%0 Journal Article %J J Alzheimers Dis %D 2023 %T Montreal Cognitive Assessment in Mild Cognitive Impairment: Relationship with Cerebrospinal Fluid Biomarkers and Conversion to Dementia. %A Bernardes, Catarina %A Lima, Marisa %A Duro, Diana %A Silva-Spínola, Anuschka %A Durães, João %A Tábuas-Pereira, Miguel %A Baldeiras, Ines %A Freitas, Sandra %A Santana, Isabel %X

BACKGROUND: Mild cognitive impairment (MCI) is considered a prodromal state of dementia. Abnormal values of cerebrospinal fluid Alzheimer's disease biomarkers (CSF-AD-b) have been associated with a higher risk of conversion to dementia (due to Alzheimer's disease), but studies evaluating the ability of Montreal Cognitive Assessment (MoCA) in this task are lacking.

OBJECTIVE: This study aims to investigate the relationship between MoCA and CSF-AD-b, as well as the ability of those tools to predict conversion to dementia.

METHODS: Taking advantage of our MCI cohort with biological characterization on longitudinal follow-up (180 patients followed for 62.6 months during which 41.3% converted), we computed MoCA and MMSE z-scores, using Portuguese normative data. The performance in MoCA z-score was correlated with CSF-AD-b and the relative time to conversion and risk according to baseline characteristics were analyzed using Kaplan-Meier analysis and Cox regression models.

RESULTS: MoCA z-scores were correlated with Aβ42 (p = 0.026), t-tau (p = 0.033), and p-tau (p = 0.01). Impaired MMSE (p < 0.001) and MoCA z-scores (p = 0.019), decreased Aβ42 (p < 0.001) and increased t-tau (p < 0.001) and p-tau (p < 0.001) were associated with shorter estimated time of conversion. Aβ42 (p < 0.001) and MMSE z-scores (p = 0.029) were independent predictors of conversion. For those with at least 9 years of education, MoCA z-score (p = 0.004) (but not MMSE) was an independent predictor of conversion as well as Aβ42.

CONCLUSIONS: This study confirms the role of CSF-AD-b, namely Aβ42, in predicting conversion from MCI to dementia and suggests the utility of MoCA in predicting conversion in highly educated subjects, supporting its use in the evaluation of MCI patients.

%B J Alzheimers Dis %V 96 %P 1173-1182 %8 2023 Nov 21 %G eng %N 3 %R 10.3233/JAD-230916 %0 Journal Article %J J Alzheimers Dis %D 2020 %T APOEɛ4-TOMM40L Haplotype Increases the Risk of Mild Cognitive Impairment Conversion to Alzheimer's Disease. %A Cardoso, Remy %A Lemos, Carolina %A Oliveiros, Bárbara %A Rosário Almeida, Maria %A Baldeiras, Ines %A Fragão Pereira, Cláudia %A Santos, Ana %A Duro, Diana %A Vieira, Daniela %A Santana, Isabel %A Resende Oliveira, Catarina %X

BACKGROUND: Mild cognitive impairment (MCI) has been considered as a pre-dementia stage, although the factors leading to Alzheimer's disease (AD) conversion remain controversial.

OBJECTIVE: Evaluate whether TOMM40 poly-T (TOMM40' 523) polymorphism is associated with the risk and conversion time from MCI to AD and secondly with AD cerebrospinal fluid (CSF) biomarkers, disentangling the APOE genotype.

METHODS: 147 AD patients, 102 MCI patients, and 105 cognitively normal controls were genotyped for poly-T polymorphism. MCI patients were subdivided into two groups, the group of patients that converted to AD (MCI-AD) and the group of those that remained stable (MCI-S).

RESULTS: TOMM40' 523 L allele was significantly more frequent in the MCI-AD group and having at least one L allele significantly increased the risk of conversion from MCI to AD (OR = 8.346, p <  0.001, 95% CI: 2.830 to 24.617). However, when adjusted for the presence of APOEɛ4 allele, both the L allele and ɛ4 allele lost significance in the model (p >  0.05). We then analyzed the APOEɛ4-TOMM40' 523 haplotype and observed that patients carrying this haplotype had significantly higher risk (OR = 5.83; 95% CI = 2.30-14.83) and mean lower times of conversion to AD (p = 0.003). This haplotype was also significantly associated with a biomarker profile compatible with AD (p = 0.007).

