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Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aß42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
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Doença de Alzheimer , Cadeias HLA-DRB1 , Doença de Parkinson , Humanos , Doença de Alzheimer/genética , Antígenos de Histocompatibilidade , Antígenos HLA , Cadeias HLA-DRB1/genética , Doença de Parkinson/genéticaRESUMO
Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer's disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10-20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Masculino , Feminino , Doença de Alzheimer/genética , Cromossomos Humanos Y/genética , Estudo de Associação Genômica Ampla , Mosaicismo , Fatores de Risco , Disfunção Cognitiva/genética , Proteínas tau/genética , Biomarcadores , Peptídeos beta-Amiloides/genéticaRESUMO
The role of immunosuppression among coronavirus disease 2019 (COVID-19) patients has not been elucidated and management may be challenging. This observational study included confirmed COVID-19 patients. The primary endpoint was the development of moderate-severe acute respiratory distress syndrome (ARDS). Time to moderate-severe ARDS, the need for mechanical or noninvasive ventilation (MV/NIV), death, and a composite of death or MV/NIV were secondary endpoints. Of 138 patients included, 27 (19.6%) were immunosuppressed (IS) and 95 (68.8%) were male, with a median (IQR) age of 68 (54-78) years. A significantly lower proportion of IS patients (25.9%) compared to non-IS patients (52.3%) developed moderate-severe ARDS, in both unadjusted (0.32; 95% CI, 0.13-0.83; p = .017) and adjusted (aOR, 0.25; 95% CI, 0.08-0.80; p = .019) analyses. After stratifying by pathologies, only IS patients with autoimmune diseases remained significant (aOR 0.25; 95% CI, 0.07-0.98; p = .046). Nonsignificant trends toward a longer time to moderate or severe ARDS, a lower need for MV/NIV, and a lower risk of death or MV/NIV were detected among IS. In our cohort of COVID-19 patients, nonsevere immunosuppression was associated with a lower risk of moderate-severe ARDS, especially among AD. This suggests a potential protective effect from a hypothesized hyper-inflammatory response.
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COVID-19/imunologia , Síndrome do Desconforto Respiratório/imunologia , Idoso , Idoso de 80 Anos ou mais , COVID-19/epidemiologia , COVID-19/virologia , Estudos de Coortes , Coinfecção , Feminino , Hospitalização , Humanos , Terapia de Imunossupressão , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Síndrome do Desconforto Respiratório/epidemiologia , Síndrome do Desconforto Respiratório/virologia , Estudos Retrospectivos , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Espanha/epidemiologiaRESUMO
INTRODUCTION: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. METHODS: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. RESULTS: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. DISCUSSION: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.
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Doença de Alzheimer/genética , Endofenótipos , Loci Gênicos , Estudo de Associação Genômica Ampla , Idoso , Doença de Alzheimer/classificação , Demência/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , EspanhaRESUMO
Synaptic dysfunction is a core deficit in Alzheimer's disease, preceding hallmark pathological abnormalities. Resting-state magnetoencephalography (MEG) was used to assess whether functional connectivity patterns, as an index of synaptic dysfunction, are associated with CSF biomarkers [i.e., phospho-tau (p-tau) and amyloid beta (Aß42) levels]. We studied 12 human subjects diagnosed with mild cognitive impairment due to Alzheimer's disease, comparing those with normal and abnormal CSF levels of the biomarkers. We also evaluated the association between aberrant functional connections and structural connectivity abnormalities, measured with diffusion tensor imaging, as well as the convergent impact of cognitive deficits and CSF variables on network disorganization. One-third of the patients converted to Alzheimer's disease during a follow-up period of 2.5 years. Patients with abnomal CSF p-tau and Aß42 levels exhibited both reduced and increased functional connectivity affecting limbic structures such as the anterior/posterior cingulate cortex, orbitofrontal cortex, and medial temporal areas in different frequency bands. A reduction in posterior cingulate functional connectivity mediated by p-tau was associated with impaired axonal integrity of the hippocampal cingulum. We noted that several connectivity abnormalities were predicted by CSF biomarkers and cognitive scores. These preliminary results indicate that CSF markers of amyloid deposition and neuronal injury in early Alzheimer's disease associate with a dual pattern of cortical network disruption, affecting key regions of the default mode network and the temporal cortex. MEG is useful to detect early synaptic dysfunction associated with Alzheimer's disease brain pathology in terms of functional network organization. SIGNIFICANCE STATEMENT: In this preliminary study, we used magnetoencephalography and an integrative approach to explore the impact of CSF biomarkers, neuropsychological scores, and white matter structural abnormalities on neural function in mild cognitive impairment. Disruption in functional connectivity between several pairs of cortical regions associated with abnormal levels of biomarkers, cognitive deficits, or with impaired axonal integrity of hippocampal tracts. Amyloid deposition and tau protein-related neuronal injury in early Alzheimer's disease are associated with synaptic dysfunction and a dual pattern of cortical network disorganization (i.e., desynchronization and hypersynchronization) that affects key regions of the default mode network and temporal areas.
