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1.
Int J Mol Sci ; 23(8)2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35457051

RESUMO

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.


Assuntos
Doença de Alzheimer , Demência , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Predisposição Genética para Doença , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Neuroimagem
3.
Neuroepidemiology ; 47(1): 32-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27398595

RESUMO

BACKGROUND: To assess the diagnostic agreement of cognitive status (dementia, mild cognitive impairment (MCI), normal cognition) among neurologists in the field of neurological disorders in Central Spain 2 study. METHODS: Full medical histories of 30 individuals were provided to 27 neurologists: 9 seniors, 10 juniors and 8 residents. For each case, we were asked to assign a diagnosis of dementia, MCI or normal cognition using the National Institute on Aging-Alzheimer's Association workgroup (NIA-AA) core clinical criteria for all-cause dementia, Winblad et al. criteria for MCI, and analyze intensity and etiology if dementia was diagnosed. Inter-rater agreement was assessed both with percent concordance and non-weighted κ statistics. RESULTS: Overall inter-rater agreement on cognitive status was κ = 0.76 (95% CI 0.65-0.86), being slightly higher among junior neurologists (κ = 0.85, 95% CI 0.73-0.95) than among seniors (κ = 0.71, 95% CI 0.59-0.83) and residents (κ = 0.69, 95% CI 0.54-0.81) but without statistical significance among groups. Dementia severity showed an overall κ of 0.34, 0.44 and 0.64 for mild, moderate and severe dementia respectively. CONCLUSIONS: Substantial agreement was demonstrated for the diagnosis of cognitive status (dementia, MCI and normal cognition) among neurologists of different levels of experience in a population-based epidemiological study using NIA-AA and Winblad et al. CRITERIA: The agreement rate was lower in the diagnosis of dementia severity.


Assuntos
Disfunção Cognitiva/diagnóstico , Demência/diagnóstico , Variações Dependentes do Observador , Humanos , Neurologistas , Reprodutibilidade dos Testes , Espanha
4.
Artigo em Inglês | MEDLINE | ID: mdl-34009082

RESUMO

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.


Assuntos
Esclerose Lateral Amiotrófica , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Adolescente , Idoso , Demência Frontotemporal/complicações , Demência Frontotemporal/genética , Humanos , Masculino , Transtornos da Personalidade/genética , Proteína Sequestossoma-1/genética
5.
Neurology ; 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380749

RESUMO

OBJECTIVE: Anti-IgLON5 disease is a recently described neurological disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are under-reported. Here we describe the frequency and types of movement disorders in a series of consecutive patients with this disease. METHODS: In this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by three experts in movement disorders. RESULTS: Seventy two patients were included. In 41 (57%) the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least one movement disorder with a median of three per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients, 72%), chorea (24, 33%), bradykinesia (20, 28%), dystonia (19, 26%), abnormal body postures or rigidity (18, 25%), and tremor (15, 21%). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients, 32%) including dystonia (13), myorhythmia (6), chorea (4) or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31(43%) of patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only seven (13%) cases. CONCLUSIONS: Movement disorders are a frequent and leading cause of initial neurological consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment.

6.
J Alzheimers Dis ; 78(4): 1367-1372, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33074239

RESUMO

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.


Assuntos
COVID-19/psicologia , Disfunção Cognitiva/psicologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , COVID-19/epidemiologia , COVID-19/mortalidade , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Comorbidade , Feminino , Mortalidade Hospitalar , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Admissão do Paciente/estatística & dados numéricos , Estudos Retrospectivos , Espanha/epidemiologia , Adulto Jovem
7.
EBioMedicine ; 57: 102834, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32586758

RESUMO

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 0•95 (0•911-0•992) for the differentiation of the prodromal AD/AD group positive for amyloid-PET (PET+) versus healthy group, and 0•97 (0•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 0•93 (0•876-0•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.


Assuntos
Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/genética , Lactoferrina/genética , Glândulas Salivares/metabolismo , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/patologia , Feminino , Humanos , Imunidade Inata/genética , Lactoferrina/metabolismo , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X , Proteínas tau/genética
8.
Sleep Med ; 75: 388-394, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32950884

RESUMO

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.


Assuntos
COVID-19/psicologia , Pessoal de Saúde/psicologia , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Adulto , Estudos de Casos e Controles , Estudos Transversais , Humanos , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2 , Autorrelato , Jornada de Trabalho em Turnos/efeitos adversos , Jornada de Trabalho em Turnos/psicologia , Jornada de Trabalho em Turnos/estatística & dados numéricos , Distúrbios do Início e da Manutenção do Sono/diagnóstico
9.
J Alzheimers Dis ; 72(3): 677-681, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31640101

RESUMO

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.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Angiopatia Amiloide Cerebral/metabolismo , Tomografia por Emissão de Pósitrons , Trombose Venosa/metabolismo , Precursor de Proteína beta-Amiloide/genética , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Tomografia por Emissão de Pósitrons/métodos , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/genética
11.
Mol Neurobiol ; 55(12): 8815-8825, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29603091

RESUMO

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.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/imunologia , Plaquetas/metabolismo , Citoesqueleto/metabolismo , Proteômica/métodos , Idoso , Peptídeos beta-Amiloides/sangue , Estudos de Casos e Controles , Disfunção Cognitiva/sangue , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes
12.
J Neurol ; 264(1): 121-130, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27815682

RESUMO

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.


