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INTRODUCTION: The Rey-Osterrieth Complex Figure Test (RCFT) is one of the most commonly used neuropsychological tests in Sweden and Norway. However, no publications provide normative data for this population. The objective of this study was to present demographically adjusted norms for a Swedish and Norwegian population and to evaluate these in an independent comparison group. METHODS: The RCFT was administrated to 344 healthy controls recruited from the Swedish Gothenburg MCI study, the Norwegian Dementia Disease Initiation study, and the Swedish Cardiopulmonary Bioimage Study. Age ranged from 49 to 77 years (mean = 62.4 years, SD = 5.0 years), and education ranged from 6 to 24 years (mean = 13.3 years, SD = 3.0 years). Using a regression-based procedure, we investigated the effects of age, sex, and years of education on test performance. We compared and evaluated our Swedish and Norwegian norms with North American norms in an independent comparison group of 145 individuals. RESULTS: In healthy controls, age and education were associated with performance on the RCFT. When comparing normative RCFT performance in an independent comparison group, North American norms generally overestimated immediate and delayed recall performance. In contrast, our Swedish and Norwegian norms appear to better take into account factors of age and education. CONCLUSIONS: We presented demographically adjusted norms for the RCFT in a Swedish and Norwegian sample. This is the first normative study of the RCFT that presents normative data for this population. In addition, we showed that North American norms might produce inaccurate normative estimations in an independent comparison group.
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Rememoração Mental , Humanos , Pessoa de Meia-Idade , Idoso , Suécia , Escolaridade , Testes Neuropsicológicos , América do NorteRESUMO
BACKGROUND: The subcortical small vessel type of dementia (SSVD) is a common subtype of vascular dementia, but there is a lack of disease-specific cerebrospinal fluid (CSF) biomarkers. OBJECTIVE: We investigated whether CSF concentrations of neurofilament light chain (NFL), soluble amyloid-ß protein precursor α (sAßPPα), sAßPPß, and CSF/serum albumin ratio could separate SSVD from healthy controls, Alzheimer's disease (AD), and mixed dementia (combined AD and SSVD). METHODS: This was a mono-center study of patients with SSVD (nâ=â38), AD (nâ=â121), mixed dementia (nâ=â62), and controls (nâ=â96). The CSF biomarkers were measured using immunoassays, and their independent contribution to the separation between groups were evaluated using the Wald test. Then, the area under the receiver operating characteristics curve (AUROC) and 95% confidence intervals (CIs) were calculated. RESULTS: Elevated neurofilament light chain (NFL) and decreased sAßPPß independently separated SSVD from controls, and sAßPPß also distinguished SSVD from AD and mixed dementia. The combination of NFL and sAßPPß discriminated SSVD from controls with high accuracy (AUROC 0.903, 95% CI: 0.834-0.972). Additionally, sAßPPß combined with the core AD biomarkers (amyloid-ß42, total tau, and phosphorylated tau181) had a high ability to separate SSVD from AD (AUROC 0.886, 95% CI: 0.830-0.942) and mixed dementia (AUROC 0.903, 95% CI: 0.838-0.968). CONCLUSIONS: The high accuracy of NFL and sAßPPß to separate SSVD from controls supports that SSVD is a specific diagnostic entity. Moreover, SSVD was distinguished from AD and mixed dementia using sAßPPß in combination with the core AD biomarkers.
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Doença de Alzheimer , Demência , Demências Mistas , Humanos , Precursor de Proteína beta-Amiloide/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Filamentos Intermediários , Proteínas tau/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Demência/diagnóstico , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidianoRESUMO
Brain tumours are the most common cause of death among children with solid tumours, and high-grade gliomas (HGG) are among the most devastating forms with very poor outcomes. In the search for more effective treatments for paediatric HGG, there is a need for better experimental models. To date, there are no xenograft zebrafish models developed for human paediatric HGG; existing models rely on adult cells. The use of paediatric models is of great importance since it is well known that the genetic and epigenetic mechanisms behind adult and paediatric disease differ greatly. In this study, we present a clinically relevant in vivo model based on paediatric primary glioma stem cell (GSC) cultures, which after orthotopic injection into the zebrafish larvae, can be monitored using confocal imaging over time. We show that cells invade the brain tissue and can be followed up to 8 days post-injection while they establish in the fore/mid brain. This model offers an in vivo system where tumour invasion can be monitored and drug treatments quickly be evaluated. The possibility to monitor patient-specific cells has the potential to contribute to a better understanding of cellular behaviour and personalised treatments in the future.