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Peptídeos beta-Amiloides/líquido cefalorraquidiano , Encéfalo/patologia , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/patologia , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Mapeamento Encefálico , Imagem de Tensor de Difusão , Feminino , Humanos , Magnetocardiografia , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
BACKGROUND: Physician burnout has a negative impact on both physicians and patients. Limited information is available on professional burnout of neurologists. The aim of this study was to assess the presence of burnout among neurologists caring for patients with cognitive disorders and to identify associated factors. METHODS: An online, cross-sectional study was conducted in collaboration with the Spanish Society of Neurology. Neurologists involved in the care of patients with cognitive disorders answered a survey composed of demographic characteristics, professional background, clinical practice setting, and behavioral factors. Burnout was assessed using a single-item measure from the Physician Work Life Study. A multivariate logistic regression analysis was conducted to determine the association between neurologists' characteristics and burnout. RESULTS: A total of 188 neurologists answered the survey. The mean age (standard deviation-SD) was 40.6 (11.3) years and 52.7% were male. The majority of participants were general neurologists (60.6%) who attending a median of 20 patients with cognitive disorders (interquartile range 10.0-30.0) weekly. Thirty-nine participants (20.7%) reported burnout. Participants with burnout had greater experiences of regret associated with past clinical decisions than their counterparts (mean Regret Intensity Scale scores of 2.3 and 1.9, respectively; p = 0.003). Burnout was associated with non-academic practice (OR = 3.02 [95% CI 1.18, 7.73], p = 0.021) and care-related regret (OR = 2.53 [95% CI 1.13, 5.64], p = 0.023) in the multivariate analysis after adjustment for confounders. CONCLUSIONS: Professional burnout was a common phenomenon among neurologists managing cognitive disorders. Identifying physician burnout and its associated factors may be critical for implementing preventive intervention strategies.
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Esgotamento Profissional , Disfunção Cognitiva , Humanos , Masculino , Adulto , Feminino , Neurologistas/psicologia , Esgotamento Profissional/epidemiologia , Esgotamento Profissional/psicologia , Espanha/epidemiologia , Estudos Transversais , Satisfação no Emprego , Inquéritos e Questionários , Assistência ao PacienteRESUMO
BACKGROUND: Alzheimer's disease (AD) biomarkers reflect key elements of pathophysiology and improve the diagnostic process. However, their use in routine clinical practice is still limited. OBJECTIVE: We aimed to assess neurologists' barriers and enablers to early AD diagnosis using core AD biomarkers. METHODS: We conducted an online study in collaboration with the Spanish Society of Neurology. Neurologists answered a survey exploring their attitudes towards AD diagnosis using biomarkers in mild cognitive impairment (MCI) or mild AD dementia. Multivariate logistic regression analyses were conducted to determine the association between neurologists' characteristics and diagnostic attitudes. RESULTS: We included 188 neurologists with a mean age (SD) of 40.6 (11.3) years, 52.7% male. Most participants had access to AD biomarkers, mainly in cerebrospinal fluid (CSF) (89.9%,#x0025;, nâ=â169). The majority of participants (95.2%,#x0025;, nâ=â179) considered CSF biomarkers useful for an etiological diagnosis in MCI. However, 85.6% of respondents (nâ=â161) used them in less than 60% of their MCI patients in routine clinical practice. Facilitating patients and their families to plan for the future was the most frequent enabler for the use of biomarkers. Short consultation time and practicalities associated with the programming of a lumbar puncture were the most common barriers. A younger neurologist age (pâ=â0.010) and a higher number of patients managed weekly (pâ=â0.036) were positively associated with the use of biomarkers. CONCLUSION: Most neurologists had a favorable attitude to the use of biomarkers, especially in MCI patients. Improvements in resources and consultation time may increase their use in routine clinical practice.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Masculino , Feminino , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Neurologistas , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Atitude , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Progressão da Doença , Fragmentos de Peptídeos/líquido cefalorraquidianoRESUMO
