RESUMEN
Plasma amyloid-beta (Aß) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aß alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) mutation-carriers (MC) and non-carriers (NC) using two Aß measurement platforms. Seventeen pre-symptomatic members of a D-CAA pedigree were assembled and followed up 3-4 years later (NC = 8; MC = 9). Plasma Aß1-40 and Aß1-42 were cross-sectionally and longitudinally analysed at baseline (T1) and follow-up (T2) and were found to be lower in MCs compared to NCs, cross-sectionally after adjusting for covariates, at both T1(Aß1-40: p = 0.001; Aß1-42: p = 0.0004) and T2 (Aß1-40: p = 0.001; Aß1-42: p = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aß1-40 revealed decreased levels in MCs using data from the Simoa platform (p = 0.041) and pairwise longitudinal analyses of plasma Aß1-42 revealed decreased levels in MCs using data from the xMAP platform (p = 0.041). Findings from the Simoa platform suggest that plasma Aß may add value to a panel of biomarkers for the diagnosis of pre-symptomatic CAA, however, further validation studies in larger sample sets are required.
Asunto(s)
Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Angiopatía Amiloide Cerebral Familiar/genética , Fragmentos de Péptidos/genética , Adulto , Péptidos beta-Amiloides/sangre , Precursor de Proteína beta-Amiloide/sangre , Enfermedades Asintomáticas , Biomarcadores/sangre , Angiopatía Amiloide Cerebral Familiar/sangre , Angiopatía Amiloide Cerebral Familiar/diagnóstico , Angiopatía Amiloide Cerebral Familiar/patología , Progresión de la Enfermedad , Femenino , Expresión Génica , Genes Dominantes , Heterocigoto , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mutación , Pruebas Neuropsicológicas , Linaje , Fragmentos de Péptidos/sangreRESUMEN
BACKGROUND: Cerebral amyloid angiopathy (CAA) is one of the major causes of intracerebral hemorrhage and vascular dementia in older adults. Early diagnosis will provide clinicians with an opportunity to intervene early with suitable strategies, highlighting the importance of pre-symptomatic CAA biomarkers. OBJECTIVE: Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs). METHODS: Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ® p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n = 9) and non-carriers (D-CAA NCs, n = 8) from the same pedigree. Metabolites that survived correction for multiple comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults). RESULTS: 275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in theD-CAAMCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE ε4 (p < 00.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in theD-CAAMCscompared to theD-CAA NCs (p < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p < 0.01). Spermidinewas also observed to correlate with CSF Aß40 (rs = 0.621, p = 0.024), CSF Aß42 (rs = 0.714, p = 0.006), and brain Aß load (rs = -0.527, p = 0.030). CONCLUSION: The current study provides pilot data on D-CAA linked metabolite signals, that also associated with Aß neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia.
Asunto(s)
Angiopatía Amiloide Cerebral Familiar/sangre , Adulto , Enfermedades Asintomáticas , Biomarcadores/sangre , Estudios de Casos y Controles , Angiopatía Amiloide Cerebral Familiar/genética , Angiopatía Amiloide Cerebral Familiar/metabolismo , Femenino , Heterocigoto , Humanos , Masculino , Espectrometría de Masas , Pruebas de Estado Mental y Demencia , Metabolómica , Neuroimagen , Linaje , Placa Amiloide/diagnóstico por imagen , Tomografía de Emisión de Positrones , Espermidina/sangre , Espermidina/metabolismoRESUMEN
The involvement of apolipoproteins, such as the ApoE4 isoform, in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) highlights the fact that certain lipid carriers may participate in soluble ß-amyloid (Aß) transport. Our general aim was to characterize the soluble levels of the apolipoproteins apoE, apoA1 and apoJ/clusterin and their genotype status in patients with CAA. We analyzed the genotypes frequency of APOA1 (rs5069, rs670), CLU (rs11136000, rs1532278, rs7012010, rs9331888) and APOE (rs429358, rs7412) in a cohort of patients with CAA-associated intracerebral hemorrhage (ICH) (n = 59) and compared the results with those from hypertension-associated ICH (n = 42), AD patients (n = 73) and controls (n = 88). In a subgroup of patients, we also determined the plasma concentrations of apoE, apoA1 and apoJ/clusterin. We found increased plasma apoJ/clusterin levels in CAA patients compared to AD patients or controls after adjusting for sex and age (CAA vs. controls, p = 0.033; CAA vs. AD, p = 0.013). ApoA1 levels were not altered between groups, although a strong correlation was observed between plasma Aß(1-40) and apoA1 among CAA patients (r = 0.583, p = 0.007). Regarding plasma apoE concentration, a robust association between circulating levels and genotype status was confirmed (p < 0.001). Whereas the APOE4 frequency was higher in AD (p < 0.001) and CAA (p = 0.013), the APOA1 and CLU genotypes were not different among groups. In the CAA cohort, the risk-linked CLU variant (C) rs11136000 was associated with white matter hyperintensities (p = 0.045) and the presence of lobar microbleeds (p = 0.023) on MRI. In summary, our findings suggest that apoA1 may act as a physiological transporter of Aß(1-40) and that apoJ/clusterin appears to be a chaperone related to distinctive lesions in CAA brains.
