[Show abstract][Hide abstract] 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 & dementia: the journal of the Alzheimer's Association 08/2014; · 14.48 Impact Factor
[Show abstract][Hide abstract] 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; · 3.53 Impact Factor
[Show abstract][Hide abstract] 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; · 5.94 Impact Factor
[Show abstract][Hide abstract] 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; · 4.17 Impact Factor
[Show abstract][Hide abstract] 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; · 2.19 Impact Factor
[Show abstract][Hide abstract] 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; · 4.17 Impact Factor
[Show abstract][Hide abstract] 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; · 1.68 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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. · 2.16 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Mild cognitive impairment (MCI) is considered to be an early stage of a neurodegenerative disorder, particularly Alzheimer's disease, and the clinical diagnosis requires the objective demonstration of cognitive deficits. The aim of the present study was to evaluate the predictive value of MCI for the conversion to dementia when using four different verbal memory tests (Logical Memory, LM; California Verbal Learning Test, CVLT; Verbal Paired-Associate Learning, VPAL; and Digit Span, DS) in the MCI criteria.
Participants were consecutive patients with subjective cognitive complaints who performed a comprehensive neuropsychological evaluation and were not demented, observed in a memory clinic setting.
At baseline, 272 non-demented patients reporting subjective cognitive complaints were included. During the follow-up time (3.0 ± 1.9 years), 58 patients converted to dementia and 214 did not. Statistically significant differences between the converters and non-converters were present in LM, VPAL, and CVLT. A multivariate Cox regression analysis combining the four memory tests revealed that only the CVLT test remained significant as a predictor of conversion to dementia. Non-demented patients with cognitive complaints diagnosed as having MCI according to abnormal (<1.5 SD) learning in the CVLT test had a 3.61 higher risk of becoming demented during the follow-up.
The verbal memory assessment using the CVLT should be preferred in the diagnostic criteria of MCI for a more accurate prediction of conversion to dementia.
Dementia and geriatric cognitive disorders extra. 01/2012; 2:120-31.
[Show abstract][Hide abstract] 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.
International journal of Alzheimer's disease. 01/2012; 2012:725329.
[Show abstract][Hide abstract] 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.
Dementia and geriatric cognitive disorders extra. 01/2012; 2(1):321-31.
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT:
Dementia and cognitive impairment associated with aging are a major medical and social concern. Neuropsychological testing is a key element in the diagnostic procedures of Mild Cognitive Impairment (MCI), but has presently a limited value in the prediction of progression to dementia. We advance the hypothesis that newer statistical classification methods derived from data mining and machine learning methods like Neural Networks, Support Vector Machines and Random Forests can improve accuracy, sensitivity and specificity of predictions obtained from neuropsychological testing. Seven non parametric classifiers derived from data mining methods (Multilayer Perceptrons Neural Networks, Radial Basis Function Neural Networks, Support Vector Machines, CART, CHAID and QUEST Classification Trees and Random Forests) were compared to three traditional classifiers (Linear Discriminant Analysis, Quadratic Discriminant Analysis and Logistic Regression) in terms of overall classification accuracy, specificity, sensitivity, Area under the ROC curve and Press'Q. Model predictors were 10 neuropsychological tests currently used in the diagnosis of dementia. Statistical distributions of classification parameters obtained from a 5-fold cross-validation were compared using the Friedman's nonparametric test.
Press' Q test showed that all classifiers performed better than chance alone (p < 0.05). Support Vector Machines showed the larger overall classification accuracy (Median (Me) = 0.76) an area under the ROC (Me = 0.90). However this method showed high specificity (Me = 1.0) but low sensitivity (Me = 0.3). Random Forest ranked second in overall accuracy (Me = 0.73) with high area under the ROC (Me = 0.73) specificity (Me = 0.73) and sensitivity (Me = 0.64). Linear Discriminant Analysis also showed acceptable overall accuracy (Me = 0.66), with acceptable area under the ROC (Me = 0.72) specificity (Me = 0.66) and sensitivity (Me = 0.64). The remaining classifiers showed overall classification accuracy above a median value of 0.63, but for most sensitivity was around or even lower than a median value of 0.5.
When taking into account sensitivity, specificity and overall classification accuracy Random Forests and Linear Discriminant analysis rank first among all the classifiers tested in prediction of dementia using several neuropsychological tests. These methods may be used to improve accuracy, sensitivity and specificity of Dementia predictions from neuropsychological testing.
