RESUMEN
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.
Asunto(s)
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
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.
Asunto(s)
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
INTRODUCTION: Biomarker-informed criteria were proposed for the diagnosis of Alzheimer's disease (AD) by the National Institute on Aging and the Alzheimer's Association (NIA-AA) in 2011; however, the adequacy of this criteria has not been sufficiently evaluated. METHODS: ReDeMa (Red de Demencias de Madrid) is a regional cohort of patients attending memory and neurology clinics. Core cerebrospinal fluid biomarkers were obtained, NIA-AA diagnostic criteria were considered, and changes in diagnosis and management were evaluated. RESULTS: A total of 233 patients were analyzed (mean age 70 years, 50% women, 73% AD). The diagnostic language was modified significantly, with a majority assumption of NIA-AA definitions (69%). Confidence in diagnosis increased from 70% to 92% (p < 0.0005) and management was changed in 71% of patient/caregivers. The influence of neurologist's age or expertise on study results was minimal. DISCUSSION: The NIA-AA criteria are adequate and utile for usual practice in memory and neurology clinics, improving diagnostic confidence and significantly modifying patient management. HIGHLIGHTS: Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers increase diagnostic certainty regardless of the neurologist.AD CSF biomarkers lead to changes in disease management .Biomarker-enriched, 2011 NIA-AA diagnostic criteria are adequate for usual practice.
RESUMEN
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.
Asunto(s)
Afasia Progresiva Primaria , Fluorodesoxiglucosa F18 , Humanos , Afasia Progresiva Primaria/diagnóstico por imagen , Encéfalo/metabolismo , Tomografía de Emisión de Positrones , AmiloideRESUMEN
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.
Asunto(s)
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
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.
Asunto(s)
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
The original version of this article unfortunately contained some mistakes.
RESUMEN
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.
Asunto(s)
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.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Disfunción Cognitiva/genética , Lactoferrina/genética , Glándulas Salivales/metabolismo , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Disfunción Cognitiva/patología , Femenino , Humanos , Inmunidad Innata/genética , Lactoferrina/metabolismo , Masculino , Persona de Mediana Edad , Neuroimagen/métodos , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada por Rayos X , Proteínas tau/genéticaRESUMEN
Kynurenic acid (KYNA) is a product of the tryptophan (TRP) metabolism via the kynurenine pathway (KP). This pathway is activated in neurodegenerative disorders, such as Alzheimer´s disease (AD). KYNA is primarily produced by astrocytes and is considered neuroprotective. Thus, altered KYNA levels may suggest an inflammatory response. Very recently, significant increases in KYNA levels were reported in cerebrospinal fluid (CSF) from AD patients compared with normal controls. In this study, we assessed the accuracy of KYNA in CSF for the classification of patients with AD, cognitively healthy controls, and patients with a variety of other neurodegenerative diseases, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and progressive supranuclear palsy (PSP). Averaged KYNA concentration in CSF was higher in patients with AD when compared with healthy subjects and with all the other differentially diagnosed groups. There were no significant differences in KYNA levels in CSF between any other neurodegenerative groups and controls. These results suggest a specific increase in KYNA concentration in CSF from AD patients not seen in other neurodegenerative diseases.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Ácido Quinurénico/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/metabolismo , Estudios de Casos y Controles , Femenino , Humanos , Ácido Quinurénico/metabolismo , Masculino , Persona de Mediana Edad , Triptófano/líquido cefalorraquídeo , Triptófano/metabolismoRESUMEN
INTRODUCTION: The development of sleep disorders, and specifically insomnia, has been linked to the exposure to different stressors. In this line, Coronavirus disease 2019 (COVID-19) outbreak caused by the new coronavirus SARS-CoV-2, has caused a huge impact on our environment, and has exposed healthcare workers to an unprecedented threat. In this study, we try to assess sleep quality and the development of sleep disorders in health personnel directly dedicated to the care of COVID-19 patients at the height of the pandemic, compared to the general population. MATERIALS AND METHODS: A cross-sectional, anonymized, self-reported questionnaire survey was carried out at the "12 de Octubre" Hospital, in Madrid, Spain, during the outbreak of COVID-19, from March 1st to April 30th 2020. We compared two groups, healthcare workers who have treated directly COVID-19 patients versus non-healthcare workers. The questionnaire included demographic data, sleep related aspects, Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI) and 17-items Hamilton Rating Scale (HRS). RESULTS: In total 170 participants completed the questionnaire successfully, 100 healthcare workers and 70 non-healthcare workers. Self-reported insomnia, nightmares, sleepwalking, sleep terrors and PSQI>6 were more frequent in the healthcare group (p < 0,05). Shift work was associated to greater risk when performing multiple logistic regression analysis. CONCLUSIONS: We observed that, during the outbreak of COVID-19, healthcare workers on the front line developed more sleep disturbances than non-healthcare professionals, and they had worse quality of sleep. Special attention should be paid to shift workers. Concrete protection and prevention measures for particularly exposed population should be considered in pandemic situations.