BACKGROUND: There are few updated studies on the prevalence and management of Alzheimer's disease (AD), which could be underdiagnosed or undertreated. The COVID-19 pandemic may have worsened the deficiencies in the diagnosis and treatment of these patients. Electronic medical records (EMR) offer an opportunity to assess the impact and management of medical processes and contingencies in the population. OBJECTIVE: To estimate AD prevalence in Spain over a 6-year period, based on treated patients, according to usual clinical practice. Additionally, to describe the management of AD-treated patients and the evolution of that treatment during the 2020 COVID-19 pandemic. METHODS: Retrospective study using the Spanish IQVIA EMR database. Patients treated with donepezil, galantamine, rivastigmine, and/or memantine were included in the study. Annual AD prevalence (2015-2020) was estimated and extrapolated to the national population level. Most frequent treatments and involved specialties were described. To assess the effect of COVID-19, the incidence of new AD cases in 2020 was calculated and compared with newly diagnosed cases in 2019. RESULTS: Crude AD prevalence (2015-2020) was estimated at 760.5 per 100,000 inhabitants, and age-standardized prevalence (2020) was 664.6 (male 595.7, female 711.0). Monotherapy was the most frequent way to treat AD (86.2%), in comparison with dual therapy (13.8%); rivastigmine was the most prescribed treatment (37.3%), followed by memantine (36.4%) and donepezil (33.0%). Rivastigmine was also the most utilized medication in newly treated patients (46.7%), followed by donepezil (29.8%), although donepezil persistence was longer (22.5 vs. 20.6 months). Overall, donepezil 10 mg, rivastigmine 9.5 mg, and memantine 20 mg were the most prescribed presentations. The incidence rate of AD decreased from 148.1/100,000 (95% confidence interval [CI] 147.0-149.2) in 2019 to 118.4/100,000 (95% CI 117.5-119.4) in 2020. CONCLUSIONS: The obtained prevalence of AD-treated patients was consistent with previous face-to-face studies. In contrast with previous studies, rivastigmine, rather than donepezil, was the most frequent treatment. A decrease in the incidence of AD-treated patients was observed during 2020 in comparison with 2019, presumably due to the significant impact of the COVID-19 pandemic on both diagnosis and treatment. EMR databases emerge as valuable tools to monitor in real time the incidence and management of medical conditions in the population, as well as to assess the health impact of global contingencies and interventions.
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Doença de Alzheimer , COVID-19 , Humanos , Masculino , Feminino , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/epidemiologia , Donepezila/uso terapêutico , Rivastigmina/uso terapêutico , Memantina/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Estudos Retrospectivos , Pandemias , Prevalência , Piperidinas/uso terapêutico , Fenilcarbamatos/uso terapêutico , Indanos/uso terapêutico , COVID-19/epidemiologia , Galantamina/uso terapêuticoRESUMO
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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Widespread access to emerging information and communication technologies (ICT) allows its use for the screening of diseases in the general population. At the initiative of the Spanish Confederation of Associations of Families of People with Alzheimer's disease and other dementias (CEAFA), a website (http://www.problemasmemoria.com) has been created that provides information about Alzheimer's disease and includes questionnaires to be completed by family or friends concerned about memory problems of a relative. A cross-sectional, randomized, multicenter study was performed to evaluate feasibility, validity, and user satisfaction with an electronic method of completion vs. the current method of paper-based questionnaires for clinically dementia screening completed by the informants: the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and the Alzheimer's disease-8 screening test (AD8). A total of 111 pairs were recruited by seven memory clinics. Informants completed IQCODE and AD8 questionnaires both in their paper and electronic versions. The correlation between paper and electronic versions was significantly positive for IQCODE (r = 0.98; p < 0.001) and AD8 (r = 0.96; p < 0.001). The execution time did not differ significantly, and participants considered their use equally easy. This study shows that an electronic version of the IQCODE and AD8 questionnaires is suitable for its online use via the internet and achieves the same results as the traditional paper versions.