Assuntos
Amiloide/metabolismo , Afasia Primária Progressiva/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Idoso , Afasia Primária Progressiva/metabolismo , Afasia Primária Progressiva/psicologia , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Rev Neurol ; 56(2): 109-14, 2013 Jan 16.
Artigo em Espanhol | MEDLINE | ID: mdl-23307357

RESUMO

Nikola Tesla (1856-1943) was one of the greatest inventors in history and a key player in the revolution that led to the large-scale use of electricity. He also made important contributions to such diverse fields as x-rays, remote control, radio, the theory of consciousness or electromagnetism. In his honour, the international unit of magnetic induction was named after him. Yet, his fame is scarce in comparison with that of other inventors of the time, such as Edison, with whom he had several heated arguments. He was a rather odd, reserved person who lived for his inventions, the ideas for which came to him in moments of inspiration. In his autobiography he relates these flashes with a number of neuropsychiatric manifestations, which can be seen to include migraine auras, synaesthesiae, obsessions and compulsions.


Assuntos
Eletricidade/história , Criatividade , História do Século XIX , História do Século XX , Transtorno Obsessivo-Compulsivo , Sérvia
15.
Rev Neurol ; 57(12): 542-8, 2013 Dec 16.
Artigo em Espanhol | MEDLINE | ID: mdl-24288103

RESUMO

INTRODUCTION: Alzheimer's disease (AD) is the most frequent degenerative dementia in our setting. In most patients the initial manifestations of the disease consist in a selective and progressive compromise of memory. Yet, it is not a homogeneous process and in some cases the mode of presentation can be atypical. The presentation of AD in the form of an early disorder affecting personality, behaviour and the executive functions has been called the frontal variant of AD. In our case, its definitive diagnosis was only possible by means of a histological analysis, given the fact that the applicable clinical criteria were then insufficient to reach a diagnosis of this atypical form of AD. CASE REPORTS: We report the cases of two patients, one female and one male aged 60 and 52 respectively, who presented a progressive picture of cognitive impairment with initial involvement of the executive functions and personality changes, together with mood disorders. As a result, the initial diagnosis was one of probable frontotemporal dementia. However, in both cases, the autopsy revealed data consistent with a diagnosis of AD, with a distribution of the pathology that essentially affected the frontal lobes. CONCLUSIONS: AD has a heterogeneous form of presentation, which can give rise to errors in its initial diagnosis, since current clinical criteria do not take this clinical variability sufficiently into account. We therefore consider it important to pay attention to the atypical forms of AD with the aim of developing new diagnostic methods that allow AD to be distinguished from other degenerative processes.


TITLE: Variante frontal de la enfermedad de Alzheimer. Dos casos confirmados anatomopatologicamente y revision de la bibliografia.Introduccion. La enfermedad de Alzheimer (EA) es la causa mas frecuente de demencia en nuestro medio. En la mayoria de los pacientes, las manifestaciones iniciales consisten en una afectacion selectiva y progresiva de la memoria. Sin embargo, no se trata de un proceso homogeneo y, en algunos casos, el modo de presentacion puede ser atipico. La presentacion de la EA en forma de alteracion precoz de la personalidad, el comportamiento y las funciones ejecutivas se ha denominado variante frontal de la EA. En nuestro caso, su diagnostico definitivo solo fue posible mediante el estudio histologico, pues los criterios clinicos vigentes resultaron entonces insuficientes para el diagnostico de esta forma atipica de la EA. Casos clinicos. Dos pacientes, una mujer y un hombre de 60 y 52 años respectivamente, presentaron un cuadro progresivo de deterioro cognitivo con afectacion inicial de las funciones ejecutivas y cambio de personalidad, junto con alteraciones del estado de animo, por lo que se realizo el diagnostico inicial de probable demencia frontotemporal. No obstante, en ambos casos, la autopsia revelo datos compatibles con el diagnostico de EA, con una distribucion de la patologia que afectaba fundamentalmente a los lobulos frontales. Conclusiones. La EA tiene una forma heterogenea de presentacion, lo que puede originar errores en su diagnostico inicial, dado que los criterios clinicos actuales no recogen de modo suficiente esta variabilidad clinica. Por ello, consideramos importante prestar atencion a las formas atipicas de la EA con el objeto de desarrollar nuevos metodos diagnosticos que permitan diferenciar la EA del resto de procesos degenerativos.


Assuntos
Doença de Alzheimer/patologia , Lobo Frontal/fisiopatologia , Atividades Cotidianas , Transtornos de Adaptação/diagnóstico , Doença de Alzheimer/classificação , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Ansiedade/etiologia , Afasia/etiologia , Depressão/etiologia , Diagnóstico Diferencial , Progressão da Doença , Função Executiva , Feminino , Lobo Frontal/química , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Demência Frontotemporal/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Neuroimagem , Cintilografia , Avaliação de Sintomas
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