Alexandre de Mendonça

University of Lisbon, Lisboa, Lisbon, Portugal

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Publications (104)379.05 Total impact

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    ABSTRACT: Meta-analysis of existing genome-wide association studies on Alzheimer’s Disease (AD) showed sub-genome wide association of an intronic variant in the Sequestosome 1 gene (SQSTM1) with AD. We performed targeted resequencing of SQSTM1 in Flanders-Belgian AD patients selected to be enriched for a genetic background (n=435) and geographically matched non-affected individuals (n=872) to investigate the role of both common and rare SQSTM1 variants. Results were extended to the European Early-Onset Dementia (EU EOD) cohorts (926 EOAD patients and 1,476 non-affected individuals). Of the 61 detected exonic variants in SQSTM1, the majority was rare (n=57). Rare variant (MAF<0.01) burden analysis did not reveal an increased frequency of rare variants in EOAD patients in any of the separate study populations nor when meta-analyzing all cohorts. Common variants p.D292= and p.R312= showed nominal association with AD (ORp.D292==1.11[95%C.I.1-1.22];p-value 0.04), only when including the Flanders-Belgian cohort in the meta-analysis. We cannot exclude a role of SQSTM1 genetic variability in late-onset AD, but our data indicate that SQSTM1 does not play a major role in the etiology of EOAD.
    Neurobiology of aging 05/2015; DOI:10.1016/j.neurobiolaging.2015.02.014 · 5.94 Impact Factor
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    ABSTRACT: Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Brain 02/2015; DOI:10.1093/brain/awv029 · 10.23 Impact Factor
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    ABSTRACT: Verbal language deteriorates in Alzheimer's disease, contributing to dramatic disturbances in the ability to communicate. The presence of language disturbances may be detected at earlier phases of the neurodegenerative process, like mild cognitive impairment (MCI). In daily verbal interactions, people mostly use literal language, but sometimes they employ non-literal language, which requires listeners to interpret messages beyond the plain meaning of the words and can be quite demanding. In the present study, we tested the hypotheses that patients with MCI may have deficits in non-literal language, and these deficits are more pronounced than deficits in literal language. Participants were recruited in a private memory clinic and senior universities. General cognitive evaluation included a comprehensive neuropsychological battery, the Mini-Mental State Examination, and the instrumental activities of daily living scale. Literal language was assessed with the semantic decision test, Token Test, and literal text comprehension test, and non-literal language with the proverbs comprehension, idiomatic expressions and non-literal text comprehension tests. Fifty-two participants with MCI and 31 controls were recruited. Patients with MCI had lower scores in all complex language tests, both literal (Token Test, semantic decision and literal text) and non-literal (proverbs, idiomatic expressions, and non-literal text), than the controls; the difference in literal text score was marginally significant. As much as 69% of MCI participants had deficits (performance below 1.5 SD of the mean) on at least one of the complex language tasks. Deficits were more frequent on the proverbs comprehension and semantic decision tests, and the deficits on these tests did not significantly differ from that on the Token Test. Patients with MCI are hindered in understanding complex language, both literal and non-literal. In daily living, these complex language deficits could compromise effective verbal interactions with the others. Amelioration of these deficits should be an important intervention target as part of a comprehensive rehabilitation strategy for patients with cognitive decline. © 2014 The Authors. Psychogeriatrics © 2014 Japanese Psychogeriatric Society.
    Psychogeriatrics 12/2014; 14(4):222-8. DOI:10.1111/psyg.12101 · 1.22 Impact Factor
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    ABSTRACT: We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it “always/frequently”) followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as “moderate”. Seventy-nine percent of responders felt “very/extremely” comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.
    Alzheimer's and Dementia 08/2014; DOI:10.1016/j.jalz.2014.06.006 · 17.47 Impact Factor
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    ABSTRACT: Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.
    Acta Neuropathologica 06/2014; DOI:10.1007/s00401-014-1298-7 · 9.78 Impact Factor
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    ABSTRACT: The clinical significance of subjective memory complaints in the elderly participants, particularly regarding liability of subsequent progression to dementia, has been controversial. In the present study, we tested the hypothesis that severity or type of subjective memory complaints reported by patients in a clinical setting may predict future conversion to dementia. A cohort of nondemented patients with cognitive complaints, followed up for at least 2 years or until conversion to dementia, underwent a neuropsychological evaluation and detailed assessment of memory difficulties with the Subjective Memory Complaints (SMC) Scale. At baseline, patients who converted to dementia (36.8%) had less years of formal education and generally a worse performance in the neuropsychological assessment. There were no differences in the total SMC score between nonconverters (9.5 ± 4.2) and converters (8.9 ± 4.0, a nonsignificant difference), but nonconverters scored higher in several items of the scale. For patients with cognitive complaints observed in a memory clinic setting, the severity of subjective memory complaints is not useful to predict future conversion to dementia.
    Journal of Geriatric Psychiatry and Neurology 04/2014; 27(4). DOI:10.1177/0891988714532018 · 1.63 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia in the elderly individuals, resulting from a complex interaction between environmental and genetic factors. Impaired brain iron homeostasis has been recognized as an important mechanism underlying the pathogenesis of this disease. Nevertheless, the knowledge gathered so far at the systemic level is clearly insufficient. Herein, we used an integrative approach to study iron metabolism in the periphery, at both genotypic and phenotypic levels, in a sample of 116 patients with AD and 89 healthy control subjects. To assess the potential impact of iron metabolism on the risk of developing AD, genetic analyses were performed along with the evaluation of the iron status profile in peripheral blood by biochemical and gene expression studies. The results obtained showed a significant decrease of serum iron, ferritin, and transferrin concentrations in patients compared with the control subjects. Also, a significant decrease of ferroportin (SLC40A1) and both transferrin receptors TFRC and TFR2 transcripts was found in peripheral blood mononuclear cells from patients. At the genetic level, significant associations with AD were found for single nucleotide polymorphisms in TF, TFR2, ACO1, and SLC40A1 genes. Apolipoprotein E gene, a well-known risk factor for AD, was also found significantly associated with the disease in this study. Taken together, we hypothesize that the alterations on systemic iron status observed in patients could reflect an iron homeostasis dysregulation, particularly in cellular iron efflux. The intracellular iron accumulation would lead to a rise in oxidative damage, contributing to AD pathophysiology.
    Neurobiology of aging 10/2013; 35(4). DOI:10.1016/j.neurobiolaging.2013.10.078 · 5.94 Impact Factor
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    ABSTRACT: The clinical phenotype of frontotemporal dementia patients carrying progranulin (GRN) mutations is known to be heterogeneous. We present a patient with corticobasal syndrome and a family with progressive aphasia and behavioral features who were found to have the same p.Gln257Profs*27 mutation. These cases depict the variability of GRN mutation carriers regarding clinical presentation and age of onset. In addition to giving a detailed report of a GRN mutation, we highlight the importance of searching for the presence of GRN mutations in selected sporadic cases and suggest a broadening of GRN genetic screening to better understand the clinical spectrum of these mutations.
    Journal of Alzheimer's disease: JAD 06/2013; 37(2). DOI:10.3233/JAD-130146 · 3.61 Impact Factor
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    ABSTRACT: ABSTRACT Background: Quality of Life-Alzheimer's Disease (QOL-AD) is a widely used scale for the study of quality of life in patients with dementia. The aim of this study is the transcultural adaptation and validation of the QOL-AD scale in Portugal. Methods: Translation and transcultural adaptation was performed according to state-of-the-art recommendations. For the validation study, 104 patient/caregiver pairs were enrolled. Patients had mild cognitive impairment or mild-to-moderate dementia (due to Alzheimer's disease or vascular dementia). Participants were recruited in a dementia outpatient clinic setting and a long-term care dementia ward. An additional comparison group of 22 patients without cognitive impairment, and their proxies, was recruited in a family practice outpatient clinic. Sociodemographic information on patients and caregivers was obtained. Acceptability, reliability, and construct validity were analyzed. Results: Internal consistency of the Portuguese version of QOL-AD was good for both patient and caregiver report (Cronbach's α = 0.867 and 0.858, respectively). Construct validity was confirmed by the correlation of patient reported QOL-AD with patient geriatric depression scale scores (ρ = -0.702, p < 0.001) and satisfaction with life scale scores (ρ = 0.543, p < 0.001). Caregiver ratings were correlated with neuropsychiatric inventory (NPI) total score (ρ = -0.404, p < 0.001), NPI-distress (ρ = -0.346, p < 0.001), and patient Mini-Mental State Examination (ρ = 0.319, p < 0.01). QOL-AD patient ratings were higher than caregiver ratings (p < 0.001). Both patient- and caregiver-rated QOL-AD scores were lower in patients with cognitive impairment than in the comparison group without cognitive impairment (p < 0.01). Conclusions: A Portuguese version of QOL-AD with consistent psychometric properties was obtained and is proposed as a useful tool for research and clinical purposes.
    International Psychogeriatrics 03/2013; 25(7):1-12. DOI:10.1017/S1041610213000379 · 1.89 Impact Factor
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    ABSTRACT: The use of neuropsychological tests to detect cognitive decline in the initial phases of Alzheimer's disease (AD) has faced significant limitations, namely the fact that most cohort studies of conversion to dementia had relatively short follow-up periods. The aim of the present study is to assess the predictive value for future conversion to dementia of a comprehensive neuropsychological battery applied to a cohort of non-demented patients followed-up for 5 years. Participants (n = 250) were selected from the Cognitive Complaints Cohort (CCC) having cognitive complaints, assessment with a comprehensive neuropsychological battery, and a follow-up period of 5 years (unless patients have converted to dementia earlier). During the follow-up period (2.6 ± 1.8 years for converters and 6.1 ± 2.1 years for non-converters), 162 patients (64.8%) progressed to dementia (mostly AD), and 88 (35.2%) did not. A Linear Discriminant Analysis (LDA) model constituted by Digit Span backward, Semantic Fluency, Logical Memory (immediate recall), and Forgetting Index significantly discriminated converters from non-converters (λ Wilks = 0.64; χ2 (4) = 81.95; p < 0.001; RCanonical = 0.60). Logical Memory (immediate recall) was the strongest predictor with a standardized canonical discriminant function coefficient of 0.70. The LDA classificatory model showed good sensitivity, specificity and accuracy values (78.8%, 79.9% and 78.6%, respectively) of the neuropsychological tests to predict long-term conversion to dementia. The present results show that it is possible to predict, on the basis of the initial clinical and neuropsychological evaluation, whether non-demented patients with cognitive complaints will probably convert to dementia, or remain stable, at a reasonably long and clinically relevant term.
    Journal of Alzheimer's disease: JAD 12/2012; 34(3). DOI:10.3233/JAD-122098 · 3.61 Impact Factor
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    ABSTRACT: Background: Quality of life (QoL) is affected in patients with dementia, but it is not clear whether it is already disturbed in more initial phases of cognitive decline, like Mild Cognitive Impairment (MCI). Aim: Compare the QoL in MCI patients with controls without cognitive impairment, and ascertain whether there are differences in the reports of QoL made by the subjects and by their informants. Methods: Two hundred participants were enrolled, divided into MCI patients (n = 50), MCI informants (n = 50), recruited from a memory clinic and a dementia outpatient clinic, and controls (n = 50) and controls informants (n = 50), recruited in a family practice clinic. QoL was assessed with the QoL in Alzheimer disease (QOL-AD) scale. Results: The total scores of the QOL-AD questionnaire were 32.1 ± 6.9 for MCI patients self-report, 27.2 ± 6.7 for MCI patients in the opinion of their informants, 35.3 ± 4.9 for controls self-report and 35.6 ± 4.9 for controls in the opinion of their informants. MCI patients had lower QOL-AD scores than controls. The QoL reported by patients with MCI was more favorable than the opinion of their informants. Conclusion: The QoL is affected at early stages of cognitive decline. The QoL reported by patients with MCI is better than the opinion of their informants, similarly to what is known in Alzheimer's disease patients. QoL appears to be an important domain to be evaluated in aging studies.
    Aging and Mental Health 12/2012; DOI:10.1080/13607863.2012.747083 · 1.78 Impact Factor
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    ABSTRACT: We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7 to 24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence (LCS) adjacent to the G(4) C(2) repeat in C9orf72 expansion carriers (p < 0.001) with the most common indel creating one long contiguous imperfect G(4) C(2) repeat which is likely more prone to replication slippage and pathological expansion.
    Human Mutation 10/2012; DOI:10.1002/humu.22244 · 5.05 Impact Factor
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    ABSTRACT: Primary progressive aphasia (PPA) is a neurodegenerative disorder with no effective pharmacological treatment. Cognition-based interventions are adequate alternatives, but their benefit has not been thoroughly explored. Our aim was to study the effect of speech and language therapy (SLT) on naming ability in PPA. An open parallel prospective longitudinal study involving two centers was designed to compare patients with PPA submitted to SLT (1 h/week for 11 months) with patients receiving no therapy. Twenty patients were enrolled and undertook baseline language and neuropsychological assessments; among them, 10 received SLT and 10 constituted an age- and education-matched historical control group. The primary outcome measure was the change in group mean performance on the Snodgrass and Vanderwart naming test between baseline and follow-up assessments. Intervention and control groups did not significantly differ on demographic and clinical variables at baseline. A mixed repeated measures ANOVA revealed a significant main effect of therapy (F(1,18) = 10.763; p = 0.005) on the performance on the Snodgrass and Vanderwart naming test. Although limited by a non-randomized open study design with a historical control group, the present study suggests that SLT may have a benefit in PPA, and it should prompt a randomized, controlled, rater-blind clinical trial.
    08/2012; 2(1):321-31. DOI:10.1159/000341602
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) form a spectrum of clinically, pathologically, and genetically overlapping disorders, as confirmed by the recent report that it can be caused by a hexanucleotide repeat expansion in C9orf72. One hundred and fourteen Portuguese cases diagnosed as probable or possible familial FTLD, as part of the EOD consortium study, and nine further Portuguese cases with familial ALS were tested for the presence of this mutation. Results showed that six Portuguese patients from unrelated families had the mutation, five (4.4%) patients from the FTLD group and one (11.1%) from the ALS sample. Of these, three patients had FTLD and rapidly progressive bulbar ALS. Electromyography confirmed diffuse loss of motor units with marked bulbar involvement. In conclusion, the cases now reported showed a very rapid progression, suggesting bulbar ALS could be particularly common and aggressive in patients with the C9orf72 hexanucleotide repeat expansion, in the Portuguese population.
    Amyotrophic Lateral Sclerosis 06/2012; 14(1). DOI:10.3109/17482968.2012.690418 · 3.40 Impact Factor
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    ABSTRACT: Serial position effects in word list learning have been used to differentiate normal aging and dementia. Prominent recency and diminished primacy have consistently been observed in Alzheimer's disease (AD). We examined serial position effects in patients with mild cognitive impairment (MCI), in patients with AD, and in normal healthy controls. Additionally, we classified MCI patients into those who progressed to AD (MCI-p) and those who did not (MCI-np). We compared two serial position measures: regional and standard scores. Regional scores, mainly the primacy effect, improved discrimination between MCI and controls and between MCI-np and MCI-p, proving to be more sensitive and specific than the recency effect.
    Journal of Clinical and Experimental Neuropsychology 06/2012; 34(8):841-52. DOI:10.1080/13803395.2012.689814 · 2.16 Impact Factor
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    ABSTRACT: In Alzheimer's disease (AD) the complex interplay between environment and genetics has hampered the identification of effective therapeutics. However, epigenetic mechanisms could underlie this complexity. Here, we explored the potential role of epigenetic alterations in AD by investigating gene expression levels and chromatin remodeling in selected AD-related genes. Analysis was performed in the brain of the triple transgenic animal model of AD (3xTg-AD) and in peripheral blood mononuclear cells (PBMCs) from patients diagnosed with AD or Mild Cognitive Impairment (MCI). BACE1 mRNA levels were increased in aged 3xTg-AD mice as well as in AD PBMCs along with an increase in promoter accessibility and histone H3 acetylation, while the BACE1 promoter region was less accessible in PBMCs from MCI individuals. Ncstn was downregulated in aged 3xTg-AD brains with a condensation of chromatin and Sirt1 mRNA levels were decreased in these animals despite alterations in histone H3 acetylation. Neither gene was altered in AD PBMCs. The ADORA2A gene was not altered in patients or in the 3xTg-AD mice. Overall, our results suggest that chromatin remodeling plays a role in mRNA alterations in AD, prompting for broader and more detailed studies of chromatin and other epigenetic alterations and their potential use as biomarkers in AD.
    Neuroscience 06/2012; 220:256-66. DOI:10.1016/j.neuroscience.2012.06.029 · 3.33 Impact Factor
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    ABSTRACT: Diagnosis of mild cognitive impairment relies on the presence of memory complaints. However, memory complaints are very frequent in healthy people. The objective of this study was to determine the severity and type of memory difficulties presented by elderly patients who seek for clinical help, as compared to the memory difficulties reported by subjects in the community. Assessment of subjective memory complaints was done with the subjective memory complaints scale (SMC). The mini-mental state examination was used for general cognitive evaluation and the geriatric depression scale for the assessment of depressive symptoms. Eight-hundred and seventy-one nondemented subjects older than 50 years were included. Participants in the clinical setting had a higher total SMC score (10.3 ± 4.2) than those in the community (5.1 ± 3.0). Item 3 of the SMC, Do you ever forget names of family members or friends? contributed significantly more to the variance of the total SMC score in the clinical sample (18%) as compared to the community sample (11%). Forgetting names of family members or friends plays an important role in subjective memory complaints in the clinical setting. This symptom is possibly perceived as particularly worrisome and likely drives people to seek for clinical help.
    03/2012; 2012:725329. DOI:10.1155/2012/725329

Publication Stats

2k Citations
379.05 Total Impact Points

Institutions

  • 2001–2015
    • University of Lisbon
      • • Institute of Molecular Medicine
      • • Faculdade de Medicina
      Lisboa, Lisbon, Portugal
  • 2005–2014
    • Instituto de Medicina Molecular
      Lisboa, Lisbon, Portugal
  • 1990–2012
    • Hospital de Santa Maria
      Lisboa, Lisbon, Portugal
  • 2010
    • Seoul National University Bundang Hospital
      Sŏul, Seoul, South Korea
  • 2006
    • University of Minho
      • School of Health Sciences
      Braga, Distrito de Braga, Portugal
  • 2003
    • ISCTE-Instituto Universitário de Lisboa
      Lisboa, Lisbon, Portugal
    • University of Coimbra
      • Faculty of Medicine
      Coímbra, Coimbra, Portugal