RESUMO
Cerebral (Aß) plaque and (pTau) tangle deposition are hallmarks of Alzheimer's disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aß/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models. The precise impact of T cells downstream of Aß/pTau, however, appears to vary depending on the animal model. Our prior work suggested that antigen-specific memory CD8 T ("hiT") cells act upstream of Aß/pTau after brain injury. Here, we examine whether hiT cells influence sporadic AD-like pathophysiology upstream of Aß/pTau. Examining neuropathology, gene expression, and behavior in our hiT mouse model we show that CD8 T cells induce plaque and tangle-like deposition, modulate AD-related genes, and ultimately result in progressive neurodegeneration with both gross and fine features of sporadic human AD. T cells required Perforin to initiate this pathophysiology, and IFNγ for most gene expression changes and progression to more widespread neurodegenerative disease. Analogous antigen-specific memory CD8 T cells were significantly elevated in the brains of human AD patients, and their loss from blood corresponded to sporadic AD and related cognitive decline better than plasma pTau-217, a promising AD biomarker candidate. We identify an age-related factor acting upstream of Aß/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD.
Assuntos
Doença de Alzheimer , Linfócitos T CD8-Positivos , Modelos Animais de Doenças , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Animais , Linfócitos T CD8-Positivos/imunologia , Camundongos , Humanos , Placa Amiloide/patologia , Placa Amiloide/imunologia , Peptídeos beta-Amiloides/metabolismo , Camundongos Transgênicos , Encéfalo/patologia , Encéfalo/imunologia , Masculino , Interferon gama/metabolismo , Interferon gama/imunologia , Envelhecimento/imunologia , Memória Imunológica , Células T de Memória/imunologia , Perforina/metabolismo , Perforina/genética , FemininoRESUMO
Alzheimer's disease (AD) is characterized by extracellular amyloid plaques containing amyloid-ß (Aß) peptides, intraneuronal neurofibrillary tangles, extracellular neuropil threads, and dystrophic neurites surrounding plaques composed of hyperphosphorylated tau protein (pTau). Aß can also deposit in blood vessel walls leading to cerebral amyloid angiopathy (CAA). While amyloid plaques in AD brains are constant, CAA varies among cases. The study focuses on differences observed between rare and poorly studied patient groups with APP duplications (APPdup) and Down syndrome (DS) reported to have higher frequencies of elevated CAA levels in comparison to sporadic AD (sAD), most of APP mutations, and controls. We compared Aß and tau pathologies in postmortem brain tissues across cases and Aß peptides using mass spectrometry (MS). We further characterized the spatial distribution of Aß peptides with MS-brain imaging. While intraparenchymal Aß deposits were numerous in sAD, DS with AD (DS-AD) and AD with APP mutations, these were less abundant in APPdup. On the contrary, Aß deposits in the blood vessels were abundant in APPdup and DS-AD while only APPdup cases displayed high Aß deposits in capillaries. Investigation of Aß peptide profiles showed a specific increase in Aßx-37, Aßx-38 and Aßx-40 but not Aßx-42 in APPdup cases and to a lower extent in DS-AD cases. Interestingly, N-truncated Aß2-x peptides were particularly increased in APPdup compared to all other groups. This result was confirmed by MS-imaging of leptomeningeal and parenchymal vessels from an APPdup case, suggesting that CAA is associated with accumulation of shorter Aß peptides truncated both at N- and C-termini in blood vessels. Altogether, this study identified striking differences in the localization and composition of Aß deposits between AD cases, particularly APPdup and DS-AD, both carrying three genomic copies of the APP gene. Detection of specific Aß peptides in CSF or plasma of these patients could improve the diagnosis of CAA and their inclusion in anti-amyloid immunotherapy treatments.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide , Encéfalo , Angiopatia Amiloide Cerebral , Síndrome de Down , Humanos , Síndrome de Down/patologia , Síndrome de Down/metabolismo , Síndrome de Down/genética , Síndrome de Down/complicações , Peptídeos beta-Amiloides/metabolismo , Angiopatia Amiloide Cerebral/patologia , Angiopatia Amiloide Cerebral/genética , Angiopatia Amiloide Cerebral/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Encéfalo/patologia , Encéfalo/metabolismo , Proteínas tau/metabolismo , Idoso de 80 Anos ou mais , Placa Amiloide/patologia , Placa Amiloide/metabolismoRESUMO
