Browsing by Author "Santana, I"
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- Adenosine Deaminase Two and Immunoglobulin M Accurately Differentiate Adult Sneddon's Syndrome of Unknown CausePublication . Santo, GC; Baldeiras, I; Guerreiro, R; Ribeiro, JA; Cunha, R; Youngstein, T; Nanthapisal, S; Leitão, J; Fernandes, C; Caramelo, F; Almeida, MR; Brás, J; Santana, IBACKGROUND: The association that exists between livedo reticularis (LR) and stroke is known as Sneddon's syndrome (SnS). The disorder is classified as primary SnS (PSnS), if the cause remains unknown and secondary SnS. The condition is rare and it occurs mainly sporadically. In 2014, 2 independent teams described a new genetic disorder with childhood-onset, which was called deficiency of adenosine deaminase 2 (DADA2), characterized by recurrent fevers and vascular pathologic features that included LR and stroke. All the patients carried recessively inherited mutations in cat eye syndrome chromosome region candidate 1 gene (CECR1), encoding the adenosine deaminase 2 (ADA2) protein. Genetic testing is the standard for the diagnosis of DADA2. However, the diagnostic accuracy of more affordable laboratorial analysis in CECR1-mutated individuals remains to be established. We aim to determine whether plasma ADA2 activity and serum immunoglobulin M (IgM) levels can distinguish (1) DADA2 from other adult patients within the SnS spectrum, and (2) healthy CECR1 heterozygous (HHZ) from healthy controls (HC). METHODS: ADA2 activity in plasma and serum IgM concentrations was measured in adult patients within the SnS spectrum, healthy first-degree relatives and HC. Genetic results were used as the reference standard. The primary outcome measures were sensitivity and specificity derived from receiver operating curve analysis. RESULTS: A total of 73 participants were included in the study: 26 patients with PSnS with no CECR1 mutation (PSnS), 6 bi-allelic (DADA2 patients) and 7 HHZ CECR1 mutations and 34 HC. Plasma ADA2 activity and serum IgM levels were significantly lower in DADA2 patients than in PSnS. With the use of the best indexes, plasma ADA2 activity differentiated PSnS from DADA2 with a sensitivity and specificity of 100.0% and HHZ from HC with a sensitivity of 97.1% and specificity of 85.7%. Serum IgM levels also differentiated PSnS from DADA2 with a sensitivity of 85.2% and specificity of 83.3%. CONCLUSION: Serum IgM levels might be used as a triage tool and plasma ADA2 activity performs perfectly as a diagnostic test for DADA2 in adult patients within the SnS spectrum. ADA2 activity in plasma also reliably distinguishes HHZ from HC.
- Adenosine Deaminase Two and Immunoglobulin M Accurately Differentiate Adult Sneddon's Syndrome of Unknown CausePublication . Santo, GC; Baldeiras, I; Guerreiro, R; Ribeiro, JA; Cunha, R; Youngstein, T; Nanthapisal, S; Leitão, J; Fernandes, C; Caramelo, F; Almeida, MR; Brás, J; Santana, IThe association that exists between livedo reticularis (LR) and stroke is known as Sneddon's syndrome (SnS). The disorder is classified as primary SnS (PSnS), if the cause remains unknown and secondary SnS. The condition is rare and it occurs mainly sporadically. In 2014, 2 independent teams described a new genetic disorder with childhood-onset, which was called deficiency of adenosine deaminase 2 (DADA2), characterized by recurrent fevers and vascular pathologic features that included LR and stroke. All the patients carried recessively inherited mutations in cat eye syndrome chromosome region candidate 1 gene (CECR1), encoding the adenosine deaminase 2 (ADA2) protein. Genetic testing is the standard for the diagnosis of DADA2. However, the diagnostic accuracy of more affordable laboratorial analysis in CECR1-mutated individuals remains to be established. We aim to determine whether plasma ADA2 activity and serum immunoglobulin M (IgM) levels can distinguish (1) DADA2 from other adult patients within the SnS spectrum, and (2) healthy CECR1 heterozygous (HHZ) from healthy controls (HC).
