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Alzheimer's disease (AD), the most common cause of dementia, is a complex and multifactorial condition without cure at present. The latest treatments, based on anti-amyloid monoclonal antibodies, have only a modest effect in reducing the progression of cognitive decline in AD, whereas the possibility of preventing AD has become a crucial area of research. In fact, recent studies have observed a decrease in dementia incidence in developed regions such as the US and Europe. However, these trends have not been mirrored in non-Western countries (Japan or China), and the contributing factors of this reduction remain unclear. The Lancet Commission has delineated a constrained classification of 12 risk factors across different life stages. Nevertheless, the scientific literature has pointed to over 200 factors-including sociodemographic, medical, psychological, and sociocultural conditions-related to the development of dementia/AD. This narrative review aims to synthesize the risk/protective factors of dementia/AD. Essentially, we found that risk/protective factors vary between individuals and populations, complicating the creation of a unified prevention strategy. Moreover, dementia/AD explanatory mechanisms involve a diverse array of genetic and environmental factors that interact from the early stages of life. In the future, studies across different population-based cohorts are essential to validate risk/protective factors of dementia. This evidence would help develop public health policies to decrease the incidence of dementia.
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OBJECTIVE: To estimate the test-retest and inter-rater reliability of the new Spanish abbreviated version of the Luria Neuropsychological Diagnosis (DNA-2) battery for older adults. METHOD: A total of thirty cognitively healthy volunteers were examined in this study. The participants completed a comprehensive standardized assessment, encompassing cognitive and functional performance. Intraclass correlation coefficients (ICC) were used to examine test-retest and inter-rater reliability. One month was allowed between administrations. Furthermore, correlations between Luria DNA-2 (total and domain subscores) and other classical cognitive measures were explored. RESULTS: The test-retest reliability on the overall Luria DNA-2 score was high (ICC= .834, 95% CI [.680, .917], p < .001). Furthermore, the inter-rater reliability for the total score demonstrated an excellent concordance between administrators (ICC= .990, 95% CI [.979, .995], p < .001). Positive and significant correlations were observed between Luria DNA-2 (both total and domain subscores) and the Addenbrooke's Cognitive Examination (ACE-III; ρ = .857, p < .001). CONCLUSIONS: This study supports the adequate reliability of the Luria DNA-2, as an abbreviated neuropsychological battery, for assessing cognitive performance in Spaniards aged 55 years and older. Future studies should continue to explore the psychometric properties of the Luria DNA-2, particularly those related to its diagnostic validity for early detection of cognitive impairment.
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BACKGROUND AND OBJECTIVES: Older adults experiencing neurocognitive disease (NCD) contend with complex care often characterized by high emotional strain. Mitigating complex care with decision support tools can clarify options. When used in conjunction with the practice of shared decision making (SDM), these tools can improve satisfaction and confidence in treatment. The use of these tools for cognitive health has increased, but more is needed to understand how these tools incorporate social needs into treatment plans. RESEARCH DESIGN AND METHODS: We conducted an environmental scan using a MEDLINE-informed search strategy and feedback from an expert steering committee to characterize current tools and approaches for engaging older adults experiencing NCD. We assessed their application and development, incorporation of social determinants, goals or preferences, and inclusion of caregivers in their design. RESULTS: We identified 11 articles, 7 of which show that SDM helps guide tool development and that most center on clinical decision making. Types of tools varied by clinical site and those differences reflected patient need. A collective value across tools was their use to forge meaningful conversations. Most tools appeared designed without the explicit goal to elicit patient social needs or incorporate nonclinical strategies into treatment plans. DISCUSSION AND IMPLICATIONS: Several challenges and opportunities exist that center on strategies to engage patients in the design and testing of tools that support conversations with clinicians about cognitive health. Future work should focus on building and testing adaptable tools that support patient and family social care needs beyond clinical care settings.