INTRODUCTION: Studies suggest a role of vitamin D in the progression and symptomatology of Alzheimer's disease (AD), with few in vitro studies pointing to effects on serotonergic and amyloidogenic turnover. However, limited data exist in AD patients on the potential association with cognition and behavioral and psychological signs and symptoms of dementia (BPSD). In this retrospective cross-sectional study, we, therefore, explored potential correlations of serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations, indicative of vitamin D status, with serum serotonin (5-hydroxytryptamine, 5-HT) levels, cognitive/BPSD scorings, and cerebrospinal fluid (CSF) biomarker levels. METHODS: Frozen serum samples of 25 well-characterized AD subjects as part of a previous BPSD cohort were analyzed, of which 15 had a neuropathologically confirmed diagnosis. Serum 25(OH)D3 levels were analyzed by means of LC-MS/MS, whereas 5-HT concentrations were quantified by competitive ELISA. RESULTS: Among AD patients, vitamin D deficiency was highly prevalent, defined as levels below 50 nmol/L. Regression analyses, adjusted for age, gender, and psychotropic medications, revealed that serum 25(OH)D3 and 5-HT levels were positively associated (p = 0.012). Furthermore, serum 25(OH)D3 concentrations correlated inversely with CSF amyloid-beta (Aß1-42) levels (p = 0.006), and serum 5-HT levels correlated positively with aggressiveness (p = 0.001), frontal behavior (p = 0.001), depression (p = 0.004), and partly with cognitive performance (p < 0.005). Lastly, AD patients on cholinesterase inhibitors had higher serum 25(OH)D3 (p = 0.030) and lower serum 5-HT (p = 0.012) levels. CONCLUSIONS: The molecular associations between low vitamin D status, serum 5-HT, and CSF Aß1-42 levels are highly remarkable, warranting further mechanistic and intervention studies to disclose potential involvement in the clinico-biobehavioral pathophysiology of AD.
Assuntos
Doença de Alzheimer , Deficiência de Vitamina D , Humanos , Serotonina , Doença de Alzheimer/diagnóstico , Cromatografia Líquida , Estudos Transversais , Estudos Retrospectivos , Espectrometria de Massas em Tandem , Vitamina D , CalcifediolRESUMO
Amyloid-beta 42 (Aß42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aß42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aß42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquidiano , Proteínas de Ciclo Celular , Humanos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genéticaRESUMO
OBJECTIVES: To investigate the presence, nature and direction of the daily temporal association between depressive symptoms, cognitive performance and sleep in older individuals. DESIGN, SETTING, PARTICIPANTS: Single-subject study design in eight older adults with cognitive impairments and depressive symptoms. MEASUREMENTS: For 63 consecutive days, depressive symptoms, working memory performance and night-time sleep duration were daily assessed with an electronic diary and actigraphy. The temporal associations of depressive symptoms, working memory and total sleep time were evaluated for each participant separately with time-series analysis (vector autoregressive modeling). RESULTS: For seven out of eight participants we found a temporal association between depressive symptoms and/or sleep and/or working memory performance. More depressive symptoms were preceded by longer sleep duration in one person (r = 0.39; p < .001), by longer or shorter sleep duration than usual in one other person (B = 0.49; p < .001), by worse working memory in one person (B = -0.45; p = .007), and by better working memory performance in one other person (B = 0.35; p = .009). Worse working memory performance was preceded by longer sleep duration (r = -.35; p = .005) in one person, by shorter or longer sleep duration in three other persons (B = -0.76; p = .005, B = -0.61; p < .001; B = -0.34; p = .002), and by more depressive symptoms in one person (B = -0.25; p = .009). CONCLUSION: The presence, nature and direction of the temporal associations between depressive symptoms, cognitive performance and sleep differed between individuals. Knowledge of personal temporal associations may be valuable for the development of personalized intervention strategies in order to maintain their health, quality of life, functional outcomes and independence.