- Aphasia Rapid Test: Translation, Adaptation and Validation Studies for the Portuguese PopulationPublication . Tábuas-Pereira, M; Freitas, S; Beato-Coelho, J; Ribeiro, JA; Parra, J; Martins, C; Silva, M; Matos, MA; Nogueira, AR; Silva, F; Sargento-Freitas, J; Cordeiro, G; Cunha, L; Santana, IClassical aphasia evaluation scales are too long to use in the context of acute stroke or as a monitoring tool. The Aphasia Rapid Test is a 26-point scale developed as a bedside assessment to rate aphasia severity in acute stroke patients in less than 3 minutes. We aimed to adapt and validate this scale for European Portuguese.
- Apolipoprotein E epsilon4 allele is a risk factor for Alzheimer's disease: the central region of portugal (Coimbra) as a case studyPublication . Fernandes, MA; Oliveira, CR; Oliveira, LM; Nogueira, AJ; Santiago, B; Santana, I
- Association between Adipokines and Biomarkers of Alzheimer's Disease: A Cross-Sectional StudyPublication . Letra, L; Matafome, P; Rodrigues, T; Duro, D; Lemos, R; Baldeiras, I; Patrício, M; Castelo-Branco, M; Caetano, G; Seiça, R; Santana, IBACKGROUND: Adipose tissue dysfunction has been implicated in the pathophysiology of Alzheimer's disease. However, the involvement of adipokines, particularly adiponectin, remains unclear. OBJECTIVE: To compare serum and cerebrospinal fluid (CSF) levels of adiponectin, leptin and leptin-to-adiponectin ratio in patients within the spectrum of Alzheimer's disease and evaluate their relationship with classical biomarkers and their value as markers of progression. METHODS: Amnestic mild cognitive impairment (MCI, n = 71) and Alzheimer's dementia (AD, n = 53) subjects were consecutively recruited for serum and CSF adiponectin and leptin determination using an analytically validated commercial enzyme-linked immunosorbent assay (ELISA). Correlations were explored using adjusted Spearman's correlation coefficients. A logistic regression model and ROC analysis were performed to evaluate the staging predictive value of adipokines. RESULTS: Serum adiponectin was 33% higher in AD when compared to MCI patients. Adiponectin CSF levels, similar in both groups, were positively correlated with Aβ42 and cognitive function, though only in women. The area under the ROC curve was 0.673 (95% CI:0.57-0.78) for serum adiponectin as predictor of dementia stage and the cut-off 10.85μg/ml maximized the sum of specificity (87%) and sensitivity (44%). CONCLUSION: Although longitudinal studies are required, we hypothesize that higher serum adiponectin in AD patients constitutes a strategy to compensate possible central signaling defects. In addition, adiponectin might be specifically assigned to neuroprotective functions in women and eventually involved in the female-biased incidence of Alzheimer's disease.
- Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort.Publication . Guerreiro, RJ; Brás, JM; Santana, I; Januário, C; Morgadinho, A; Ribeiro, MH; Hardy, J; Singleton, A; Oliveira, CRBACKGROUND: Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer (AD) and Parkinson diseases (PD). Iron metabolism is associated with the gene hemochromatosis (HFE Human genome nomenclature committee ID:4886), and mutations in HFE are a cause of the iron mismetabolism disease, hemochromatosis. Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results. METHODS: Genotypes were analysed for the two most common variants of HFE in a series of 130 AD, 55 Mild Cognitive Impairment (MCI) and 132 PD patients. Additionally, a series of 115 healthy age-matched controls was also screened. RESULTS: A statistically significant association was found in the PD group when compared to controls, showing that the presence of the C282Y variant allele may confer higher risk for developing the disease. CONCLUSION: Taken together these results suggest that the common variants in HFE may be a risk factor for PD, but not for AD in the Portuguese population.