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With laboratory zebrafish (Danio rerio) being an established and popular research model, there is a need for universal, research-based husbandry guidelines for this species, since guidelines can help promote good welfare through providing appropriate care. Despite the widespread use of zebrafish in research, it remains unclear how holding densities affect their welfare. Previous studies have mainly evaluated the effects of holding densities on a single parameter, such as growth, reproductive output, or social interactions, rather than looking at multiple welfare parameters simultaneously. Here we investigated how chronic (nine weeks) exposure to five different holding densities (1, 4, 8, 12, and 16 fish/L) affected multiple welfare indicators. We found that fish in the 1 fish/L density treatment had higher free water cortisol concentrations per fish, increased vertical distribution, and displayed aggressive behaviour more frequently than fish held at higher densities. On the other hand, density treatments had no effect on anxiety behaviour, whole-brain neurotransmitter levels, egg volume, or the proportion of fertilised eggs. Our results demonstrate that zebrafish can be held at densities between 4 and 16 fish/L without compromising their welfare. However, housing zebrafish in the density of 1 fish/L increased their stress level and aggressive behaviour.
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Introduction: In this study, we examine similarities and differences between 52 patients with idiopathic normal pressure hydrocephalus (iNPH) and 17 patients with subcortical small vessel disease (SSVD), in comparison to 28 healthy controls (HCs) by a panel of cerebrospinal fluid (CSF) biomarkers. Methods: We analyzed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPß), Aß isoforms -38, -40, and -42, neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), matrix metalloproteinases (MMP -1, -2, -3, -9, and -10), and tissue inhibitors of metalloproteinase 1 (TIMP1). Radiological signs of white matter damage were scored using the age-related white matter changes (ARWMC) scale. Results: All amyloid fragments were reduced in iNPH and SSVD (p < 0.05), although more in iNPH than in SSVD in comparison to HC. iNPH and SSVD showed comparable elevations of NFL, MBP, and GFAP (p < 0.05). MMPs were similar in all three groups except for MMP-10, which was increased in iNPH and SSVD. Patients with iNPH had larger ventricles and fewer WMCs than patients with SSVD. Conclusion: The results indicate that patients with iNPH and SSVD share common features of subcortical neuronal degeneration, demyelination, and astroglial response. The reduction in all APP-derived proteins characterizing iNPH patients is also present, indicating that SSVD encompasses similar pathophysiological phenomena as iNPH.
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Introduction: Subcortical small-vessel disease (SSVD) is the most common vascular cognitive disorder. However, because no disease-specific cerebrospinal fluid (CSF) biomarkers are available for SSVD, our aim was to identify such markers. Methods: We included 170 healthy controls and patients from the Gothenburg Mild Cognitive Impairment (MCI) study clinically diagnosed with SSVD dementia, Alzheimer's disease (AD), or mixed AD/SSVD. We quantified CSF levels of amyloid-ß (Aß)x-38, Aßx-40, Aßx-42, as well as soluble amyloid precursor protein (sAPP)-α and sAPP-ß. Results: sAPP-ß was lower in SSVD patients than in AD patients and controls. Receiver-operating characteristic (ROC) analyses showed that sAPP-ß moderately separated SSVD from AD and controls. Moreover, the CSF/serum albumin ratio was elevated exclusively in SSVD and could moderately separate SSVD from the other groups in ROC analyses. Discussion: SSVD has a biomarker profile that differs from that of AD and controls, and to some extent also from mixed AD/SSVD, suggesting that signs of blood-brain barrier (BBB) dysfunction and sAPP-ß could be additional tools to diagnose SSVD. Highlights: Patients with subcortical small-vessel disease (SSVD) exhibited reduced levels of sAPP-ß and disturbances of the blood-brain barrier (BBB).This biochemical pattern is different from that of Alzheimer's disease (AD) and to some degree from that of mixed AD/SSVD.Our findings are speaking in favor of the concept that SSVD is a distinct vascular cognitive disorder (VCD) form.
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BACKGROUND: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives. METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD. RESULTS: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046). CONCLUSIONS: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.