CONCLUSION: This study shows that the APOEɛ4-TOMM40' 523 haplotype is associated with a higher risk and shorter times of conversion from MCI to AD, possibly driven by CSF biomarkers and mitochondrial dysfunction.

%B J Alzheimers Dis %V 78 %P 587-601 %8 2020 Nov 10 %G eng %N 2 %R 10.3233/JAD-200556 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Association between Adipokines and Biomarkers of Alzheimer's Disease: A Cross-Sectional Study. %A Letra, Liliana %A Matafome, Paulo %A Rodrigues, Tiago %A Duro, Diana %A Lemos, Raquel %A Baldeiras, Ines %A Patrício, Miguel %A Castelo-Branco, Miguel %A Caetano, Gina %A Seiça, Raquel %A Santana, Isabel %X

BACKGROUND: 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.

%B J Alzheimers Dis %V 67 %P 725-735 %8 2019 %G eng %N 2 %R 10.3233/JAD-180669 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Can Subjective Memory Complaints Identify Aβ Positive and Aβ Negative Amnestic Mild Cognitive Impairment Patients? %A Mendes, Tiago %A Cardoso, Sandra %A Guerreiro, Manuela %A Maroco, João %A Silva, Dina %A Alves, Luísa %A Schmand, Ben %A Gerardo, Bianca %A Lima, Marisa %A Santana, Isabel %A de Mendonça, Alexandre %X

BACKGROUND: The use of biomarkers, in particular amyloid-β (Aβ) changes, has allowed the possibility to identify patients with subjective memory complaints (SMCs) and amnestic mild cognitive impairment (aMCI) who suffer from Alzheimer's disease (AD). Since it is unfeasible that all patients with aMCI could presently undergo biomarkers assessment, it would be important that SMCs might contribute to identify the aMCI patients who have AD amyloid pathology.

OBJECTIVES: To know whether aMCI patients with amyloid biomarkers (Aβ+) present greater SMCs as compared to those without amyloid biomarkers (Aβ-).

METHODS: Participants were selected from a cohort of nondemented patients with cognitive complaints and a comprehensive neuropsychological evaluation, on the basis of 1) diagnosis of aMCI; 2) detailed assessment of memory difficulties with the SMC Scale; and 3) known amyloid status. The amyloid status was determined on the basis of either CSF Aβ1-42 concentration or amyloid PET imaging.

RESULTS: Of the 176 patients with aMCI studied, 90 were Aβ+ and 86 were Aβ-. The two groups did not differ in terms of age, gender, and education. The SMC total score was not significantly different in the Aβ+ aMCI patients (9.48±4.18) when compared to the Aβ- aMCI patients (10.52±4.57). The Aβ+ aMCI patients had lower scores on the MMSE and memory/learning tests, but not on the Geriatric Depression Scale, when comparing to the Aβ- aMCI patients.

CONCLUSIONS: Evaluating SMCs does not seem helpful to identify, among patients with aMCI, those who have AD.

%B J Alzheimers Dis %V 70 %P 1103-1111 %8 2019 Aug 20 %G eng %N 4 %R 10.3233/JAD-190414 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Influence of Butyrylcholinesterase in Progression of Mild Cognitive Impairment to Alzheimer's Disease. %A Gabriel, António José %A Almeida, Maria Rosário %A Ribeiro, Maria Helena %A Carneiro, Diogo %A Valério, Daniela %A Pinheiro, Ana Cristina %A Pascoal, Rui %A Santana, Isabel %A Baldeiras, Ines %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Biomarkers %K Butyrylcholinesterase %K Cognitive Dysfunction %K Disease Progression %K Female %K Genetic Predisposition to Disease %K Humans %K Kaplan-Meier Estimate %K Male %K Middle Aged %K Risk Factors %K tau Proteins %X

BACKGROUND: Several demographic and genetic prognostic factors of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) have been recognized so far. The most frequent polymorphism of butyrylcholinesterase (BuChE), the K-variant, has been proposed as a risk factor for AD, but data regarding its influence on early disease progression is still limited.