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Disfunción Cognitiva , Trastornos Neurocognitivos , Humanos , Disfunción Cognitiva/psicología , Disfunción Cognitiva/terapia , Anciano , Trastornos Neurocognitivos/psicología , Trastornos Neurocognitivos/diagnóstico , Toma de Decisiones Conjunta , Prioridad del Paciente , Cuidadores/psicología , Técnicas de Apoyo para la DecisiónRESUMEN
OBJECTIVE: To study the correlation between a static PET image of the first-minute-frame (FMF) acquired with 18F-labeled amyloid-binding radiotracers and brain [18F]FDG PET in patients with primary progressive aphasia (PPA). MATERIAL AND METHODS: The study cohort includes 17 patients diagnosed with PPA with the following distribution: 9 nonfluent variant PPA, 4 logopenic variant PPA, 1 semantic variant PPA, 3 unclassifiable PPA. Regional SUVRs are extracted from FMFs and their corresponding [18F]FDG PET images and Pearson's correlation coefficients are calculated. RESULTS: SUVRs of both images show similar patterns of regional cerebral alterations. Intrapatient correlation analyses result in a mean coefficient of r=0.94±0.06. Regional interpatient correlation coefficients of the study cohort are greater than 0.81. Radiotracer-specific and variant-specific subcohorts show no difference in the similarity between the images. CONCLUSIONS: The static FMF could be a valid alternative to dynamic early-phase amyloid PET proposed in the literature, and a neurodegeneration biomarker for the diagnosis and classification of PPA in amyloid PET studies.
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Afasia Progresiva Primaria , Fluorodesoxiglucosa F18 , Humanos , Afasia Progresiva Primaria/diagnóstico por imagen , Encéfalo/metabolismo , Tomografía de Emisión de Positrones , AmiloideRESUMEN
Background: Limited information is available on the active process of seeking medical help in patients with Alzheimer's disease (AD) at early stages. The aim of this study was to assess the phenomenon of medical help-seeking in early AD and to identify associated factors. Methods: A multicenter, non-interventional study was conducted including patients of 50-90 years of age with prodromal or mild AD (National Institute on Aging/Alzheimer's Association criteria), a Mini-Mental State Examination (MMSE) score ≥ 22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5-1.0. A multivariate logistic regression analysis was conducted. Results: A total of 149 patients were included. Mean age (SD) was 72.3 (7.0) years, 50.3% were female, and 87.2% had a CDR-GS score of 0.5. Mean disease duration was 1.4 (1.8) years. Ninety-four (63.1%) patients sought medical help, mostly from neurologists. Patients with help-seeking intentions were mostly female (60.6%) with a CDR-GS score of 0.5 (91.5%) and had a greater awareness of diagnosis, poorer quality of life, more depressive symptoms, and a more severe perception of their condition than their counterparts. Lack of help-seeking intentions was associated with male sex (p = 0.003), fewer years of education (p = 0.005), a low awareness of diagnosis (p = 0.005), and a low emotional consequence of the condition (p = 0.016). Conclusion: Understanding the phenomenon of active medical help-seeking may facilitate the design of specific strategies to improve the detection of cognitive impairment, especially in patients with a lower level of educational attainment and poor awareness of their condition.
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BACKGROUND: There is a need to better understand the experience of patients living with Alzheimer's disease (AD) in the early stages. OBJECTIVE: The aim of the study was to evaluate the perception of quality of life in patients with early-stage AD. METHODS: A multicenter, non-interventional study was conducted including patients of 50-90 years of age with prodromal or mild AD, a Mini-Mental State Examination (MMSE) score ≥22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5.-1.0. The Quality of Life in Alzheimer 's Disease (QoL-AD) questionnaire was used to assess health-related quality of life. A battery of self-report instruments was used to evaluate different psychological and behavioral domains. Associations between the QoL-AD and other outcome measures were analyzed using Spearman's rank correlations. RESULTS: A total of 149 patients were included. Mean age (SD) was 72.3 (7.0) years and mean disease duration was 1.4 (1.8) years. Mean MMSE score was 24.6 (2.1). The mean QoL-AD score was 37.9 (4.5). Eighty-three percent (n = 124) of patients had moderate-to-severe hopelessness, 22.1% (n = 33) had depressive symptoms, and 36.9% (n = 55) felt stigmatized. The quality of life showed a significant positive correlation with self-efficacy and negative correlations with depression, emotional and practical consequences, stigma, and hopelessness. CONCLUSION: Stigma, depressive symptoms, and hopelessness are frequent scenarios in AD negatively impacting quality of life, even in a population with short disease duration and minimal cognitive impairment.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/psicología , Calidad de Vida/psicología , Encuestas y Cuestionarios , AutoinformeRESUMEN
