líquido cefalorraquídeo , Hidrocéfalo Normotenso/diagnóstico , Enfermedad por Cuerpos de Lewy/sangre , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Enfermedad por Cuerpos de Lewy/diagnóstico , Funciones de Verosimilitud , Sensibilidad y Especificidad
3.
Medicine (Baltimore) ; 100(7): e24837, 2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33607852

RESUMEN

ABSTRACT: Dysautonomia is common in patients with Parkinson disease (PD) since disease early phase. Scales for Outcomes in Parkinson's disease - Autonomic (SCOPA-AUT) is a well-designed scale assessing the autonomic dysfunctions of PD patients. Our objectives were to examine the autonomic dysfunction in PD and scan without evidence of dopaminergic deficit (SWEDD) patients and to assess the correlation of autonomic dysfunctions with cerebrospinal fluid (CSF) biomarkers.An analysis of the Parkinson's Progression Markers Initiative (PPMI) data including 414 PD patients, 60 SWEDD patients, and 170 healthy controls (HCs) with baseline CSF biomarker measurements and SCOPA-AUT assessments was presented. Autonomic symptoms including gastrointestinal, urinary, cardiovascular, pupillomotor, thermoregulatory and sexual dysfunctions were assessed by SCOPA-AUT scales. Spearman correlation test was used to examine the correlations between CSF measurements and each section of SCOPA-AUT scales in HCs and subjects with PD or SWEDD.More severe autonomic dysfunctions were observed in patients with SWEDD than those with PD (P < .001). Specifically, patients with PD have lower scores on the urinary scale [4 (0-17) vs 5 (1-18)], pupillomotor scale [0 (0-3) vs 0 (0-3)], thermoregulatory scale [0 (0-4) vs 1.5 (0-10)] and sexual scale [1 (0-6) vs 2 (0-6)] compared with SWEDD patients. Thermoregulatory dysfunction scores were found correlated with CSF α-syn levels in SWEDD group, and gastrointestinal dysfunction scores were correlated with CSF Abeta1-42 in PD group. Additionally, urinary dysfunction scores were correlated with CSF total tau and tau phosphorylated at threonine 181(p-tau181) levels in both HCs and PD patients.


Asunto(s)
Biomarcadores/líquido cefalorraquídeo , Dopamina/deficiencia , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Sistema Nervioso Autónomo/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Regulación de la Temperatura Corporal/fisiología , Estudios de Casos y Controles , Femenino , Enfermedades Gastrointestinales/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/líquido cefalorraquídeo , Enfermedad de Parkinson/fisiopatología , Disautonomías Primarias/etiología , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Enfermedades Urológicas/metabolismo
4.
Biomed Environ Sci ; 34(1): 19-28, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33531104

RESUMEN

Objective: In the present study, the ABCA1 was used as a label to capture specific exosomes, the level of ABCA1-labeled exosomal microRNA-135a (miR-135a) was evaluated for the diagnosis of Alzheimer's disease (AD), especially in patients with early stages of AD. Methods: This is a preliminary research focused on the levels of ABCA1 in WBCs, RBCs, HT-22 cells, and neuron cells. The diagnostic value of ABCA1-labeled exosomal miR-135a was examined using the CSF and serum of APP/PS1 double transgenic mice, and 152 patients with SCD, 131 patients with MCI, 198 patients with DAT, and 30 control subjects. Results: The level of ABCA1 exosomes harvested from HT-22 cells and neuron culture medium was significantly higher compared to that of RBCs and WBCs ( P < 0.05). The levels of ABCA1-labeled exosomal miR-135a increased in the CSF of MCI and DAT group compared to those of control group ( P < 0.05), slightly increased ( P > 0.05) in the serum of SCD patient group, and significantly increased in MCI and DAT patient groups compared to those of the control group ( P < 0.05). Conclusion: This study outlines a method to capture specific exosomes and detect them using immunological methods, which is more efficient for early diagnosis of AD.