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The zebrafish is becoming an increasingly popular research animal around the world. Its welfare is affected by an array of environmental factors, such as food access and water quality. Holding density is an important welfare aspect, not least due to its interaction with other housing conditions. Despite the extensive use of zebrafish in research, little is known of how densities affect its welfare. In this systematic review, we have performed a large literature search, compiled, and evaluated all publications regarding zebrafish holding density. We have analyzed how density effects growth, reproduction, and stress response, including behavior, water quality, and pathogenic outbreaks in young and adult fish. Our review shows that the holding densities tested vary largely depending on the research focus, for example, body growth or behavior. In fact, research indicates that future recommendations on holding density could depend on which welfare aspects are considered. Overall, there is a need for more studies investigating the interactive effects of density on welfare indicators, such as reproduction coupled with stress response. We stress the necessity of including holding density in universal housing guidelines and reporting information on holding conditions of larvae and adults when publishing zebrafish work.
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Bem-Estar do Animal , Aglomeração , Peixe-Zebra , Animais , Larva , Reprodução , Peixe-Zebra/fisiologiaRESUMO
BACKGROUND: Sulfatides (STs) in cerebrospinal fluid (CSF), as well as magnetic resonance imaging (MRI)-detected white matter hyperintensities (WMHs), may reflect demyelination. Here, we investigated the diagnostic utility of CSF ST levels in the subcortical small vessel type of dementia (SSVD), which is characterized by the presence of brain WMHs. OBJECTIVE: To study the diagnostic utility of CSF ST levels in SSVD. METHODS: This was a mono-center, cross-sectional study of SSVD (nâ=â16), Alzheimer's disease (nâ=â40), mixed dementia (nâ=â27), and healthy controls (nâ=â33). Totally, 20 ST species were measured in CSF by liquid chromatography-mass spectrometry (LC-MS/MS). RESULTS: CSF total ST levels, as well as CSF levels of hydroxylated and nonhydroxylated ST species, did not differ across the study groups. In contrast, CSF neurofilament light chain (NFL) levels separated the patient groups from the controls. CSF total ST level correlated with CSF/serum albumin ratio in the total study population (râ=â0.64, pâ<â0.001) and in all individual study groups. Furthermore, CSF total ST level correlated positively with MRI-estimated WMH volume in the total study population (râ=â0.30, pâ<â0.05), but it did not correlate with CSF NFL level. CONCLUSION: Although there was some relation between CSF total ST level and WMH volume, CSF ST levels were unaltered in all dementia groups compared to the controls. This suggests that CSF total ST level is a poor biomarker of demyelination in SSVD. Further studies are needed to investigate the mechanisms underlying the marked correlation between CSF total ST level and CSF/serum albumin ratio.
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Doença de Alzheimer , Demência Vascular , Doenças Desmielinizantes , Imageamento por Ressonância Magnética/métodos , Sulfoglicoesfingolipídeos/líquido cefalorraquidiano , Substância Branca/diagnóstico por imagem , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Cromatografia Líquida/métodos , Estudos Transversais , Demência Vascular/líquido cefalorraquidiano , Demência Vascular/diagnóstico , Demência Vascular/fisiopatologia , Doenças Desmielinizantes/líquido cefalorraquidiano , Doenças Desmielinizantes/diagnóstico , Diagnóstico Diferencial , Técnicas de Diagnóstico Neurológico , Feminino , Humanos , Masculino , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Utilização de Procedimentos e Técnicas , Reprodutibilidade dos Testes , Substância Branca/patologiaRESUMO
INTRODUCTION: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. METHODS: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. RESULTS: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. DISCUSSION: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
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Doença de Alzheimer , Peptídeos beta-Amiloides/sangue , Biomarcadores/sangue , Proteínas Sanguíneas , Proteômica , Proteínas tau/sangue , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Apolipoproteína E4/sangue , Apolipoproteína E4/genética , Disfunção Cognitiva/sangue , Disfunção Cognitiva/patologia , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Brevican and neurocan are central nervous system-specific extracellular matrix proteoglycans. They are degraded by extracellular enzymes, such as metalloproteinases. However, their degradation profile is largely unexplored in cerebrospinal fluid (CSF). OBJECTIVE: The study aim was to quantify proteolytic peptides derived from brevican and neurocan in human CSF of patients with Alzheimer's disease (AD) and vascular dementia (VaD) compared with controls. METHODS: The first cohort consisted of 75 individuals including 25 patients with AD, 7 with mild cognitive impairment (MCI) diagnosed with AD upon follow-up, 10 patients with VaD or MCI diagnosed with VaD upon follow-up, and 33 healthy controls and cognitively stable MCI patients. In the second cohort, 31 individuals were included (5 AD patients, 14 VaD patients and 12 healthy controls). Twenty proteolytic peptides derived from brevican (n = 9) and neurocan (n = 11) were quantified using high-resolution parallel reaction monitoring mass spectrometry. RESULTS: In the first cohort, the majority of CSF concentrations of brevican and neurocan peptides were significantly decreased inVaDas compared withADpatients (AUC = 0.83.0.93, p≤0.05) and as compared with the control group (AUC = 0.79.0.87, p ≤ 0.05). In the second cohort, CSF concentrations of two brevican peptides (B87, B156) were significantly decreased in VaD compared with AD (AUC = 0.86.0.91, p ≤ 0.05) and to controls (AUC = 0.80.0.82, p ≤ 0.05), while other brevican and neurocan peptides showed a clear trend to be decreased in VaD compared with AD (AUC = 0.64.80, p > 0.05). No peptides differed between AD and controls. CONCLUSION: Brevican and neurocan peptides are potential diagnostic biomarkers for VaD, with ability to separate VaD from AD.