[Show abstract][Hide abstract] ABSTRACT: Adenosine neuromodulation depends on a balanced activation of inhibitory A₁ (A₁R) and facilitatory A(₂A) receptors (A(₂A) R). Both A₁ R and A(₂A) R modulate hippocampal glutamate release and NMDA-dependent long-term potentiation (LTP) but ageing affects the density of both A₁ R and A(₂A) R. We tested the effects of selective A₁ R and A(2A) R antagonists in the modulation of synaptic transmission and plasticity in rat hippocampal slices from three age groups (young adults, 2-3 month; middle-aged adults, 6-8 months; aged, 18-20 months). The selective A(₂A) R antagonist SCH58261 (50 nm) attenuated LTP in all age groups, with a larger effect in aged (-63 ± 7%) than in middle-aged adults (-36 ± 9%) or young adult rats (-36 ± 9%). In contrast, the selective A₁ R antagonist DPCPX (50 nm) increased LTP magnitude in young adult rats (+42 ± 6%), but failed to affect LTP magnitude in the other age groups. Finally, in the continuous presence of DPCPX, SCH58261 caused a significantly larger inhibition of LTP amplitude in aged (-71 ± 45%) than middle-aged (-28 ±9%) or young rats (-11 ± 2%). Accordingly, aged rats displayed an increased expression of A(₂A) R mRNA in the hippocampus and a higher number of glutamatergic nerve terminals equipped with A(2A) R in aged (67 ± 6%) compared with middle-aged (34 ± 7%) and young rats (25 ± 5%). The results show an enhanced A(₂A) R-mediated modulation of LTP in aged rats, in accordance with the age-associated increased expression and density of A(₂A) R in glutamatergic terminals. This age-associated gain of function of A(₂A) R modulating synaptic plasticity may underlie the ability of A(₂A) R antagonists to prevent memory dysfunction in aged animals.
European Journal of Neuroscience 05/2011; 34(1):12-21. · 3.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In most European countries the ethnic minority migrant populations are currently reaching an age where dementia becomes an increasingly important issue. There is no European consensus on good clinical practice with these patient groups, who often have special needs and expectations with regard to dementia services.
A survey was conducted in clinical dementia centers in 15 European countries. Questionnaires focusing on different points in the clinical assessment of dementia in ethnic minority patients were mailed to leading dementia experts of the European Alzheimer's Disease Consortium.
Thirty-six centers from 15 countries responded to the survey. Ethnic minority patients were seen on a regular basis in 69% of these centers. The diagnostic evaluation was in accordance with evidence-based clinical guidelines in 84-100% of the centers, but most centers performed cognitive assessment with instruments that are only validated in Western cultures and frequently relied on family members for interpretation. Diagnostic evaluation of the patients was considered to be challenging in 64% of the centers, mainly because of communication problems and lack of adequate assessment tools. In general, there were few indicators of culturally sensitive dementia services in the centers.
Ethnic minority patients are seen on a regular basis in European dementia clinics. Assessment of such patients is difficult for a number of reasons. Results from this study show that the most challenging issues are communication problems and assessment of cognitive function where there is a need to develop specific tests for ethnic minority patients.
International Psychogeriatrics 02/2011; 23(1):86-95. · 2.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The centres dedicated to dementia throughout Europe use different neuropsychological tests in clinical practice. The European Federation of Neurological Societies task force on neuropsychological tests produced this survey on neuropsychological tests currently being used in different European countries to gather knowledge on the practice of dementia centres and to promote the harmonization of such instruments and future multicentre collaborations.
National representatives of 34 countries received a questionnaire and 25 (73.5%) sent it back.
A few instruments, Mini-Mental State Examination (MMSE), Trail Making Test (TMT), Verbal Fluency and Clock Drawing Test, were available in all countries. Wechsler Adult Intelligence Scales and MMSE were reported to be valid, respectively, in 20 (80%) and 19 (76%) countries, whereas Verbal Fluency and Stroop Test are valid in 18 (72%) of them. Of the 25 countries, 17 have validation norms for Clock Drawing Test and TMT (68%), and Neuropsychiatric Inventory, Alzheimer's Disease Assessment Scale - Cognitive Subscale, Rey Complex Figure Test, Digit Symbol and Beck Depression Inventory were standardized in 16 countries (64%). The remaining tests were validated, at most, in about half of them. Not all countries certificate neuropsychology.
Despite the substantial differences in the tools used by the EFNS countries for most domains surveyed by the questionnaire, there is at least one neuropsychological instrument used by about 80% of the countries. There is clearly the need for a broader consensus in the use of neuropsychological tests for dementia diagnosis.
European Journal of Neurology 02/2011; 18(2):279-85. · 4.16 Impact Factor