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Background. Interest in electroencephalographic (EEG) coronavirus disease 2019 (COVID-19) findings has been growing, especially in the search for a specific-features EEG of encephalopathy. Methods. We made a retrospective analysis of 29 EEGs recorded in 15 patients with COVID-19 and neurological symptoms. We classified the EEGs as "Acute EEG" and "follow-up EEG." We did a statistical analysis between voltage and respiratory status of the patient, stay or not in the intensive care unit (ICU), days of stay in the ICU, sedative drugs, pharmacological treatment, type of symptoms predominating, and outcome. Results. We found EEG abnormalities in all patients studied. We observed the amplitude of background <20â µV at 93% of "acute EEG," versus only 21.4% of "follow-up EEG." The average voltage went from 12.33 ± 5.09â µV in the acute EEGs to 32.8 ± 20.13â µV in the follow-up EEGs. A total of 60% of acute EEGs showed an intermittent focal rhythmic. We have not found a statistically significant association between voltage of acute EEG and nonneurological clinical status (including respiratory) that may interfere with the EEG findings. Conclusions. Nonspecific diffuse slowing EEG pattern in COVID-19 is the most common finding reported, but we found in addition to that, as a distinctive finding, low voltage EEG, that could explain the low prevalence of epileptic activity published in these patients. A metabolic/hypoxic mechanism seems unlikely on the basis of our EEG findings. This pattern in other etiologies is reminiscent of severe encephalopathy states associated with poor prognosis. However, an unreactive low voltage pattern in COVID-19 patients is not necessarily related to poor prognosis.
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Encefalopatias , COVID-19 , Eletroencefalografia/métodos , Seguimentos , Humanos , Estudos RetrospectivosRESUMO
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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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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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Doença de Alzheimer/psicologia , Qualidade de Vida/psicologia , Inquéritos e Questionários , AutorrelatoRESUMO
BACKGROUND: The Multidimensional Alcohol Craving Scale (MACS) and Single Photon Emission Computerized Tomography (SPECT) with (123)I-iodobenzamide ((123)I-IBZM) can be useful tools for assessing relapse risk in early recovery from alcohol-dependency. The aim of this study was to assess possible relationships between MACS score, (123)I-IBZM binding and time to first heavy drinking day (TFHD) after detoxification treatment. METHODS: Nineteen alcohol-dependent in-patients were evaluated by MACS scale and an 123I-IBZM-SPECT, performed following alcohol detoxification treatment. At discharge, participants were advised to take naltrexone 50 mg/day for relapse prevention. TFHD was assessed over a 12-week follow up. RESULTS: The MACS score at the beginning of the detoxification process and naltrexone treatment after detoxification were independent predictive factors for TFHD. CONCLUSIONS: The MACS scale is a better predictor of TFHD than IBZM binding. It is simple, non-invasive and inexpensive and appears to be a useful instrument both for clinical practice and for research.
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Alcoolismo/diagnóstico por imagem , Alcoolismo/psicologia , Iodobenzenos , Tomografia Computadorizada de Emissão de Fóton Único , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recidiva , Índice de Gravidade de Doença , Fatores de TempoRESUMO
INTRODUCTION: The Alzheimer's Disease Knowledge Scale (ADKS) is one of the most popular instruments for assessing a person's knowledge regarding Alzheimer's disease (AD). The objective of this study was to explore ADKS item characteristics with item response theory (IRT) procedures. METHODS: A noninterventional web-based study was conducted. A nonparametric IRT procedure, Mokken analysis, was used to explore the underlying latent structure of the ADKS and ADKS item characteristics regarding scalability and violations of the monotone homogeneity (MH) model. A random-effects meta-analysis was implemented that combined ADKS scores from independent studies. RESULTS: A total of 447 employees of a pharmaceutical company participated in the study. The mean ADKS score was 21.2 (SD 2.8). Mokken analysis showed that most ADKS items (22 of 30) do not fit to any scale and can be considered to be scale independent. Two items (#1: particularly prone to depression; #20: depression can be mistaken for AD) fit to a domain relating to depression, another two items (#2: mental exercise can prevent AD development; #8: benefit of psychotherapy) can be related to potential prevention and improvement, and four items (#12: poor nutrition can make the symptoms worse; #18: high cholesterol may increase the risk of AD; #26: high blood pressure may increase the risk of AD; #27: genes can only partially account for AD development) fit to a risk factor domain. As expected from those results, neither the overall scale (H = 0.033) nor its items showed appropriate scalability index values, suggesting that ADKS does not fit to a MH model. Eleven items showed violations of the assumptions of the MH model. The meta-analytical average score was 21.78 (95% CI 20.67-22.90), with healthcare professionals and caregivers showing the highest levels of AD knowledge. CONCLUSION: Although the ADKS does not present a unidimensional structure, its independent items together provide a comprehensive spectrum of information regarding AD knowledge.