Assuntos
Disfunção Cognitiva , Depressão , Idoso , Idoso de 80 Anos ou mais , Cognição , Depressão/psicologia , Humanos , Qualidade de Vida , SonoRESUMO
Given the unprecedented rise in the world's population, the prevalence of prominent age-related disorders, like cardiovascular disease and dementia, will further increase. Recent experimental and epidemiological evidence suggests a mechanistic overlap between cardiovascular disease and dementia with a specific focus on the linkage between arterial stiffness, a strong independent predictor of cardiovascular disease, and/or hypertension with Alzheimer's disease. In the present study, we investigated whether pharmacological induction of arterial stiffness and hypertension with angiotensin II (1 µg·kg-1·min-1 for 28 days via an osmotic minipump) impairs the progression of Alzheimer's disease in two mouse models (hAPP23+/- and hAPPswe/PSEN1dE9 mice). Our results show increased arterial stiffness in vivo and hypertension in addition to cardiac hypertrophy after angiotensin II treatment. However, visuospatial learning and memory and pathological cerebral amyloid load in both Alzheimer's disease mouse models were not further impaired. It is likely that the 28-day treatment period with angiotensin II was too short to observe additional effects on cognition and cerebral pathology.
Assuntos
Doença de Alzheimer , Amiloidose , Doenças Cardiovasculares , Hipertensão , Rigidez Vascular , Doença de Alzheimer/patologia , Amiloide , Peptídeos beta-Amiloides , Proteínas Amiloidogênicas , Angiotensina II , Animais , Modelos Animais de Doenças , CamundongosRESUMO
Alzheimer's disease (AD) has long been considered a brain-specific dementia syndrome. However, in recent decades, the occurrence of cardiovascular (CV) disease in the progression of AD has been confirmed by increasing epidemiological evidence. In this study, we conducted an in-depth cardiovascular characterization of a humanized amyloid precursor protein (APP) overexpressing mouse model (hAPP23+/-), which overexpresses the Swedish mutation (KM670/671NL). At the age of 6 mo, hAPP23+/- mice had a lower survival, lower body weight, and increased corticosterone and VMA levels compared with C57BL/6 littermates. Systolic blood pressure was increased in hAPP23+/- animals compared with C57BL/6 littermates, but diastolic blood pressure was not statistically different. Pulse pressure remained unchanged but abdominal and carotid pulse-wave velocity (aPWV and cPWV) were increased in hAPP23+/- compared with C57BL/6 mice. Echocardiography showed no differences in systolic or diastolic cardiac function. Ex vivo evaluation of vascular function showed decreased adreno receptor dependent vasoconstriction of hAPP23+/- aortic segments, although the isobaric biomechanics of the aortic wall were similar to C57BL/6 aortic segments. In conclusion, hAPP23+/- mice exhibited high serum corticosterone levels, elevated systolic blood pressure, and increased arterial stiffness in vivo. However, ex vivo aortic stiffness of hAPP23+/- aortic segments was not changed and vascular reactivity to α1-adrenoceptor stimulation was attenuated. These findings highlight the need for more frequent assessment of circulating stress hormone levels and PWV measurements in daily clinical practice for people at risk of AD.NEW & NOTEWORTHY We showed that male amyloid precursor protein (APP) transgenic mice have higher circulating stress hormone levels. As a result, higher systolic blood pressure and pulse-wave velocity were measured in vivo in addition to a smaller α-adrenergic receptor-dependent contraction upon ex vivo stimulation with phenylephrine. Our findings highlight the need for more frequent assessment of circulating stress hormone levels and PWV measurements in daily clinical practice for people at risk of Alzheimer's disease.
Assuntos
Doença de Alzheimer/sangue , Precursor de Proteína beta-Amiloide/metabolismo , Aorta Torácica/metabolismo , Pressão Arterial , Corticosterona/sangue , Rigidez Vascular , Vasoconstrição , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/genética , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Receptores Adrenérgicos alfa 1/metabolismo , Regulação para Cima , Vasoconstrição/efeitos dos fármacosRESUMO
Progressive accumulation of hyperphosphorylated tau is a hallmark of various neurodegenerative disorders including Alzheimer's disease. However, to date, the functional effects of tau pathology on brain network connectivity remain poorly understood. To directly interrogate the impact of tau pathology on functional brain connectivity, we conducted a longitudinal experiment in which we monitored a fibril-seeded hTau.P301L mouse model using correlative whole-brain microscopy and resting-state functional MRI. Despite a progressive aggravation of tau pathology across the brain, the major resting-state networks appeared unaffected up to 15 weeks after seeding. Targeted analyses also showed that the connectivity of regions with high levels of hyperphosphorylated tau was comparable to that observed in controls. In line with the ostensible retention of connectivity, no behavioural changes were detected between seeded and control hTau.P301L mice as determined by three different paradigms. Our data indicate that seeded tau pathology, with accumulation of tau aggregates throughout different regions of the brain, does not alter functional connectivity or behaviour in this mouse model. Additional correlative functional studies on different mouse models should help determine whether this is a generalizable trait of tauopathies.
Assuntos
Encéfalo/fisiopatologia , Rede Nervosa/fisiopatologia , Vias Neurais/fisiopatologia , Agregação Patológica de Proteínas/fisiopatologia , Proteínas tau/metabolismo , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Humanos , Imageamento por Ressonância Magnética , Camundongos , Rede Nervosa/patologia , Vias Neurais/patologia , Agregação Patológica de Proteínas/patologiaRESUMO
Parkinson's disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synuclein-positive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.97%; 1/226 DLB patients, 0.44%). We established that ATP10B encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in ATP10B increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene GBA1, reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver.
Assuntos
Adenosina Trifosfatases/genética , Glucosilceramidas/metabolismo , Lisossomos/metabolismo , Proteínas de Membrana Transportadoras/genética , Mutação/genética , Doença de Parkinson/genética , Idoso , Idoso de 80 Anos ou mais , Neurônios Dopaminérgicos/metabolismo , Feminino , Glucosilceramidase/genética , Glucosilceramidas/genética , Humanos , Corpos de Lewy/patologia , Lisossomos/genética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , alfa-Sinucleína/metabolismoRESUMO
OBJECTIVE: To investigate the relationship between Alzheimer's disease biomarkers and neuropsychiatric symptoms. METHODS: Data from two large cohort studies, the Dutch Parelsnoer Institute - Neurodegenerative Diseases and the Alzheimer's Disease Neuroimaging Initiative was used, including subjects with subjective cognitive decline (Nâ¯=â¯650), mild cognitive impairment (Nâ¯=â¯887), and Alzheimer's disease dementia (Nâ¯=â¯626). Cerebrospinal fluid (CSF) levels of Aß42, t-tau, p-tau, and hippocampal volume were associated with neuropsychiatric symptoms (measured with the Neuropsychiatric Inventory) using multiple logistic regression analyses. The effect of the Mini-Mental State Examination (as proxy for cognitive functioning) on these relationships was assessed with mediation analyses. RESULTS: Alzheimer's disease biomarkers were not associated with depression, agitation, irritability, and sleep disturbances. Lower levels of CSF Aß42, higher levels of t- and p-tau were associated with presence of anxiety. Lower levels of CSF Aß42 and smaller hippocampal volumes were associated with presence of apathy. All associations were mediated by cognitive functioning. CONCLUSION: The association between Alzheimer's disease pathology and anxiety and apathy is partly due to impairment in cognitive functioning.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Ansiedade/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Ansiedade/epidemiologia , Apatia , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Progressão da Doença , Feminino , Hipocampo/patologia , Humanos , Humor Irritável/fisiologia , Modelos Logísticos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Países Baixos , Testes NeuropsicológicosRESUMO
Lung cancer, chronic obstructive pulmonary disease (COPD), and coronary artery disease (CAD) are expected to cause most deaths by 2050. State-of-the-art computed tomography (CT) allows early detection of lung cancer and simultaneous evaluation of imaging biomarkers for the early stages of COPD, based on pulmonary density and bronchial wall thickness, and of CAD, based on the coronary artery calcium score (CACS), at low radiation dose. To determine cut-off values for positive tests for elevated risk and presence of disease is one of the major tasks before considering implementation of CT screening in a general population. The ImaLife (Imaging in Lifelines) study, embedded in the Lifelines study, is designed to establish the reference values of the imaging biomarkers for the big three diseases in a well-defined general population aged 45 years and older. In total, 12,000 participants will undergo CACS and chest acquisitions with latest CT technology. The estimated percentage of individuals with lung nodules needing further workup is around 1-2%. Given the around 10% prevalence of COPD and CAD in the general population, the expected number of COPD and CAD is around 1000 each. So far, nearly 4000 participants have been included. The ImaLife study will allow differentiation between normal aging of the pulmonary and cardiovascular system and early stages of the big three diseases based on low-dose CT imaging. This information can be finally integrated into personalized precision health strategies in the general population.
Assuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Detecção Precoce de Câncer , Neoplasias Pulmonares/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Vigilância da População , Valor Preditivo dos TestesRESUMO
Seizure severity in experimental models of epilepsy is often evaluated by means of the Racine scale, in spite of the use of seizure induction methods that are different from those of the original paper by Racine in 1972. In such cases, the use of this scale is not always justified because some seizure behaviors are significantly different from those originally described or not present at all. Correspondingly, the pentylenetetrazole (PTZ) model, which is frequently used for antiepileptic drug research, lacked an adequate assessment tool to measure seizure severity. In 2009, an adapted intensity scale for PTZ-induced seizures was already designed for rats. Here, we evaluated electroencephalographic (EEG) and behavioral parameters after a single PTZ injection, to determine whether this scale is also suitable for use in mouse studies. We found that the scale designed for rats is quite robust and can thus be applied to score seizure severity in mice. Yet, certain convulsive behaviors and EEG characteristics were distinct between species. Therefore, a species-specific scale was designed, which included the concomitant EEG characteristic next to the behavioral expressions we observed, in order to establish a user-friendly scoring scale for PTZ-induced seizures in mice. To evaluate applicability, we utilized the scale in a seizure susceptibility study of a transgenic mouse model. We demonstrated that the maximum severity scores obtained with the newly revised Racine scale highly correlated with the administered dose. Hence, the revised scale differentiates well between different classes of seizure severity.
Assuntos
Convulsivantes , Modelos Animais de Doenças , Camundongos Transgênicos , Pentilenotetrazol , Convulsões/diagnóstico , Índice de Gravidade de Doença , Animais , Eletroencefalografia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Convulsões/induzido quimicamente , Convulsões/psicologiaRESUMO
OBJECTIVES: Cognitive frailty is characterized by the presence of cognitive impairment in exclusion of dementia. In line with other frailty domains, cognitive frailty is associated with negative outcomes. The Comprehensive Frailty Assessment Instrument (CFAI) measures 4 domains of frailty, namely physical, psychological, social, and environmental frailty. The absence of cognitive frailty is a limitation. METHOD: An expert panel selected 6 questions from the Informant Questionnaire on Cognitive Decline that were, together with the CFAI and the Montreal cognitive assessment administered to 355 older community dwelling adults (mean age = 77). RESULTS: After multivariate analysis, 2 questions were excluded. All the questions from the original CFAI were implemented in a principal component analysis together with the 4 cognitive questions, showing that the 4 cognitive questions all load on 1 factor, representing the cognitive domain of frailty. By adding the cognitive domain to the CFAI, the reliability of the adapted CFAI (CFAI-Plus), remains good (Cronbach's alpha: .767). CONCLUSIONS: This study showed that cognitive frailty can be added to the CFAI without affecting its good psychometric properties. In the future, the CFAI-Plus needs to be validated in an independent cohort, and the interaction with the other frailty domains needs to be studied.
Assuntos
Disfunção Cognitiva/diagnóstico , Fragilidade/diagnóstico , Avaliação Geriátrica/métodos , Inquéritos e Questionários , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Idoso Fragilizado/psicologia , Humanos , Masculino , Análise Multivariada , Psicometria/normas , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Frail community-dwelling older adults, whom might experience problems regarding physical, cognitive, psychological, social and environmental factors, are at risk for adverse outcomes such as disability, institutionalization and mortality. People in need of help do not always find their way to care and support services and are left undetected. The aim of the D-SCOPE project is to detect frail community-dwelling older adults who previously went unnoticed and to improve their access to care and support. Goal is to increase their frailty-balance, quality of life, meaning in life, life satisfaction, mastery, community inclusion and ageing well in place. METHODS/DESIGN: The study is a prospective, longitudinal randomized four-armed controlled trial with follow-up at 6 months. The study group aims to include 900 community-dwelling older adults aged 60 years and over from 3 municipalities in Flanders (Belgium). While selecting the study group, risk profiles for frailty will be taken into account. Participants will be randomly selected from the census records in each municipality. Data will be collected prospectively at baseline (T0) and at follow-up, 6 months after baseline (T1). At baseline, participants who are at least mild frail on one of the 5 domains of frailty (CFAI-plus) or feel frail based on the subjective assessment of frailty will be randomly assigned to (1) the study group or (2) the control group. A mixed method design with the inclusion of quantitative and qualitative data analyses will be used to evaluate the efficacy and experiences of the detection and prevention program on frailty. DISCUSSION: The study will contribute to an innovative vision concerning the organization of care and support, and a timely and accurate detection and support of community-dwelling older adults at risk for frailty. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov, on May 26, 2017, identifier: NCT03168204 .
Assuntos
Idoso Fragilizado , Fragilidade/epidemiologia , Fragilidade/prevenção & controle , Vida Independente , Idoso , Idoso de 80 Anos ou mais , Bélgica/epidemiologia , Emoções/fisiologia , Feminino , Seguimentos , Idoso Fragilizado/psicologia , Fragilidade/psicologia , Humanos , Vida Independente/psicologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida/psicologiaRESUMO
BACKGROUND: The debate on frailty in later life focuses primarily on deficits and their associations with adverse (health) outcomes. In addition to deficits, it may also be important to consider the abilities and resources of older adults. This study was designed to gain insights into the lived experiences of frailty among older adults to determine which strengths can balance the deficits that affect frailty. METHODS: Data from 121 potentially frail community-dwelling older adults in Flemish-speaking Region of Belgium and Brussels were collected using a mixed-methods approach. Quantitative data were collected using the Comprehensive Frailty Assessment Instrument (CFAI), Montreal Cognitive Assessment (MoCA), and numeric rating scales (NRS) for quality of life (QoL), care and support, meaning in life, and mastery. Bivariate analyses, paired samples t-tests and means were performed. Qualitative data on experiences of frailty, frailty balance, QoL, care and support, meaning in life, and mastery were collected using semi-structured interviews. Interviews were subjected to thematic content analysis. RESULTS: The "no to mild frailty" group had higher QoL, care and support, meaning in life, and mastery scores than the "severe frailty" group. Nevertheless, qualitative results indicate that, despite being classified as frail, many older adults experienced high levels of QoL, care and support, meaning in life, and mastery. Respondents mentioned multiple balancing factors for frailty, comprising individual-level circumstances (e.g., personality traits, coping strategies, resilience), environmental influences (e.g., caregivers, neighborhood, social participation), and macro-level features (e.g., health literacy, adequate financial compensation). Respondents also highlighted that life changes affected their frailty balance, including changes in health, finances, personal relationships, and living situation. CONCLUSION: The findings indicate that frailty among older individuals can be considered as a dynamic state and, regardless of frailty, balancing factors are important in maintaining a good QoL. The study investigated not only the deficits, but also the abilities, and resources of frail, older adults. Public policymakers and healthcare organizations are encouraged to include these abilities, supplementary or even complementary to the usual focus on deficits.
Assuntos
Idoso Fragilizado/psicologia , Idoso Fragilizado/estatística & dados numéricos , Fragilidade/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Bélgica , Estudos Transversais , Feminino , Humanos , Vida Independente , Masculino , Pesquisa Qualitativa , Qualidade de Vida , Fatores SocioeconômicosRESUMO
Purpose/aim of the study: Cognitive functioning in the Morris Water Maze (MWM) is assumed to be reflected by path length. In this study, the interference of motor deficits, as a confounding factor on cognitive functioning, was assessed by means of a lateralization study with hemicerebellectomized (HCX) mice. This model is characterized by motor deficits restricted to the lesion side, allowing comparison within the model itself (left vs. right), rather than the effect of the manipulation on this measure (experimental vs. control). MATERIALS AND METHODS: Spatial learning was assessed after left or right hemicerebellectomy in adult mice by means of two MWM designs in which the location of the starting positions was altered for one condition in the adapted (Adap) MWM experiment, hypothesizing that motor impairments ipsilateral to the lesion side result in a difference in path length. RESULTS: When the starting positions were equal for both conditions in the traditional (Trad) MWM experiment, path length during the acquisition phase and spatial memory were more affected for the left HCX, while these effects disappeared after mirroring the starting positions in the Adap MWM, implying that motor phenotype and corresponding increase in task difficulty are responsible for the contradictory results in the Trad MWM experiment. CONCLUSION: The differences found in the latter experiment were circumvented in the adapted MWM protocol, and therefore, excluding the motor deficit as a confounding factor on cognitive MWM parameters.
Assuntos
Cerebelo/lesões , Transtornos Cognitivos/reabilitação , Terapia por Exercício/métodos , Aprendizagem em Labirinto , Transtornos dos Movimentos/reabilitação , Análise de Variância , Animais , Transtornos Cognitivos/etiologia , Modelos Animais de Doenças , Reação de Fuga/fisiologia , Lateralidade Funcional/fisiologia , Marcha/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos dos Movimentos/etiologia , NataçãoRESUMO
The underlying pathophysiology of primary open-angle glaucoma remains unclear, but the lamina cribrosa seems to be the primary site of injury, and raised intraocular pressure is a major risk factor. In recent years, a decreased intracranial pressure, leading to an abnormally high trans-lamina cribrosa pressure difference, has gained interest as a new risk factor for glaucoma. New research now lends support to the hypothesis that a paravascular transport system is present in the eye analogous to the recently discovered 'glymphatic system' in the brain, which is a functional waste clearance pathway that promotes elimination of interstitial solutes, including ß-amyloid, from the brain along paravascular channels. Given that ß-amyloid has been reported to increase by chronic elevation of intraocular pressure in glaucomatous animal models and to cause retinal ganglion cell death, the discovery of a paravascular clearance system in the eye may provide powerful new insights into the pathophysiology of primary open-angle glaucoma. In this review, we provide a new conceptual framework for understanding the pathogenesis of primary open-angle glaucoma, present supporting preliminary data from our own post-mortem study and hypothesize that the disease may result from restriction of normal glymphatic flow at the level of the lamina cribrosa owing to a low intracranial pressure and/or a high trans-lamina cribrosa pressure gradient. If confirmed, this viewpoint could offer new perspectives for the development of novel diagnostic and therapeutic strategies for this devastating disorder.
Assuntos
Pressão do Líquido Cefalorraquidiano/fisiologia , Glaucoma de Ângulo Aberto , Pressão Intraocular/fisiologia , Disco Óptico/patologia , Células Ganglionares da Retina/patologia , Animais , Glaucoma de Ângulo Aberto/etiologia , Glaucoma de Ângulo Aberto/patologia , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Tonometria OcularRESUMO
OBJECTIVES: This paper investigates risk profiles of frailty among older people, as these are essential for detecting those individuals at risk for adverse outcomes and to undertake specific preventive actions. Frailty is not only a physical problem, but also refers to emotional, social, and environmental hazards. METHODS: Using data generated from the Belgian Ageing Studies, a cross-sectional study (n = 28,049), we tested a multivariate regression model that included sociodemographic and socioeconomic indicators as well as four dimensions of frailty, for men and women separately. RESULTS: The findings indicated that for both men and women, increased age, having no partner, having moved house in the previous 10 years, having a lower educational level and having a lower household income are risk characteristics for frailty. Moreover, when looking at the different frailty domains, different risk profiles arose, and gender-specific risk characteristics were detected. DISCUSSION: This paper elaborates on practical implications, and formulates a number of future research recommendations to tackle frailty in an aging society. The conclusion demonstrates the necessity for a thorough knowledge of risk profiles of frailty, as this will save both time and money and permit preventive actions to be more individually tailored.