INTRODUCTION: Limited information is available on people's experiences of living with Alzheimer's disease (AD) at earlier stages. This study assessed awareness of diagnosis among people with early-stage AD and its impact on different person-centered outcome measures. METHODS: We conducted an observational, cross-sectional study in 21 memory clinics in Spain. Persons aged 50-90 years, diagnosed with prodromal or mild AD (NIA/AA criteria), a Mini Mental State Examination (MMSE) score ≥ 22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5 or 1.0 were recruited. The Representations and Adjustment to Dementia Index (RADIX) was used to assess participants' beliefs about their condition and its consequences. RESULTS: A total of 149 persons with early-stage AD were studied. Mean (SD) age was 72.3 (7.0) years and 50.3% were female. Mean duration of AD was 1.4 (1.8) years. Mean MMSE score was 24.6 (2.1) and 87.2% had a CDR-GS score of 0.5. Most participants (n = 84, 57.5%) used a descriptive term related to specific AD symptoms (e.g., memory difficulties) when asked what they called their condition. Participants aware of their diagnosis using the term AD (n = 66, 45.2%) were younger, had more depressive symptoms, and poorer life satisfaction and quality of life compared to those without awareness of their specific diagnosis. Practical and emotional consequences RADIX scores showed a significant negative correlation with Quality of Life in Alzheimer's Disease score (rho = - 0.389 and - 0.413, respectively; p < 0.0001). Years of education was the only predictor of awareness of AD diagnosis [OR = 1.04 (95% CI 1.00-1.08); p = 0.029]. CONCLUSIONS: Awareness of diagnosis was a common phenomenon in persons with early-stage AD negatively impacting their quality of life. Understanding illness representations in earlier stages may facilitate implementing optimized care that supports improved quality of life and well-being.
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Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an autosomal recessive vascular disorder caused by biallellic variants in HTRA1. Recently, it has been reported that several heterozygous mutations in HTRA1 are responsible for a milder late-onset cerebral small vessel disease (CSVD) with an autosomal dominant pattern of inheritance. The majority of them are missense that affects the Htr1A protease activity due to a dominant-negative effect caused by defective trimerization or monomer activation. The molecular mechanism related to the structural destabilization of the protein supports the practical utility of integrating computational stability predictors to prioritize candidate variants in this gene. In this work, we report a family with several members diagnosed with subcortical ischemic events and progressive cognitive impairment caused by the novel c.820C > G, p.(Arg274Gly) heterozygous variant in HTRA1 segregating in an autosomal dominant manner and propose its molecular mechanism by a three-dimensional model of the protein's structure.
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Enfermedades de los Pequeños Vasos Cerebrales , Trastornos Cerebrovasculares , Leucoencefalopatías , Enfermedades de los Pequeños Vasos Cerebrales/genética , Serina Peptidasa A1 que Requiere Temperaturas Altas/genética , Serina Peptidasa A1 que Requiere Temperaturas Altas/metabolismo , Humanos , Leucoencefalopatías/genética , Mutación , Estabilidad Proteica , Serina Endopeptidasas/genéticaRESUMEN
In the last few years, the SORL1 gene has been strongly implicated in the development of Alzheimer's disease (AD). We performed whole-exome sequencing on 37 patients with early-onset dementia or family history suggestive of autosomal dominant dementia. Data analysis was based on a custom panel that included 46 genes related to AD and dementia. SORL1 variants were present in a high proportion of patients with candidate variants (15%, 3/20). We expand the clinical manifestations associated with the SORL1 gene by reporting detailed clinical and neuroimaging findings of six unrelated patients with AD and SORL1 mutations. We also present for the first time a patient with the homozygous truncating variant c.364C>T (p.R122*) in SORL1, who also had severe cerebral amyloid angiopathy. Furthermore, we report neuropathological findings and immunochemistry assays from one patient with the splicing variant c.4519+5G>A in the SORL1 gene, in which AD was confirmed by neuropathological examination. Our results highlight the heterogeneity of clinical presentation and familial dementia background of SORL1-associated AD and suggest that SORL1 might be contributing to AD development as a risk factor gene rather than as a major autosomal dominant gene.