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We report a patient with sporadic Alzheimer's disease with onset in his twenties found to carry the de novo Pro436Gln mutation in the presenilin 1 gene (PS1). Clinical phenotype featured a posterior cortical syndrome with severe visual agnosia and mild limb spasticity with brisk reflexes. Brain MRI and FDG-PET scans revealed severe parieto-occipital atrophy/hypometabolism. Cerebrospinal fluid biomarkers showed a decrease in Aß42 level and Aß42/40 ratio, increased phospho-tau, and normal total tau. Amyloid PET identified a very high burden of amyloid-ß neuritic plaques in the posterior cortex. Similarities between this and two previously reported cases with this variant support that this mutation has a very strong impact on the clinical phenotype and is consistently associated with spasticity.
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Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Espasticidade Muscular/etiologia , Mutação , Presenilina-1/genética , Adulto , Agnosia/etiologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Humanos , Imageamento por Ressonância Magnética , Masculino , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Proteínas tau/líquido cefalorraquidianoRESUMO
Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.
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Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [ßAVROH (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10-5; ßFROH (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10-16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482â11,305,456), (ß (CI 95%) = 1.09 (0.48 â 1.48), p value = 9.03 × 10-4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/genética , Homozigoto , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Raising knowledge about Alzheimer's disease (AD) may help in identifying the disorder, seeking earlier appropriate healthcare, and decreasing its stigma. The aim of this study was to determine the knowledge and perceptions towards people with AD among employees of a pharmaceutical company in Spain. METHODS: A non-interventional, cross-sectional study was conducted among 447 employees. Participants answered demographic questions and completed the Alzheimer's Disease Knowledge Scale (ADKS). Caregivers also answered questions related to their personal experience with patients with AD and completed the Satisfaction with Life Scale (SWLS), the Revised Memory and Behavior Problems Checklist (RMBPC), and the Beck Depression Inventory-Fast Screen (BDI-FS). RESULTS: Participants were mostly between 30 and 50 years old (63%), female (65.3%), and had bachelor or master degrees (82.7%). Forty-two (9.4%) of participants were caregivers, mainly of moderate to severe dementia subjects. Overall knowledge about AD was moderate (mean ADKS score = 21.2 ± 2.8 [70.6% of correct answers]). Risk factors and caregiving were the domains with lowest scores (correct answers: 58.58% and 63%, respectively). Mean total ADKS score was significantly higher in participants caring for people with AD compared with non-caregivers (22.1 ± 2.9 and 21.0 ± 2.8; p=0.02, respectively). There was no statistically significant association between total ADKS score and age, sex, educational level, or relative's AD severity. Most caregivers were satisfied with life (mean SWLS score = 26.8 ± 5.6) showing a low impact from behavioral problems (mean RMBPC reaction score = 26.81 ± 20.2). Six of them (14.3%) were scored as depressed. CONCLUSION: There is a continuing need to improve understanding of AD to fill the gaps in knowledge of the disease, even in a population working in healthcare sector with a high educational level.
RESUMO
The allele ε4 of the apolipoprotein E gene (APOE ε4) is the major genetic risk factor for non-dominantly inherited Alzheimer's Disease (AD). Current techniques for APOE ε4 carriers identification show good accuracy but have several disadvantages that limit its implementation in a clinical laboratory. These include the need for sample preprocessing, poor automation, low throughput, requirement of additional equipment, and high cost. We followed ISO 13485 guidelines to validate the e4Risk test, a new latex-enhanced immunoturbidimetric blood assay for apolipoprotein E4 (ApoE4) determination in human plasma samples. The test showed high performance in terms of lot to lot variability, precision, interferences, reagents stability, prozone, and detectability. Furthermore, diagnostic accuracy is almost equal (99%) to the gold standard, APOE ε4 genotyping by polymerase chain reaction (PCR). Furthermore, we demonstrated that the e4Risk test can be adapted to any clinical chemistry analyzer, including the high throughput analyzers present in most hospitals and clinical laboratories. The e4Risk test versatility, low cost, and easiness provides an excellent solution for APOE ε4 carriers identification using the same blood sample drawn for biochemical diagnostic work-up of AD patients, which can have important advantages for patient stratification in clinical trials, preventative strategies for AD, and clinical assessment of risk for brain amyloidosis.