OBJECTIVE: To investigate the influence of the BuChE-K variant in MCI progression to AD.

METHODS: 96 MCI patients were included in the study and were genotyped for BuChE-K variant and Apolipoprotein E (ApoE). Cerebrospinal fluid (CSF) BuChE activity, as well as the levels of AD biomarkers amyloid-β 42 (Aβ42), total and hyperphosphorylated tau (t-tau and p-tau) were also determined.

RESULTS: No significant differences were found in either BuChE-K variant or BuChE activity between MCI patients that progressed to AD (MCI-AD) and patients that remained stable during clinical follow-up (MCI-St). As expected, baseline CSF levels of Aβ42 were significantly lower and t-Tau, p-Tau, and ApoE ɛ4 allele frequency were significantly higher in MCI-AD patients. An association between the ApoE ɛ4 allele and the BuChE-K variant in MCI-AD, but not in MCI-St patients, was found with patients carrying both alleles presenting the highest incidence of progression and the lowest estimated time of progression to AD.

CONCLUSION: Although BuChE-K alone does not seem to play a major role in progression to AD in MCI patients, a synergistic effect with the ApoE ɛ4 allele was found, highlighting the importance of assessing these combined genotypes for evaluating risk progression in MCI patients.

%B J Alzheimers Dis %V 61 %P 1097-1105 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254094?dopt=Abstract %R 10.3233/JAD-170695 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers. %A Ramos de Matos, Mafalda %A Ferreira, Catarina %A Herukka, Sanna-Kaisa %A Soininen, Hilkka %A Janeiro, André %A Santana, Isabel %A Baldeiras, Ines %A Almeida, Maria Rosário %A Lleo, Alberto %A Dols-Icardo, Oriol %A Alcolea, Daniel %A Benussi, Luisa %A Binetti, Giuliano %A Paterlini, Anna %A Ghidoni, Roberta %A Nacmias, Benedetta %A Meulenbroek, Olga %A van Waalwijk van Doorn, Linda J C %A Kuiperi, H Bea J %A Hausner, Lucrezia %A Waldemar, Gunhild %A Simonsen, Anja Hviid %A Tsolaki, Magda %A Gkatzima, Olymbia %A Resende de Oliveira, Catarina %A Verbeek, Marcel M %A Clarimón, Jordi %A Hiltunen, Mikko %A de Mendonça, Alexandre %A Martins, Madalena %X

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

%B J Alzheimers Dis %V 66 %P 639-652 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320580?dopt=Abstract %R 10.3233/JAD-180512 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Underlying Biological Processes in Mild Cognitive Impairment: Amyloidosis Versus Neurodegeneration. %A Santana, Isabel %A Baldeiras, Ines %A Santiago, Beatriz %A Duro, Diana %A Freitas, Sandra %A Pereira, Miguel Tábuas %A Almeida, Maria Rosário %A Oliveira, Catarina Resende %X

The amyloid cascade hypothesis proposes amyloid-β (Aβ) as the earliest and key pathological hallmark of Alzheimer's disease (AD), but this mandatory "amyloid-first pathway" has been contested. Longitudinal studies of mild cognitive impairment (MCI) patients represent an opportunity to investigate the intensity of underlying biological processes (amyloidosis versus neurodegeneration) and their relevance for progression to AD. We re-examined our cohort of amnestic MCI, grouped according to cerebrospinal fluid (CSF) biomarkers, aiming at establishing their prognostic value for Alzheimer-type dementia and testing the hypothetical model of biomarkers sequence, based on the amyloid cascade. Our baseline population consisted of 217 MCI patients, 63% with neurodegeneration markers and 47% with amyloidosis. Within the longitudinal study-group (n = 165), 85 progressed to AD and 80 remained cognitively stable. Age, CSF Aβ42, and t-Tau were identified as the best single predictors of conversion to AD. Regarding MCI classification according to the NIA-AA criteria, the high-AD-likelihood group (HL-both amyloid and neurodegeneration markers) was the most frequent (42%); followed by the Suspected Non-Alzheimer Pathophysiology group (SNAP-26%), the low-AD-likelihood group (LL-negative biomarkers-22%), and the Isolated Amyloid Pathology group (IAP-10%). Risk of progression to AD was higher in HL in relation to the LL group (HR = 6.1, 95% CI = 2.1-18.0, p = 0.001). SNAP and IAP groups were equivalent in terms of risk of progression to AD (IAP: HR = 2.6, 95% CI = 0.7-9.3, p = 0.141; SNAP: HR = 3.1, 95% CI = 1.1-9.6; p = 0.046), but only SNAP was significantly different from the LL group. These results support different neurobiological pathways to AD beyond the amyloid hypothesis, highlighting the alternative "neurodegeneration-first pathway" for further investigation.