Asunto(s)
Apolipoproteína A-I/genética , Apolipoproteínas E/genética , Angiopatía Amiloide Cerebral/genética , Clusterina/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/genética , Apolipoproteína A-I/sangre , Apolipoproteínas E/sangre , Angiopatía Amiloide Cerebral/sangre , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Angiopatía Amiloide Cerebral Familiar/sangre , Angiopatía Amiloide Cerebral Familiar/complicaciones , Angiopatía Amiloide Cerebral Familiar/diagnóstico por imagen , Angiopatía Amiloide Cerebral Familiar/genética , Hemorragia Cerebral/etiología , Clusterina/sangre , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Hipertensión/sangre , Hipertensión/complicaciones , Hipertensión/genética , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Sustancia Blanca/patologíaRESUMEN
Human cystatin C (CysC) is a reversible cysteine protease inhibitor, which is abundantly secreted to body fluids. It is a potential marker of kidney dysfunction, but has been suggested to be of diagnostic importance in a number of neurodegenerative diseases, as well. The amyloid formation by a L68Q variant CysC accounts for the hereditary CysC amyloid angiopathy (HCCAA). Also, the wild type CysC forms inactive dimers at partly denaturing conditions through a domain swapping mechanism. Here, we have developed an immunoassay for the detection of dimeric CysC consisting of either a full length or an N-terminally truncated form. A codon optimized gene encoding a full length CysC was expressed in Escherichia coli, where the product was directed to the periplasmic space. Two different forms of CysC were isolated, a full length product and a form proteolytically truncated by 8 N-terminal amino acid residues. In vitro dimerization experiments were conducted in order to enable the selection of monoclonal antibodies for the construction of an immunoassay being able to primarily recognize the dimers. The analytical detection limit of the assay was 0.043 microg/l, with assay imprecision below 16%. The assay was linear in the range of 5-100 microg/l (R(2)=0.997). The dimer assay was employed for the measurement of serum and cerebrospinal fluid (CSF) sample panel of 20 multiple sclerosis (MS) and 22 non-MS patients. A dimer signal was observed in both serum and CSF samples. The dimer signals from CSF were approximately 2-22 times higher (average 13) than the corresponding signals from serum samples. However, the measured signal levels between the different patient groups showed no statistically significant difference in serum or in CSF (P=0.07 and P=0.98 respectively). In conclusion, the immunoassay provides direct means for detecting CysC dimers in serum and CSF in respect to the amount of total CysC.
Asunto(s)
Angiopatía Amiloide Cerebral Familiar/sangre , Angiopatía Amiloide Cerebral Familiar/líquido cefalorraquídeo , Cistatina C/sangre , Cistatina C/líquido cefalorraquídeo , Multimerización de Proteína , Adulto , Sustitución de Aminoácidos , Amiloide/sangre , Amiloide/líquido cefalorraquídeo , Amiloide/inmunología , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Angiopatía Amiloide Cerebral Familiar/genética , Angiopatía Amiloide Cerebral Familiar/inmunología , Cistatina C/genética , Cistatina C/inmunología , Femenino , Humanos , Inmunoensayo/métodos , Masculino , Mutación Missense , Proteínas Recombinantes , Sensibilidad y EspecificidadRESUMEN
Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is a rare autosomal dominant disorder caused by an amyloid-beta precursor protein (AbetaPP) 693 mutation that clinically leads to recurrent hemorrhagic strokes and dementia. The disease is pathologically characterised by the deposition of Abeta in cerebral blood vessels and as plaques in the brain parenchyma. This study measured the Abeta40 and Abeta42 concentration in plasma of Dutch AbetaPP693 mutation carriers and controls. We found that the Abeta40 concentration was not different between AbetaPP693 mutation carriers and controls. However, the Abeta42 concentration was significantly decreased in the mutation carriers. No correlation exists between the APOE(epsilon)4 allele and the plasma of Abeta40 and Abeta42 levels in HCHWA-D patients. This finding contrasted with the increased concentrations found in Alzheimer's disease. Therefore it is suggested that the Dutch AbetaPP693 mutation located within the Abeta coding region of the AbetaPP gene has a different effect not only on clinical and pathological expression but also on Abeta processing.