Asunto(s)
Transportador 1 de Casete de Unión a ATP , Disfunción Cognitiva/sangre , Exosomas , MicroARNs/sangre , Transportador 1 de Casete de Unión a ATP/sangre , Transportador 1 de Casete de Unión a ATP/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Animales , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Línea Celular , Disfunción Cognitiva/líquido cefalorraquídeo , Eritrocitos/metabolismo , Femenino , Humanos , Leucocitos/metabolismo , Masculino , Ratones Transgénicos , Neuronas/metabolismo
5.
Neurology ; 96(10): e1470-e1481, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33408146

RESUMEN

OBJECTIVE: To determine whether memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer disease (AD) biomarkers, we examined associations between performance in 3 memory tasks and CSF ß-amyloid (Aß)42/Aß40 and phosopho-tau181 (p-tau181) in cognitively unimpaired older adults (CU). METHODS: CU enrolled in the Stanford Aging and Memory Study (n = 153; age 68.78 ± 5.81 years; 94 female) completed a lumbar puncture and memory assessments. CSF Aß42, Aß40, and p-tau181 were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied "target" objects, novel "foil" objects, and perceptually similar "lure" objects. Analyses examined cross-sectional relationships among memory performance, age, and CSF measures, controlling for sex and education. RESULTS: Age and lower Aß42/Aß40 were independently associated with elevated p-tau181. Age, Aß42/Aß40, and p-tau181 were each associated with (1) poorer associative memory and (2) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aß42/Aß40 on memory. Relationships between CSF proteins and delayed recall were similar but nonsignificant. CSF Aß42 was not significantly associated with p-tau181 or memory. CONCLUSIONS: Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying CU with preclinical AD pathology.


Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Hipocampo/fisiopatología , Trastornos de la Memoria/líquido cefalorraquídeo , Trastornos de la Memoria/psicología , Anciano , Anciano de 80 o más Años , Envejecimiento/psicología , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Aprendizaje por Asociación , Estudios Transversales , Señales (Psicología) , Discriminación en Psicología , Femenino , Humanos , Masculino , Memoria , Trastornos de la Memoria/fisiopatología , Memoria Episódica , Recuerdo Mental , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fragmentos de Péptidos/líquido cefalorraquídeo , Desempeño Psicomotor , Proteínas tau/líquido cefalorraquídeo
6.
J Neurosci ; 41(4): 780-796, 2021 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-33310753

RESUMEN

Huntington disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. Therapeutics that lower HTT have shown preclinical promise and are being evaluated in clinical trials. However, clinical assessment of brain HTT lowering presents challenges. We have reported that mutant HTT (mHTT) in the CSF of HD patients correlates with clinical measures, including disease burden as well as motor and cognitive performance. We have also shown that lowering HTT in the brains of HD mice results in correlative reduction of mHTT in the CSF, prompting the use of this measure as an exploratory marker of target engagement in clinical trials. In this study, we investigate the mechanisms of mHTT clearance from the brain in adult mice of both sexes to elucidate the significance of therapy-induced CSF mHTT changes. We demonstrate that, although neurodegeneration increases CSF mHTT concentrations, mHTT is also present in the CSF of mice in the absence of neurodegeneration. Importantly, we show that secretion of mHTT from cells in the CNS followed by glymphatic clearance from the extracellular space contributes to mHTT in the CSF. Furthermore, we observe secretion of wild type HTT from healthy control neurons, suggesting that HTT secretion is a normal process occurring in the absence of pathogenesis. Overall, our data support both passive release and active clearance of mHTT into CSF, suggesting that its treatment-induced changes may represent a combination of target engagement and preservation of neurons.SIGNIFICANCE STATEMENT: Changes in CSF mutant huntingtin (mHTT) are being used as an exploratory endpoint in HTT lowering clinical trials for the treatment of Huntington disease (HD). Recently, it was demonstrated that intrathecal administration of a HTT lowering agent leads to dose-dependent reduction of CSF mHTT in HD patients. However, little is known about how HTT, an intracellular protein, reaches the extracellular space and ultimately the CSF. Our findings that HTT enters CSF by both passive release and active secretion followed by glymphatic clearance may have significant implications for interpretation of treatment-induced changes of CSF mHTT in clinical trials for HD.