Asunto(s)
COVID-19/psicología , Personal de Salud/psicología , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , Adulto , Estudios de Casos y Controles , Estudios Transversales , Humanos , Persona de Mediana Edad , Pandemias , SARS-CoV-2 , Autoinforme , Horario de Trabajo por Turnos/efectos adversos , Horario de Trabajo por Turnos/psicología , Horario de Trabajo por Turnos/estadística & datos numéricos , Trastornos del Inicio y del Mantenimiento del Sueño/diagnósticoRESUMEN
Hereditary cerebral amyloid angiopathies (CAA) are rare disorders of early onset and severe course. We describe a 47-year-old patient with Iowa-type amyloid precursor protein (APP) mutation-related hereditary CAA that manifested with concomitant lobar hemorrhage and venous sinus thrombosis. To analyze the cerebral amyloid-ß burden, an amyloid-PET was performed, demonstrating low cortical retention except for the calcarine cortex. High amyloid retention was also found in the thalamus and pallidum. The co-occurrence of CAA and venous thrombosis has not been previously reported in Iowa CAA and its mechanism is yet to be elucidated. Low cortical florbetapir-PET uptake does not rule out CAA in young patients, who may benefit from genetic testing to reach diagnosis when suspicion is strong.
Asunto(s)
Precursor de Proteína beta-Amiloide/metabolismo , Angiopatía Amiloide Cerebral/metabolismo , Tomografía de Emisión de Positrones , Trombosis de la Vena/metabolismo , Precursor de Proteína beta-Amiloide/genética , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Angiopatía Amiloide Cerebral/genética , Humanos , Masculino , Persona de Mediana Edad , Linaje , Tomografía de Emisión de Positrones/métodos , Trombosis de la Vena/diagnóstico por imagen , Trombosis de la Vena/genéticaRESUMEN
Platelets are considered a good model system to study a number of elements associated with neuronal pathways as they share biochemical similarities. Platelets represent the major source of amyloid-ß (Aß) in blood contributing to the Aß accumulation in the brain parenchyma and vasculature. Peripheral blood platelet alterations including cytoskeletal abnormalities, abnormal cytoplasmic calcium fluxes or increased oxidative stress levels have been related to Alzheimer's disease (AD) pathology. Therefore, platelets can be considered a peripheral model to study metabolic mechanisms occurring in AD. To investigate peripheral molecular alterations, we examined platelet protein expression in a cohort of 164 subjects, including mild cognitive impairment (MCI), and AD patients, and healthy aged-matched controls. A two-dimensional difference gel electrophoresis (2D-DIGE) discovery phase revealed significant differences between patients and controls in five proteins: talin, vinculin, moesin, complement C3b and Rho GDP, which are known to be involved in cytoskeletal regulation including focal adhesions, inflammation and immune functions. Western blot analysis verified that talin was found to be increased in mild and moderate AD groups versus control, while the other three were found to be decreased. We also analysed amyloid precursor protein (APP), amyloid-ß 1-40 (Aß40) and 1-42 (Aß42) levels in platelets from the same groups of subjects. Upregulation of platelet APP and Aß peptides was found in AD patients compared to controls. These findings complement and expand previous reports concerning the morphological and functional alterations in AD platelets, and provide more insights into possible mechanisms that participate in the multifactorial and systemic damage in AD.