- Biparietal variant of Alzheimer's disease: a rare presentation of a common diseasePublication . Marques, IB; Tábuas-Pereira, M; Milheiro, M; Santana, IAlzheimer's disease (AD) is a clinically heterogeneous disease that may have atypical presentations with focal cortical syndromes and relatively preserved episodic memory. The posterior variant of AD has two subtypes: occipitotemporal, presenting with visuoperceptive impairment, and biparietal, presenting with visuospatial dysfunction and apraxia. We report a case of a 51-year-old woman with progressive limb apraxia and choreiform movements. Her neuropsychological evaluation was compatible with dementia, and revealed ideomotor and ideational limb apraxia, severe visuoconstructive ability impairment, dyscalculia and posterior aphasia. Workup excluded metabolic, infectious, inflammatory or neoplastic causes, and hereditary conditions as Huntington's disease and familial AD. Cerebrospinal fluid biomarkers revealed β-amyloid reduction and τ protein increase. Brain imaging showed marked biparietal atrophy and hypoperfusion, and widespread cortical β-amyloid deposition. Biparietal variant of AD was diagnosed and acetylcholinesterase inhibitor treatment induced clinical stabilisation. AD may present with atypical features and a high clinical suspicion is necessary for an early diagnosis.
- A comprehensive screening of copy number variability in dementia with Lewy bodiesPublication . Kun-Rodrigues, C; Orme, T; Carmona, S; Hernandez, DG; Ross, OA; Eicher, JD; Shepherd, C; Parkkinen, L; Darwent, L; Heckman, MG; Scholz, SW; Troncoso, JC; Pletnikova, O; Dawson, T; Rosenthal, L; Ansorge, O; Clarimon, J; Lleo, A; Morenas-Rodriguez, E; Clark, L; Honig, LS; Marder, K; Lemstra, A; Rogaeva, E; St George-Hyslop, P; Londos, E; Zetterberg, H; Barber, I; Braae, A; Brown, K; Morgan, K; Troakes, C; Al-Sarraj, S; Lashley, T; Holton, J; Compta, Y; Van Deerlin, V; Serrano, GE; Beach, TG; Lesage, S; Galasko, D; Masliah, E; Santana, I; Pastor, P; Diez-Fairen, M; Aguilar, M; Tienari, PJ; Myllykangas, L; Oinas, M; Revesz, T; Lees, A; Boeve, BF; Petersen, RC; Ferman, TJ; Escott-Price, V; Graff-Radford, N; Cairns, NJ; Morris, JC; Pickering-Brown, S; Mann, D; Halliday, GM; Hardy, J; Trojanowski, JQ; Dickson, DW; Singleton, A; Stone, DJ; Guerreiro, R; Bras, JThe role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.
- Congenital heart disease: New challengesPublication . Santana, I
- Diagnostic value of CSF protein profile in a Portuguese population of sCJD patientsPublication . Baldeiras, IE; Ribeiro, MH; Pacheco, P; Machado, A; Santana, I; Cunha, L; Oliveira, CRThe clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) is difficult, and reliable markers are highly desired. In this work we assess the value of several cerebrospinal fluid (CSF) markers for sCJD diagnosis. Within the framework of the Portuguese Epidemiological Surveillance Program for Human Prion Diseases, CSF samples from 71 patients with clinically suspected sCJD, 30 definite sCJD and 41 non-CJD patients, were analysed for the presence of 14-3-3 protein. CSF levels of tau (t-tau), and phosphorylated tau (p-tau181), S-100b and beta amyloid (Abeta42) proteins were determined. The influence of clinical and genetic characteristics on CSF markers sensitivity was also evaluated. Protein 14-3-3 was detected in 29/30 sCJD patients and 9/41 non-CJD patients. Extremely elevated t-tau and S-100b protein levels were found in sCJD patients, while p-tau181 levels were only slightly elevated and Abeta42 showed no differences compared to controls. 14-3-3 was the most sensitive parameter (97%), but its specificity was low (78%); sensitivity/specificity for other proteins were: S-100b-93/93%, t-tau-93/95%, with maximum accuracy being obtained by a combination of tests (14-3-3 combined with either t-tau or S-100b, or combining S-100b with t-tau/Abeta42 or p-tau/t-tau ratios). The sensitivity of 14-3-3, as well as of p-tau181/t-tau ratio, was decreased in younger patients with long disease duration, with the PrP-2 isotype and MV genotype. Both 14-3-3, t-tau and S-100b are sensitive markers for sCJD, but 14-3-3 specificity seems to be lower in this special clinical setting of rapidly progressing dementias. We propose that in cases with a 14-3-3 weak positive result, or in young patients with long disease duration, a second CSF marker would be valuable for the diagnosis of sCJD.