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Enfermedad de Alzheimer , Demencia , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Predisposición Genética a la Enfermedad , Humanos , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas de Transporte de Membrana/genética , NeuroimagenRESUMEN
Neurodegenerative parkinsonisms affect mainly cognitive and motor functions and are syndromes of overlapping symptoms and clinical manifestations such as tremor, rigidness, and bradykinesia. These include idiopathic Parkinson's disease (PD) and the atypical parkinsonisms, namely progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA) and dementia with Lewy body (DLB). Differences in the striatal metabolism among these syndromes are evaluated using [18F]FDG PET, caused by alterations to the dopaminergic activity and neuronal loss. A study cohort of three patients with PD, 29 with atypical parkinsonism (10 PSP, 6 CBD, 2 MSA, 7 DLB, and 4 non-classifiable), and a control group of 25 patients with normal striatal metabolism is available. Standardized uptake value ratios (SUVR) are extracted from the striatum, and the caudate and the putamen separately. SUVRs are compared among the study groups. In addition, hemispherical and caudate-putamen differences are evaluated in atypical parkinsonisms. Striatal hypermetabolism is detected in patients with PD, while atypical parkinsonisms show hypometabolism, compared to the control group. Hemispherical differences are observed in CBD, MSA and DLB, with the latter also showing statistically significant caudate-putamen asymmetry (p = 0.018). These results indicate disease-specific metabolic uptake patterns in the striatum that can support the differential diagnosis.
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BACKGROUND AND OBJECTIVES: The goal of this work was to investigate the natural history and outcomes after treatment for spontaneous amyloid-related imaging abnormalities (ARIA)-like in cerebral amyloid angiopathy-related inflammation (CAA-ri). METHODS: This was a multicenter, hospital-based, longitudinal, prospective observational study of inpatients meeting CAA-ri diagnostic criteria recruited through the Inflammatory Cerebral Amyloid Angiopathy and Alzheimer's Disease ßiomarkers International Network from January 2013 to March 2017. A protocol for systematic data collection at first-ever presentation and at subsequent in-person visits, including T1-weighted, gradient recalled echo-T2*, fluid-suppressed T2-weighted (fluid-attenuated inversion recovery), and T1 postgadolinium contrast-enhanced images acquired on 1.5T MRI, was used at the 3-, 6-, 12-, and 24-month follow-up. Centralized reads of MRIs were performed by investigators blinded to clinical, therapeutic, and time-point information. Main outcomes were survival, clinical and radiologic recovery, intracerebral hemorrhage (ICH), and recurrence of CAA-ri. RESULTS: The study enrolled 113 participants (10.6% definite, 71.7% probable, and 17.7% possible CAA-ri). Their mean age was 72.9 years; 43.4% were female; 37.1% were APOEε4 carriers; 36.3% had a history of Alzheimer disease; and 33.6% had a history of ICH. A history of ICH and the occurrence of new ICH at follow-up were more common in patients with cortical superficial siderosis at baseline (52.6% vs 14.3%, p < 0.0001 and 19.3% vs 3.6%, p < 0.009, respectively). After the first-ever presentation of CAA-ri, 70.3% (95% confidence interval [CI] 61.6%-78.5%) and 84.1% (95% CI 76.2%-90.6%) clinically recovered within 3 and 12 months, followed by radiologic recovery in 45.1% (95% CI 36.4%-54.8%) and 77.4% (95% CI 67.7%-85.9%), respectively. After clinicoradiologic resolution of the first-ever episode, 38.3% (95% CI 22.9%-59.2%) had at least 1 recurrence within the following 24 months. Recurrence was more likely if IV high-dose corticosteroid pulse therapy was suddenly stopped compared to slow oral tapering off (hazard ratio 4.68, 95% CI 1.57-13.93; p = 0.006). DISCUSSION: These results from the largest longitudinal cohort registry of patients with CAA-ri support the transient and potentially relapsing inflammatory nature of the clinical-radiologic acute manifestations of the disease and the effectiveness of slow oral tapering off after IV corticosteroid pulse therapy in preventing recurrences. Our results highlight the importance of differential diagnosis for spontaneous ARIA-like events in ß-amyloid-driven diseases, including treatment-related ARIA in patients with Alzheimer disease exposed to immunotherapy drugs.
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Angiopatía Amiloide Cerebral , Anciano , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Hemorragia Cerebral , Estudios de Cohortes , Femenino , Humanos , Inflamación , Estudios Longitudinales , Imagen por Resonancia Magnética , Estudios ProspectivosRESUMEN
Neuroinflammation is a common feature in Alzheimer's (AD) and Parkinson's (PD) disease. In the last few decades, a testable hypothesis was proposed that protein-unfolding events might occur due to neuroinflammatory cascades involving alterations in the crosstalk between glial cells and neurons. Here, we tried to clarify the pattern of two of the most promising biomarkers of neuroinflammation in cerebrospinal fluid (CSF) in AD and PD. This study included cognitively unimpaired elderly patients, patients with mild cognitive impairment, patients with AD dementia, and patients with PD. CSF samples were analyzed for YKL-40 and C-reactive protein (CRP). We found that CSF YKL-40 levels were significantly increased only in dementia stages of AD. Additionally, increased YKL-40 levels were found in the cerebral orbitofrontal cortex from AD patients in agreement with augmented astrogliosis. Our study confirms that these biomarkers of neuroinflammation are differently detected in CSF from AD and PD patients.
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The haploinsufficiency of the methyl-binding domain protein 5 (MBD5) gene has been identified as the determinant cause of the neuropsychiatric disorders grouped under the name MBD5-neurodevelopment disorders (MAND). MAND includes patients with intellectual disability, behavioral problems, and seizures with a static clinical course. However, a few reports have suggested regression. We describe a non-intellectually disabled female, with previous epilepsy and personality disorder, who developed early-onset dementia. The extensive etiologic study revealed a heterozygous nonsense de novo pathogenic variant in the MBD5 gene. This finding could support including the MBD5 gene in the study of patients with atypical early-onset dementia.
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Codón sin Sentido , Proteínas de Unión al ADN/genética , Demencia , Mutación/genética , Demencia/etiología , Demencia/genética , Epilepsia/complicaciones , Femenino , Heterocigoto , Humanos , Persona de Mediana Edad , Pruebas Neuropsicológicas/estadística & datos numéricos , Trastornos de la Personalidad/complicaciones , Fenotipo , Tomografía Computarizada por Tomografía de Emisión de Positrones , Problema de Conducta/psicologíaRESUMEN
Dynamic early-phase PET images acquired with radiotracers binding to fibrillar amyloid-beta (Aß) have shown to correlate with [18F]fluorodeoxyglucose (FDG) PET images and provide perfusion-like information. Perfusion information of static PET scans acquired during the first minute after radiotracer injection (FMF, first-minute-frame) is compared to [18F]FDG PET images. FMFs of 60 patients acquired with [18F]florbetapir (FBP), [18F]flutemetamol (FMM), and [18F]florbetaben (FBB) are compared to [18F]FDG PET images. Regional standardized uptake value ratios (SUVR) are directly compared and intrapatient Pearson's correlation coefficients are calculated to evaluate the correlation of FMFs to their corresponding [18F]FDG PET images. Additionally, regional interpatient correlations are calculated. The intensity profiles of mean SUVRs among the study cohort (r = 0.98, p < 0.001) and intrapatient analyses show strong correlations between FMFs and [18F]FDG PET images (r = 0.93 ± 0.05). Regional VOI-based analyses also result in high correlation coefficients. The FMF shows similar information to the cerebral metabolic patterns obtained by [18F]FDG PET imaging. Therefore, it could be an alternative to the dynamic imaging of early phase amyloid PET and be used as an additional neurodegeneration biomarker in amyloid PET studies in routine clinical practice while being acquired at the same time as amyloid PET images.