Asunto(s)
Química Encefálica , Proteína Huntingtina/líquido cefalorraquídeo , Enfermedad de Huntington/líquido cefalorraquídeo , Animales , Astrocitos/metabolismo , Biomarcadores/líquido cefalorraquídeo , Femenino , Sistema Glinfático/metabolismo , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Masculino , Ratones , Ratones Transgénicos , Mutación , Neuronas/metabolismo , Expansión de Repetición de Trinucleótido
7.
Int J Mol Sci ; 21(24)2020 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-33339180

RESUMEN

Protein aggregation is classically considered the main cause of neuronal death in neurodegenerative diseases (NDDs). However, increasing evidence suggests that alteration of RNA metabolism is a key factor in the etiopathogenesis of these complex disorders. Non-coding RNAs are the major contributor to the human transcriptome and are particularly abundant in the central nervous system, where they have been proposed to be involved in the onset and development of NDDs. Interestingly, some ncRNAs (such as lncRNAs, circRNAs and pseudogenes) share a common functionality in their ability to regulate gene expression by modulating miRNAs in a phenomenon known as the competing endogenous RNA mechanism. Moreover, ncRNAs are found in body fluids where their presence and concentration could serve as potential non-invasive biomarkers of NDDs. In this review, we summarize the ceRNA networks described in Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and spinocerebellar ataxia type 7, and discuss their potential as biomarkers of these NDDs. Although numerous studies have been carried out, further research is needed to validate these complex interactions between RNAs and the alterations in RNA editing that could provide specific ceRNET profiles for neurodegenerative disorders, paving the way to a better understanding of these diseases.


Asunto(s)
Ácidos Nucleicos Libres de Células/sangre , Redes Reguladoras de Genes , Enfermedades Neurodegenerativas/sangre , Animales , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/orina , Ácidos Nucleicos Libres de Células/líquido cefalorraquídeo , Ácidos Nucleicos Libres de Células/genética , Ácidos Nucleicos Libres de Células/orina , Humanos , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/orina
8.
Int J Mol Sci ; 21(24)2020 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-33321992

RESUMEN

There is a lack of reliable biomarkers for disorders of the central nervous system (CNS), and diagnostics still heavily rely on symptoms that are both subjective and difficult to quantify. The cerebrospinal fluid (CSF) is a promising source of biomarkers due to its close connection to the CNS. Extracellular vesicles are actively secreted by cells, and proteomic analysis of CSF extracellular vesicles (EVs) and their molecular composition likely reflects changes in the CNS to a higher extent compared with total CSF, especially in the case of neuroinflammation, which could increase blood-brain barrier permeability and cause an influx of plasma proteins into the CSF. We used proximity extension assay for proteomic analysis due to its high sensitivity. We believe that this methodology could be useful for de novo biomarker discovery for several CNS diseases. We compared four commercially available kits for EV isolation: MagCapture and ExoIntact (based on magnetic beads), EVSecond L70 (size-exclusion chromatography), and exoEasy (membrane affinity). The isolated EVs were characterized by nanoparticle tracking analysis, ELISA (CD63, CD81 and albumin), and proximity extension assay (PEA) using two different panels, each consisting of 92 markers. The exoEasy samples did not pass the built-in quality controls and were excluded from downstream analysis. The number of detectable proteins in the ExoIntact samples was considerably higher (~150% for the cardiovascular III panel and ~320% for the cell regulation panel) compared with other groups. ExoIntact also showed the highest intersample correlation with an average Pearson's correlation coefficient of 0.991 compared with 0.985 and 0.927 for MagCapture and EVSecond, respectively. The median coefficient of variation was 5%, 8%, and 22% for ExoIntact, MagCapture, and EVSecond, respectively. Comparing total CSF and ExoIntact samples revealed 70 differentially expressed proteins in the cardiovascular III panel and 17 in the cell regulation panel. To our knowledge, this is the first time that CSF EVs were analyzed by PEA. In conclusion, analysis of CSF EVs by PEA is feasible, and different isolation kits give distinct results, with ExoIntact showing the highest number of identified proteins with the lowest variability.


Asunto(s)
Enfermedades del Sistema Nervioso Central/líquido cefalorraquídeo , Proteínas del Líquido Cefalorraquídeo/análisis , Fraccionamiento Químico/métodos , Vesículas Extracelulares/metabolismo , Proteómica/métodos , Juego de Reactivos para Diagnóstico/normas , Biomarcadores/líquido cefalorraquídeo , Vesículas Extracelulares/química , Humanos
9.
Artículo en Inglés | MEDLINE | ID: mdl-32978291

RESUMEN

OBJECTIVE: To investigate the pathophysiologic mechanism of encephalopathy and prolonged comatose or stuporous state in severally ill patients with coronavirus disease 2019 (COVID-19). METHODS: Eight COVID-19 patients with signs of encephalopathy were tested for antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the serum and CSF using a Food and Drug Administration-approved and independently validated ELISA. Blood-brain barrier (BBB) integrity and immunoglobulin G (IgG) intrathecal synthesis were further tested using albumin and IgG indices. The CSF was also tested for autoimmune encephalitis antibodies and 14-3-3, a marker of ongoing neurodegeneration. RESULTS: All patients had anti-SARS-CoV-2 antibodies in their CSF, and 4 of 8 patients had high titers, comparable to high serum values. One patient had anti-SARS-CoV-2 IgG intrathecal synthesis, and 3 others had disruption of the blood-brain barrier. The CSF in 4 patients was positive for 14-3-3-protein suggesting ongoing neurodegeneration. In all patients, the CSF was negative for autoimmune encephalitis antibodies and SARS-CoV-2 by PCR. None of the patients, apart from persistent encephalopathic signs, had any focal neurologic signs or history or specific neurologic disease. CONCLUSIONS: High-titer anti-SARS-CoV-2 antibodies were detected in the CSF of comatose or encephalopathic patients demonstrating intrathecal IgG synthesis or BBB disruption. A disrupted BBB may facilitate the entry of cytokines and inflammatory mediators into the CNS enhancing neuroinflammation and neurodegeneration. The observations highlight the need for prospective CSF studies to determine the pathogenic role of anti-SARS-CoV-2 antibodies and identify early therapeutic interventions.


Asunto(s)
Autoanticuerpos/líquido cefalorraquídeo , Betacoronavirus/aislamiento & purificación , Barrera Hematoencefálica/metabolismo , Coma/líquido cefalorraquídeo , Infecciones por Coronavirus/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso/líquido cefalorraquídeo , Neumonía Viral/líquido cefalorraquídeo , Estupor/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Biomarcadores/líquido cefalorraquídeo , Coma/diagnóstico , Infecciones por Coronavirus/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/diagnóstico , Pandemias , Neumonía Viral/diagnóstico , Estupor/diagnóstico , Resultado del Tratamiento
10.
Neurology ; 95(16): e2295-e2304, 2020 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-32878992

RESUMEN

OBJECTIVE: To determine the cognitive consequences of anticholinergic medications (aCH) in cognitively normal older adults as well as interactive effects of genetic and CSF Alzheimer disease (AD) risk factors. METHODS: A total of 688 cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative were evaluated (mean age 73.5 years, 49.6% female). Cox regression examined risk of progression to mild cognitive impairment (MCI) over a 10-year period and linear mixed effects models examined 3-year rates of decline in memory, executive function, and language as a function of aCH. Interactions with APOE ε4 genotype and CSF biomarker evidence of AD pathology were also assessed. RESULTS: aCH+ participants had increased risk of progression to MCI (hazard ratio [HR] 1.47, p = 0.02), and there was a significant aCH × AD risk interaction such that aCH+/ε4+ individuals showed greater than 2-fold increased risk (HR 2.69, p < 0.001) for incident MCI relative to aCH-/ε4-), while aCH+/CSF+) individuals demonstrated greater than 4-fold (HR 4.89, p < 0.001) increased risk relative to aCH-/CSF-. Linear mixed effects models revealed that aCH predicted a steeper slope of decline in memory (t = -2.35, p = 0.02) and language (t = -2.35, p = 0.02), with effects exacerbated in individuals with AD risk factors. CONCLUSIONS: aCH increased risk of incident MCI and cognitive decline, and effects were significantly enhanced among individuals with genetic risk factors and CSF-based AD pathophysiologic markers. Findings underscore the adverse impact of aCH medications on cognition and the need for deprescribing trials, particularly among individuals with elevated risk for AD.