%B J Alzheimers Dis %V 64 %P S647-S657 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562515?dopt=Abstract %R 10.3233/JAD-179908 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer's Disease Patients and Controls after Correction for Ventricular Volumes. %A van Waalwijk van Doorn, Linda J C %A Gispert, Juan D %A Kuiperij, H Bea %A Claassen, Jurgen A H R %A Arighi, Andrea %A Baldeiras, Ines %A Blennow, Kaj %A Bozzali, Marco %A Castelo-Branco, Miguel %A Cavedo, Enrica %A Emek-Savaş, Derya D %A Eren, Erden %A Eusebi, Paolo %A Farotti, Lucia %A Fenoglio, Chiara %A Ormaechea, Juan Fortea %A Freund-Levi, Yvonne %A Frisoni, Giovanni B %A Galimberti, Daniela %A Genc, Sermin %A Greco, Viviana %A Hampel, Harald %A Herukka, Sanna-Kaisa %A Liu, Yawu %A Lladó, Albert %A Lleo, Alberto %A Nobili, Flavio M %A Oguz, Kader K %A Parnetti, Lucilla %A Pereira, João %A Picco, Agnese %A Pikkarainen, Maria %A de Oliveira, Catarina Resende %A Saka, Esen %A Salvadori, Nicola %A Sánchez-Valle, Raquel %A Santana, Isabel %A Scarpini, Elio %A Scheltens, Philip %A Soininen, Hilkka %A Tarducci, Roberto %A Teunissen, Charlotte %A Tsolaki, Magda %A Urbani, Andrea %A Vilaplana, Eduard %A Visser, Pieter Jelle %A Wallin, Asa K %A Yener, Görsev %A Molinuevo, José L %A Meulenbroek, Olga %A Verbeek, Marcel M %X

Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42: r = -0.28; p < 0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r = -0.15; p-tau: r = -0.13; both p < 0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aβ42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels.

%B J Alzheimers Dis %V 56 %P 543-555 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059783?dopt=Abstract %R 10.3233/JAD-160668 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations. %A Luis, Elkin %A Ortiz, Alexandra %A Eudave, Luis %A Ortega-Cubero, Sara %A Borroni, Barbara %A van der Zee, Julie %A Gazzina, Stefano %A Caroppo, Paola %A Rubino, Elisa %A D'Agata, Federico %A Le Ber, Isabelle %A Santana, Isabel %A Cunha, Gil %A Almeida, Maria R %A Boutoleau-Bretonnière, Claire %A Hannequin, Didier %A Wallon, David %A Rainero, Innocenzo %A Galimberti, Daniela %A Van Broeckhoven, Christine %A Pastor, María A %A Pastor, Pau %X

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1), among other genes. Rare SQSTM1 gene mutations have been associated with Paget's disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD).

OBJECTIVE: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction.

METHODS: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 pathogenic variants (FTD/SQSTM1 mutation carriers; n = 10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD; n = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n = 20). The groups were matched according to current age, disease duration, and gender.

RESULTS: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres.

CONCLUSIONS: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineatinga specific gene-linked atrophy pattern.

%B J Alzheimers Dis %V 53 %P 303-13 %8 2016 May 07 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163810?dopt=Abstract %R 10.3233/JAD-160006