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Enfermedad de Alzheimer , Fluorodesoxiglucosa F18 , Enfermedad de Alzheimer/diagnóstico por imagen , Amiloide/metabolismo , Péptidos beta-Amiloides , Compuestos de Anilina , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Humanos , Tomografía de Emisión de PositronesRESUMEN
To investigate whether physical activity (PA) is a protective factor for the incidence of Parkinson's disease (PD) and parkinsonism after three years of follow-up. All participants of this study were obtained from the Neurological Disorders in Central Spain (NEDICES), a prospective population-based cohort survey of older subjects (≥65 years) that comprised 5278 census-based participants at baseline (1994-1995). A modified version of Rosow-Breslau questionnaire was applied to categorize PA into active versus sedentary group. The final diagnosis of PD and parkinsonism was made by an expert neurologist. Cox regression models (CRM) adjusted for several covariates (sex, age, education, alcohol consumption, tobacco, stroke, hypertension and body mass index) were used to calculate the association between PA (active group vs. sedentary) and risk of PD and parkinsonism after three years. 22 incident PD and 25 incident parkinsonism cases were identified among 2943 participants with available PA information (57.1% female; mean age = 73.28 ± 6.24 years) after three years of follow-up. The CRM showed that the active group (vs. sedentary) showed a lower risk of parkinsonism (Hazard ratio (HR) = 0.18; 95% CI [0.07-0.51]; p = 0.0001). However, this effect was restricted to men (HR = 0.34; 95% CI [0.11-0.99], p < 0.05) for incident PD. PA may be a protective factor for incident parkinsonism, whereas this effect was only significant for men in the case of PD. The mechanisms implicated for brain maintenance in active individuals and the neurophysiological differences behind the role of sex on PD are discussed.
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Objective:SQSTM1-variants associated with frontotemporal lobar degeneration have been described recently. In this study, we investigated a heterozygous in-frame duplication c.436_462dup p. (Pro146_Cys154dup) in the SQSTM1 gene in a family with a new phenotype characterized by a personality disorder and behavioral variant frontotemporal dementia (bvFTD). We review the literature on frontotemporal dementia (FTD) associated with SQSTM1. Methods: The index case and relatives were described, and a genetic study through Whole Exome Sequencing was performed. The literature was reviewed using Medline and Web of Science. Case reports, case series, and cohort studies were included if they provided information on SQSTM1 mutations associated with FTD. Results: Our patient is a 70-year-old man with a personality disorder since youth, familial history of dementia, and personality disorders with a 10-year history of cognitive decline and behavioral disturbances. A diagnosis of probable bvFTD was established, and the in-frame duplication c.436_462dup in the SQSTM1 gene was identified. Segregation analysis in the family confirmed that both affected sons with personality disorder were heterozygous carriers, but not his healthy 65-year-old brother. A total of 14 publications about 57 patients with SQSTM1-related FTD were reviewed, in which the bvFTD subtype was the main phenotype described (66.6%), with a predominance in men (63%) and positive family history in 61.4% of the cases. Conclusions: We describe a heterozygous in-frame duplication c.436_462dup p.(Pro146_Cys154dup) in the SQSTM1 gene, which affects the zinc-finger domain of p62, in a family with a personality disorder and bvFTD, expanding the genetics and clinical phenotype related to SQSTM1.
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Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Adolescente , Anciano , Demencia Frontotemporal/complicaciones , Demencia Frontotemporal/genética , Humanos , Masculino , Trastornos de la Personalidad/genética , Proteína Sequestosoma-1/genéticaRESUMEN
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused predominantly by pathogenic variants in NOTCH3 gene. Neither germline nor somatic mosaicism has been previously published in NOTCH3 gene. CADASIL is inherited in an autosomal dominant manner; only rare cases have been associated with de novo pathogenic variants. Mosaicism is more common than previously thought because mosaic variants often stay unrevealed. An apparently de novo variant might actually be a consequence of a parental mosaicism undetectable with Sanger sequencing, especially in the case of low grade mosaicism. Parental testing by sensitive tools like deep targeted next-generation sequencing (NGS) analysis could detect cases of unrevealed medium or low level mosaicism in patients tested by Sanger sequencing. Here, we report the first patient with mosaic NOTCH3 gene pathogenic variant to our knowledge; the allelic fraction in the leucocyte DNA was low (13%); the pathogenic variant was inhered by his two daughters. The patient was diagnosed by deep targeted NGS analysis after studying his two affected daughters. This report highlights the importance of parental testing by sensitive tools like deep targeted NGS analysis. Detection of mosaicism is of great importance for diagnosis and adequate family genetic counseling.
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CADASIL/genética , Predisposición Genética a la Enfermedad , Mosaicismo , Receptor Notch3/genética , Adulto , CADASIL/diagnóstico , CADASIL/patología , Femenino , Asesoramiento Genético , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación/genéticaRESUMEN
PURPOSE OF REVIEW: To provide an updated analysis of the possible use of non-steroidal anti-inflammatory drugs (NSAIDs) as treatments for Alzheimer´s disease (AD). RECENT FINDINGS: Neuroinflammation in AD is an active field of research, with increasing evidence from basic and clinical studies for an involvement of innate or adaptive immune responses in the pathophysiology of AD. Few clinical trials with anti-inflammatory drugs have been performed in the last decade, with negative results. SUMMARY: Besides the information gathered from basic research, epidemiological studies have provided conflicting findings, with most case-control or prevalence studies suggesting an inverse relationship between NSAIDs use and AD, but divided results in prospective population-based incident cohort studies. Clinical trials with different NSAIDs are almost unanimous in reporting an absence of clear benefit in AD. CONCLUSION: The modulation of inflammatory responses is a promising therapeutic strategy in AD. After three decades of research, it seems that conventional NSAIDs are not the best pharmacological option, both for their lack of clear effects and for an unfavorable side-effect profile in long-term treatment. The development of other anti-inflammatory drugs as candidate treatments in AD may benefit from the knowledge acquired with NSAIDs.
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Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/prevención & control , Antiinflamatorios no Esteroideos/farmacología , Inflamación/tratamiento farmacológico , Enfermedad de Alzheimer/inmunología , Encéfalo/efectos de los fármacos , Ensayos Clínicos como Asunto , HumanosRESUMEN
We analyzed the frequency of cognitive impairment (CI) in deceased COVID-19 patients at a tertiary hospital in Spain. Among the 477 adult cases who died after admission from March 1 to March 31, 2020, 281 had confirmed COVID-19. CI (21.1% dementia and 8.9% mild cognitive impairment) was a common comorbidity. Subjects with CI were older, tended to live in nursing homes, had shorter time from symptom onset to death, and were rarely admitted to the ICU, receiving palliative care more often. CI is a frequent comorbidity in deceased COVID-19 subjects and is associated with differences in care.
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COVID-19/psicología , Disfunción Cognitiva/psicología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , COVID-19/epidemiología , COVID-19/mortalidad , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Comorbilidad , Femenino , Mortalidad Hospitalaria , Hospitales , Humanos , Masculino , Persona de Mediana Edad , Cuidados Paliativos , Admisión del Paciente/estadística & datos numéricos , Estudios Retrospectivos , España/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Evidences of infectious pathogens in Alzheimer's disease (AD) brains may suggest a deteriorated innate immune system in AD pathophysiology. We previously demonstrated reduced salivary lactoferrin (Lf) levels, one of the major antimicrobial proteins, in AD patients. METHODS: To assess the clinical utility of salivary Lf for AD diagnosis, we examine the relationship between salivary Lf and cerebral amyloid-ß (Aß) load using amyloid-Positron-Emission Tomography (PET) neuroimaging, in two different cross-sectional cohorts including patients with different neurodegenerative disorders. FINDINGS: The diagnostic performance of salivary Lf in the cohort 1 had an area under the curve [AUC] of 0â¢95 (0â¢911-0â¢992) for the differentiation of the prodromal AD/AD group positive for amyloid-PET (PET+) versus healthy group, and 0â¢97 (0â¢924-1) versus the frontotemporal dementia (FTD) group. In the cohort 2, salivary Lf had also an excellent diagnostic performance in the health control group versus prodromal AD comparison: AUC 0â¢93 (0â¢876-0â¢989). Salivary Lf detected prodromal AD and AD dementia distinguishing them from FTD with over 87% sensitivity and 91% specificity. INTERPRETATION: Salivary Lf seems to have a very good diagnostic performance to detect AD. Our findings support the possible utility of salivary Lf as a new non-invasive and cost-effective AD biomarker. FUNDING: Instituto de Salud Carlos III (FIS15/00780, FIS18/00118), FEDER, Comunidad de Madrid (S2017/BMD-3700; NEUROMETAB-CM), and CIBERNED (PI2016/01) to E.C.; Spanish Ministry of Economy and Competitiveness (SAF2017-85310-R) to J.L.C., and (PSI2017-85311-P) to M.A.; International Centre on ageing CENIE-POCTEP (0348_CIE_6_E) to M.A.; Instituto de Salud Carlos III (PIE16/00021, PI17/01799), to H.B.