Asunto(s)
Enfermedad de Alzheimer/epidemiología , Antagonistas Colinérgicos/efectos adversos , Disfunción Cognitiva/epidemiología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/genética , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Masculino
11.
Rinsho Shinkeigaku ; 60(10): 699-705, 2020 Oct 24.
Artículo en Japonés | MEDLINE | ID: mdl-32893247

RESUMEN

A 75-year-old woman developed low back pain, weakness of the lower extremities, and urinary retention. On day 7 after the onset of symptoms, she was brought to the emergency department of our hospital by an ambulance because of progressive weakness of both lower extremities. Spine MRI showed longitudinally extensive spinal cord lesion (LESCL) at the Th8-Th11 spinal cord level and flow voids around the lesions. Lumbar puncture revealed a normal opening pressure, yellowish appearance, pleocytosis with polymorphonuclear predominance, and decreased cerebrospinal fluid (CSF) glucose levels. Based on the rapidly progressing myelopathy, LESCL, and CSF findings, we initially diagnosed the patient with myelitis and administered acyclovir and high-dose intravenous immunoglobulin on day 7. Spine MRI with gadolinium-enhancement showed longitudinally extending flow voids of the thoracic cord, and digital subtraction arteriogram (DSA) revealed arteriovenous shunt on the dura with dilated and tortuous intradural veins. We finally diagnosed her with spinal dural arteriovenous fistula (SDAVF). Cases of SDAVF might be initially misdiagnosed as myelitis because of showing rapid progressive myelopathy, pleocytosis with polymorphonuclear predominance, and decreased CSF glucose levels. Lumbar puncture and steroid administration for the cases of SDAVF could aggravate the patient's neurological symptoms. Therefore, lumbar puncture and initiation of immunotherapy should be avoided until SDAVF is completely excluded in patients with suspected myelitis on spine MRI without gadolinium-enhancement, even if their neurological symptoms progress rapidly.


Asunto(s)
Malformaciones Vasculares del Sistema Nervioso Central/complicaciones , Malformaciones Vasculares del Sistema Nervioso Central/diagnóstico , Glucosa/líquido cefalorraquídeo , Leucocitosis/diagnóstico por imagen , Leucocitosis/etiología , Neutrófilos/patología , Enfermedades de la Médula Espinal/diagnóstico por imagen , Enfermedades de la Médula Espinal/etiología , Médula Espinal/diagnóstico por imagen , Angiografía de Substracción Digital , Biomarcadores/líquido cefalorraquídeo , Malformaciones Vasculares del Sistema Nervioso Central/patología , Malformaciones Vasculares del Sistema Nervioso Central/terapia , Progresión de la Enfermedad , Embolización Terapéutica/métodos , Femenino , Humanos , Imagen por Resonancia Magnética , Vértebras Torácicas , Resultado del Tratamiento
12.
BMC Med Genet ; 21(1): 181, 2020 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-32919460

RESUMEN

BACKGROUND: The complement component (3b/4b) receptor 1 gene (CR1) gene has been proved to affect the susceptibility of Alzheimer's disease (AD) in different ethnic and districts groups. However, the effect of CR1 genetic variants on amyloid ß (Aß) metabolism of AD human is still unclear. Hence, the aim of this study was to investigate genetic influences of CR1 gene on Aß metabolism. METHODS: All data of AD patients and normal controls (NC) were obtained from alzheimer's disease neuroimaging initiative database (ADNI) database. In order to assess the effect of each single nucleotide polymorphism (SNP) of CR1 on Aß metabolism, the PLINK software was used to conduct the quality control procedures to enroll appropriate SNPs. Moreover, the correlation between CR1 genotypes and Aß metabolism in all participants were estimated with multiple linear regression models. RESULTS: After quality control procedures, a total of 329 samples and 83 SNPs were enrolled in our study. Moreover, our results identified five SNPs (rs10494884, rs11118322, rs1323721, rs17259045 and rs41308433), which were linked to Aß accumulation in brain. In further analyses, rs17259045 was found to decrease Aß accumulation among AD patients. Additionally, our study revealed the genetic variants in rs12567945 could increase CSF Aß42 in NC population. CONCLUSIONS: Our study had revealed several novel SNPs in CR1 genes which might be involved in the progression of AD via regulating Aß accumulation. These findings will provide a new basis for the diagnosis and treatment AD.