Asunto(s)
Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/inmunología , Plaquetas/metabolismo , Citoesqueleto/metabolismo , Proteómica/métodos , Anciano , Péptidos beta-Amiloides/sangre , Estudios de Casos y Controles , Disfunción Cognitiva/sangre , Femenino , Humanos , Masculino , Reproducibilidad de los ResultadosRESUMEN
Primary progressive aphasia (PPA) is considered a heterogeneous syndrome, with different clinical subtypes and neuropathological causes. Novel PET biomarkers may help to predict the underlying neuropathology, but many aspects remain unclear. We studied the relationship between amyloid PET and PPA variant in a clinical series of PPA patients. A systematic review of the literature was performed. Patients with PPA were assessed over a 2-year period and classified based on language testing and the International Consensus Criteria as non-fluent/agrammatic (nfvPPA), semantic (svPPA), logopenic variant (lvPPA) or as unclassifiable (ucPPA). All patients underwent a Florbetapir (18-F) PET scan and images were analysed by two nuclear medicine physicians, using a previously validated reading method. Relevant studies published between January 2004 and January 2016 were identified by searching Medline and Web of Science databases. Twenty-four PPA patients were included (13 women, mean age 68.8, SD 8.3 years; range 54-83). Overall, 13/24 were amyloid positive: 0/2 (0%) nfvPPA, 0/4 (0%) svPPA, 10/14 (71.4%) lvPPA and 3/4 (75%) ucPPA (p = 0.028). The systematic review identified seven relevant studies, six including all PPA variants and one only lvPPA. Pooling all studies together, amyloid PET positivity was 122/224 (54.5%) for PPA, 14/52 (26.9%) for nfvPPA, 6/47 (12.8%) for svPPA, 101/119 for lvPPA (84.9%) and 12/22 (54.5%) for ucPPA. Amyloid PET may help to identify the underlying neuropathology in PPA. It could be especially useful in ucPPA, because in these cases it is more difficult to predict pathology. ucPPA is frequently associated with amyloid pathology.
Asunto(s)
Amiloide/metabolismo , Afasia Progresiva Primaria/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Tomografía de Emisión de Positrones , Anciano , Afasia Progresiva Primaria/metabolismo , Afasia Progresiva Primaria/psicología , Encéfalo/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
REVIEW QUESTION/OBJECTIVE: The objective of this review is to synthesize the best available evidence on the effectiveness of non-pharmacological interventions for the prevention and management of psychological and social morbidity in women who have an elective abortion.The specific review question that will be addressed is: In women (aged 13 years or more) with unwanted pregnancies who decide to have an elective abortion, which non-pharmacological interventions should be provided before, during and after the elective abortion procedure both in community and hospital environments to prevent and manage psychological and social morbidity?
Asunto(s)
Lupus Eritematoso Sistémico/diagnóstico , Mielitis Transversa/diagnóstico , Prurito/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/fisiopatología , Persona de Mediana Edad , Mielitis Transversa/tratamiento farmacológico , Mielitis Transversa/fisiopatología , Prurito/tratamiento farmacológico , Prurito/fisiopatología , Médula Espinal/diagnóstico por imagenAsunto(s)
Isquemia Encefálica/etiología , Embolia Paradójica/complicaciones , Embolia Intracraneal/complicaciones , Embolia Paradójica/diagnóstico , Embolia Paradójica/fisiopatología , Femenino , Foramen Oval Permeable/complicaciones , Foramen Oval Permeable/diagnóstico por imagen , Humanos , Hiperlipidemias/complicaciones , Embolia Intracraneal/fisiopatología , Trombosis del Seno Lateral/complicaciones , Persona de Mediana Edad , Fumar/efectos adversos , Ultrasonografía Doppler Transcraneal , Maniobra de ValsalvaRESUMEN
TITLE: Ptosis fluctuante como presentacion del sindrome de hipotension licuoral espontanea.