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Doença de Alzheimer/líquido cefalorraquidiano , Brevicam/líquido cefalorraquidiano , Demência Vascular/líquido cefalorraquidiano , Neurocam/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Demência Vascular/diagnóstico , Diagnóstico Diferencial , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Reprodutibilidade dos TestesRESUMO
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aß) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aß42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aß38 and CSF-Aß40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aß and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
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Doença de Alzheimer , Idoso , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Biomarcadores , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fragmentos de Peptídeos , Proteínas tau/genéticaRESUMO
BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E É4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
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Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Idoso , Doença de Alzheimer/genética , Biomarcadores/sangue , Feminino , Expressão Gênica , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Pessoa de Meia-IdadeRESUMO
With a strong tendency to socialise, the zebrafish is a useful model to study social behaviour, with implications for better treatments of social impairments, for instance in autism spectrum disorders. Although oxytocin is crucial for social behaviour in mammals, the importance of the fish orthologue - isotocin or zebrafish oxytocin (zOT) - for social behaviour in zebrafish is unclear. The aims of this study were firstly, to elucidate the receptor specificity of zOT and the related vasotocin or zebrafish vasopressin (zVP; the orthologue of mammalian vasopressin) and the nonpeptidergic oxytocin receptor antagonist L-368,899, and secondly to investigate if L-368,899 inhibits social preference in zebrafish. The potencies of ligands were evaluated for zOT/zVP family receptors in HEK293 cells. Adult and larval zebrafish were treated with L-368,899 or vehicle and subsequently assessed for social behaviour and anxiety (adults only). The antagonist L-368,899 specifically inhibited the two zOT receptors, but not the two zVP-1 receptors. The antagonist decreased social preference in adult and larval zebrafish. It did not affect anxiety in adults. These results indicate that endogenous zOT, and possibly zVP, is involved in social behaviour in zebrafish via either or both of the two zOT receptors, and show promise for future explorations of the anatomy and evolution of networks underlying social behaviour.
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Receptores de Ocitocina/fisiologia , Comportamento Social , Peixe-Zebra/genética , Peixe-Zebra/fisiologia , Animais , Canfanos/farmacologia , Células HEK293 , Humanos , Modelos Animais , Modelos Psicológicos , Ocitocina/fisiologia , Piperazinas/farmacologia , Receptores de Ocitocina/antagonistas & inibidores , Vasotocina/fisiologiaRESUMO
We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E É4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.
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Doença de Alzheimer/sangue , Biomarcadores/sangue , Proteínas Sanguíneas/análise , Angiopatia Amiloide Cerebral/sangue , Proteômica , Idoso , Doença de Alzheimer/diagnóstico por imagem , Apolipoproteína E4/genética , Carga Corporal (Radioterapia) , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Curva ROC , Proteínas tau/líquido cefalorraquidianoRESUMO
BACKGROUND: It is unclear if latent cognitive profiles can distinguish between dementia with subcortical vascular lesions and Alzheimer's disease (AD) at the incipient stage, and if they differ in performance from the Petersen subtypes. OBJECTIVE: To identify latent cognitive profiles in a naturalistic population of patients from a memory clinic sample, and investigate the derived classes not only in terms of conversion to AD, but also in terms of conversion to dementia with subcortical vascular lesions. Another objective was to compare the derived classes to the Petersen subtypes. METHODS: We performed a latent profile analysis (LPA) on standardized neuropsychological test scores from 476 memory clinic patients (age 64±8) without dementia, and analyzed progression to dementia after 2 years. RESULTS: The LPA resulted in two classes with impaired cognition (Amnestic and Slow/Dysexecutive) and two classes with normal cognition (Normal-Low and Normal-High cognition). Belonging to the Amnestic class predicted progression to all-cause dementia and to AD; belonging to the Slow/Dysexecutive class predicted progression to all-cause dementia, AD, and dementia with subcortical vascular lesions. Of the Petersen MCI subtypes, only amnestic multi-domain MCI predicted progression to all-cause dementia, AD, and dementia with subcortical vascular lesions. CONCLUSION: Latent cognitive profiles separated between AD and dementia with subcortical vascular lesions, while the Petersen subtypes did not. However, similar to the Petersen subtypes, LPA classes work better for ruling out progression to dementia than for case finding.