Asunto(s)
Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Neuroimagen/métodos , Fragmentos de Péptidos/líquido cefalorraquídeo , Polimorfismo de Nucleótido Simple , Receptores de Complemento 3b/genética , Anciano , Anciano de 80 o más Años , Alelos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Femenino , Genotipo , Humanos , Masculino , Fragmentos de Péptidos/metabolismo
13.
PLoS One ; 15(8): e0233820, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32804976

RESUMEN

Molecular markers derived from cerebrospinal fluid (CSF) represent an accessible means of exploring the pathobiology of Huntington's disease (HD) in vivo. The endo-lysosomal/autophagy system is dysfunctional in HD, potentially contributing to disease pathogenesis and representing a potential target for therapeutic intervention. Several endo-lysosomal proteins have shown promise as biomarkers in other neurodegenerative diseases; however, they have yet to be fully explored in HD. We performed parallel reaction monitoring mass spectrometry analysis (PRM-MS) of multiple endo-lysosomal proteins in the CSF of 60 HD mutation carriers and 20 healthy controls. Using generalised linear models controlling for age and CAG, none of the 18 proteins measured displayed significant differences in concentration between HD patients and controls. This was affirmed by principal component analysis, in which no significant difference across disease stage was found in any of the three components representing lysosomal hydrolases, binding/transfer proteins and innate immune system/peripheral proteins. However, several proteins were associated with measures of disease severity and cognition: most notably amyloid precursor protein, which displayed strong correlations with composite Unified Huntington's Disease Rating Scale, UHDRS Total Functional Capacity, UHDRS Total Motor Score, Symbol Digit Modalities Test and Stroop Word Reading. We conclude that although endo-lysosomal proteins are unlikely to have value as disease state CSF biomarkers for Huntington's disease, several proteins demonstrate associations with clinical severity, thus warranting further, targeted exploration and validation in larger, longitudinal samples.


Asunto(s)
Proteínas del Líquido Cefalorraquídeo/metabolismo , Enfermedad de Huntington/líquido cefalorraquídeo , Adulto , Anciano , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Cognición , Estudios Transversales , Progresión de la Enfermedad , Endosomas/metabolismo , Femenino , Proteína Activadora de G (M2)/líquido cefalorraquídeo , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Enfermedad de Huntington/psicología , Modelos Lineales , Estudios Longitudinales , Proteína 2 de la Membrana Asociada a los Lisosomas/líquido cefalorraquídeo , Glicoproteínas de la Membrana Asociadas a los Lisosomas/líquido cefalorraquídeo , Masculino , Espectrometría de Masas/métodos , Persona de Mediana Edad , Análisis de Componente Principal , Estudios Prospectivos , Proteínas/metabolismo , Expansión de Repetición de Trinucleótido
14.
PLoS Med ; 17(8): e1003289, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32817639

RESUMEN

BACKGROUND: The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of ß-amyloid peptide (A, ß-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. METHODS AND FINDINGS: This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44-96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44-94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1-5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4-31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. CONCLUSIONS: In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level.


Asunto(s)
Envejecimiento/líquido cefalorraquídeo , Envejecimiento/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Apolipoproteína E4/líquido cefalorraquídeo , Apolipoproteína E4/genética , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad
15.
Rinsho Shinkeigaku ; 60(9): 631-635, 2020 Sep 29.
Artículo en Japonés | MEDLINE | ID: mdl-32779602

RESUMEN

We report a 62-year-old female with rheumatoid meningitis. She presented with mental disorder, loss of consciousness, generalized seizures, and cognitive impairment. Brain MRI demonstrated high intensity lesions and abnormal enhancement along the left frontal and parietal sulci. Her serum and cerebrospinal fluid were positive for anti-cyclic citrullinated peptides (CCP) antibody, and the antibody index of cerebrospinal fluid anti-CCP antibody increased, which led us to suspect rheumatoid meningitis. Her symptoms improved immediately by methylpredonisolone pulse therapy and anti-CCP antibody turned negative in cerebrospinal fluid. However, she revealed arthritis with the reduction of betamethasone and was diagnosed as rheumatoid arthritis. We suggest that the elevation of antibody index of cerebrospinal fluid anti-CCP antibody is useful in the diagnosis of rheumatoid meningitis preceding neurological symptoms without arthritis, and anti-CCP antibody in cerebrospinal fluid may be helpful as the evaluation of the treatment.


Asunto(s)
Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico , Autoanticuerpos/líquido cefalorraquídeo , Meningitis/diagnóstico , Meningitis/etiología , Enfermedades del Sistema Nervioso/etiología , Péptidos Cíclicos/inmunología , Artritis Reumatoide/tratamiento farmacológico , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Meningitis/tratamiento farmacológico , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Quimioterapia por Pulso , Resultado del Tratamiento
16.
Neurology ; 95(17): e2378-e2388, 2020 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-32788242

RESUMEN

OBJECTIVE: To evaluate sex differences in CSF biomarkers, taking the potential modifying role of clinical disease stage and APOE ε4 genotype into account. METHOD: We included participants (n = 1,801) with probable Alzheimer disease (AD) dementia (n = 937), mild cognitive impairment (MCI; n = 437), and subjective cognitive decline (SCD; n = 427). Main outcomes were CSF ß-amyloid1-42 (Aß42), total tau (t-Tau), and tau phosphorylated at threonine 181 (p-Tau) levels. Age-corrected 3-way interactions between sex, disease stage (i.e., syndrome diagnosis at baseline), and APOE ε4 were tested with linear regression analyses for each outcome measure. In case of significant interactions (p < 0.05), sex differences were further evaluated by stratifying analyses for clinical disease stage and APOE ε4 genotype, including age as a covariate. RESULTS: Three-way interactions were significant for t-Tau (p < 0.001) and p-Tau (p < 0.01) but not Aß42. In APOE ε4 carriers, women showed higher p-Tau concentrations than men in SCD (Cohen d [95% confidence interval]: t-Tau = 0.52 [0.19-0.84], p < 0.001; p-Tau = 0.44 [0.11-0.77] p = 0.004) and MCI (Cohen d [95% CI]: t-Tau = 0.54 [0.28-0.80], p < 0.001; p-Tau = 0.52 [0.26-0.77], p < 0.001) but not in AD dementia. In APOE ε4 noncarriers, women showed higher p-Tau concentrations in MCI (Cohen d [95% CI]: t-Tau = 0.49 [0.17-0.80], p = 0.002; p-Tau = 0.47 [0.16-0.78], p = 0.003) and AD dementia (Cohen d [95% CI]: t-Tau = 0.42 [0.19-0.65], p < 0.001; p-Tau = 0.38 [0.15-0.61] p = 0.002) but not in SCD. CONCLUSIONS: Within APOE ε4 carriers, sex differences in CSF p-Tau are more evident in early disease stages, whereas for APOE ε4 noncarriers, sex differences are more evident in advanced disease stages. These findings suggest that the effect of APOE ε4 on sex differences in CSF biomarkers depends on disease stage in AD.


Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Progresión de la Enfermedad , Femenino , Genotipo , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Fosforilación , Caracteres Sexuales , Proteínas tau/líquido cefalorraquídeo
17.
J Stroke Cerebrovasc Dis ; 29(9): 105054, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32807460

RESUMEN

BACKGROUND: Phospholipids and sphingolipids are cell membrane components, that participate in signaling events and regulate a wide variety of vital cellular processes. Sphingolipids are involved in ischemic stroke pathophysiology. Throughout cleavage of membrane sphingomyelin by sphingomyelinase in stroke patients, it results in increased Ceramide (Cer) levels in brain tissue. Different studies showed the evidence that sphingomyelinase with Cer production induces expression of interleukin (IL)-6 and have vasoconstrictive proprieties. With this study, we intend to evaluate cerebrospinal fluid (CSF) lipid profile changes in a rabbit closed cranium subarachnoid hemorrhage (SAH) model. METHODS: A total of 14 New Zealand white rabbits were randomly allocated either to SAH or sham group. In the first group SAH was induced by extracranial-intracranial shunting from the subclavian artery into the cisterna magna. Intracranial pressure (ICP) and arterial blood pressure were continuously monitored. Digital subtraction angiography of the basilar artery, CSF and blood samples were performed at day 0 pre SAH and on day 3 post SAH. The amount of IL-6 and various lipids in CSF were quantified using ELISA and Liquid Chromatography-Mass Spectrometry respectively. Cell death was detected in bilateral basal cortex, hippocampus (CA1 and CA3) using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). RESULTS: SAH Induction led to acute increase of ICP and increased delayed cerebral vasospasm (DCVS). At follow up CSF IL-6 levels showed a significant increase compared to baseline. Between baseline and follow up there were no significant differences in any of the measured CSF Lipids irrespective of subgroups. No relevant correlation was found between IL-6 and any of the sphingolipids. We found a correlation between baseline and follow up for the phospholipids phosphatidylethanolamine and phosphatidylcholine. CONCLUSIONS: Neuronal apoptosis, DCVS and IL-6 seems not to be related to changes in CSF lipid profiles except for PEA and PC in a rabbit closed cranium SAH model.


Asunto(s)
Arteria Basilar/fisiopatología , Interleucina-6/líquido cefalorraquídeo , Lípidos/líquido cefalorraquídeo , Neuronas/metabolismo , Hemorragia Subaracnoidea/líquido cefalorraquídeo , Vasoconstricción , Vasoespasmo Intracraneal/líquido cefalorraquídeo , Animales , Apoptosis , Arteria Basilar/diagnóstico por imagen , Biomarcadores/líquido cefalorraquídeo , Modelos Animales de Enfermedad , Interleucina-6/biosíntesis , Presión Intracraneal , Neuronas/patología , Fosfatidilcolinas/líquido cefalorraquídeo , Fosfatidiletanolaminas/líquido cefalorraquídeo , Proyectos Piloto , Conejos , Hemorragia Subaracnoidea/diagnóstico por imagen , Hemorragia Subaracnoidea/patología , Hemorragia Subaracnoidea/fisiopatología , Vasoespasmo Intracraneal/diagnóstico por imagen , Vasoespasmo Intracraneal/patología , Vasoespasmo Intracraneal/fisiopatología
18.
Medicine (Baltimore) ; 99(31): e21458, 2020 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-32756166

RESUMEN

BACKGROUND: Parkinson disease (PD) is a common neurodegenerative disorder. Elevations of neurofilament light chain (NfL) concentrations in the cerebrospinal fluid (CSF) and blood are a marker of neuronal/axonal injury and degeneration. However, CSF and blood NfL alterations in patients with PD from existing studies remain inconclusive. To better understand these conflicting data, we will conduct a meta-analysis. METHODS: We will comprehensively search PubMed, Embase, and Web of Science databases from each database's inception to 7th June, 2020. This protocol will conform to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols. We will only include original studies published in English that evaluated differences of NfL concentrations in the CSF or blood between idiopathic PD patients and healthy controls. The Newcastle-Ottawa Scale will be used to evaluate the quality of the included studies. Meta-analyses will be carried out using the STATA software version 13.0. Between-group difference of NfL concentrations in the CSF and blood will be expressed as the weighted standardized mean difference. A random-effects model will be used. Supplementary analyses, such as heterogeneity analysis, sensitivity analysis, publication bias, subgroup analysis, and meta-regression analysis will be performed. RESULTS: The meta-analysis will provide the differences of NfL concentrations in the CSF and blood between patients with PD and healthy controls and will show the magnitudes of their effect sizes. CONCLUSIONS: This meta-analysis will provide the evidence of NfL concentrations in the CSF and blood in PD and we hope that our study has an important impact on clinical practice. REGISTRATION NUMBER: INPLASY202060025.


Asunto(s)
Proteínas de Neurofilamentos/sangre , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Enfermedad de Parkinson/metabolismo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Femenino , Voluntarios Sanos , Humanos , Masculino , Enfermedad de Parkinson/diagnóstico , Análisis de Regresión , Sensibilidad y Especificidad
19.
Nat Biomed Eng ; 4(8): 787-800, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32747831

RESUMEN

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.


Asunto(s)
Enfermedades Neurodegenerativas/clasificación , Enfermedades Neurodegenerativas/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Encéfalo/metabolismo , Encéfalo/patología , Análisis por Conglomerados , Genotipo , Humanos , Aprendizaje Automático , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Fenotipo , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología
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