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Doença de Alzheimer/diagnóstico , Cognição/fisiologia , Disfunção Cognitiva/diagnóstico , Demência Vascular/diagnóstico , Memória/fisiologia , Idoso , Doença de Alzheimer/psicologia , Disfunção Cognitiva/psicologia , Demência Vascular/psicologia , Diagnóstico Diferencial , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
BACKGROUND: Research has shown that mixed dementia is more common than previously believed but little is known of its early stages. OBJECTIVE: To examine if incipient mixed dementia can be differentiated from incipient Alzheimer's disease (AD) and subcortical ischemic vascular dementia (SVD) using neuropsychological tests, cerebrospinal fluid (CSF) markers, and magnetic resonance imaging markers. METHODS: We included 493 patients and controls from the Gothenburg MCI study and used the dementia groups for marker selection (CSF total-tau (T-tau), phospho-tau (P-tau), and amyloid-ß42 (Aß42), 11 neuropsychological tests, and 92 regional brain volumes) and to obtain cut-off values which were then applied to the MCI groups. RESULTS: Incipient mixed dementia was best differentiated from incipient AD by the Word fluency F-A-S test and the Trail making test A. CSF T-tau, P-tau, and Aß42 differentiated incipient mixed dementia from incipient SVD. CONCLUSION: Incipient mixed dementia is characterized by an AD-like biomarker profile and an SVD-like cognitive profile. Incipient mixed dementia can be separated from incipient AD and incipient SVD using CSF markers and cognitive testing.
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Biomarcadores , Cognição , Demência/diagnóstico , Demência/psicologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/psicologia , Demência/líquido cefalorraquidiano , Demência Vascular/líquido cefalorraquidiano , Demência Vascular/diagnóstico , Demência Vascular/psicologia , Diagnóstico Diferencial , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Valores de Referência , Proteínas tau/líquido cefalorraquidianoRESUMO
The zebrafish (Danio rerio) has emerged as a widely used model system during the last four decades. The fact that the zebrafish larva is transparent enables sophisticated in vivo imaging, including calcium imaging of intracellular transients in many different tissues. While being a vertebrate, the reduced complexity of its nervous system and small size make it possible to follow large-scale activity in the whole brain. Its genome is sequenced and many genetic and molecular tools have been developed that simplify the study of gene function in health and disease. Since the mid 90's, the development and neuronal function of the embryonic, larval, and later, adult zebrafish have been studied using calcium imaging methods. This updated chapter is reviewing the advances in methods and research findings of zebrafish calcium imaging during the last decade. The choice of calcium indicator depends on the desired number of cells to study and cell accessibility. Synthetic calcium indicators, conjugated to dextrans and acetoxymethyl (AM) esters, are still used to label specific neuronal cell types in the hindbrain and the olfactory system. However, genetically encoded calcium indicators, such as aequorin and the GCaMP family of indicators, expressed in various tissues by the use of cell-specific promoters, are now the choice for most applications, including brain-wide imaging. Calcium imaging in the zebrafish has contributed greatly to our understanding of basic biological principles during development and adulthood, and the function of disease-related genes in a vertebrate system.
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Cálcio , Peixe-Zebra , Animais , Encéfalo/diagnóstico por imagem , Cálcio/metabolismo , Modelos Animais , Neurônios/fisiologia , Peixe-Zebra/fisiologiaRESUMO
INTRODUCTION: Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. METHODS: 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. RESULTS: A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. DISCUSSION: The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.
Assuntos
Doença de Alzheimer , Amiloide/metabolismo , Biomarcadores/sangue , Encéfalo/metabolismo , Proteômica , Fatores Etários , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a "Holy Grail" of AD research and intensively sought; however, there are no well-established plasma markers. METHODS: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. RESULTS: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOε4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). DISCUSSION: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation.