Abstract: This work aimed at establishing the memory alteration test (M@T), which is a memory screening test, capable for discriminating between subjects with subjective memory complaints (SMC) (without objective memory impairment) and patients with amnestic mild cognitive impairment (A-MCI) and with mild Alzheimer's disease (AD). The discriminative validity was assessed in a sample of 37 subjects with SMC, 50 patients with A-MCI according to the Petersen-criteria, and 66 patients with mild AD (global deterioration scale: 4 stage) according to the NINCDS-ADRDA criteria. M@T mean scores were significantly different among groups: 39.7 + or - 5.1 (+ or - S.D.) in the SMC group, 31.5 + or - 3.9 in the A-MCI group, and 21.8 + or - 4.9 in mild AD. A cut-off score of 37 points had a sensitivity of 96% and a specificity of 70% to differentiate A-MCI from SMC (ABC = 0.88). A cut-off score of 33 points had a sensitivity of 100% and a specificity of 86% to differentiate mild AD from SMC sample (AUC = 0.99). We conclude that the M@T provides efficient and valid discrimination between SMC subjects and A-MCI, and between SMC subjects and mild AD.
Abstract: Objective: To describe a novel mutation (K239N) in the PSEN1 associated with familial Alzheimer's disease (AD). Methods and results: The proband was a man who developed cognitive decline with marked behavioural abnormalities at age 57. At age 70, he was admitted into a psychiatric facility because of aggressiveness and a suicide attempt. Family history was consistent with autosomal dominant AD. One of the two other family members studied presented also with prominent behavioural symptoms at age 42 and has also been forced into a psychiatric facility because of aggressiveness at age 56. The remainder patient has presented a prototypical AD, but starting at age 71. Direct sequencing of PSEN1 in the three living affected members disclosed a heterozygous G to C transition in exon 7 of PSEN1 leading to the K239N mutation. Conclusion: The K239N mutation is associated with autosomal dominant AD with a wide range of age of onset and incomplete penetrance at the age of 65, prominent behavioural features and slow progression.
Abstract: We report the clinical, pathologic, and biochemical characteristics of the recently described amyloid precursor protein (APP) I716F mutation. We present the clinical findings of individuals carrying the APP I716F mutation and the neuropathologic examination of the proband. The mutation was found in a patient with Alzheimer disease with onset at the age of 31 years and death at age 36 years and who had a positive family history of early-onset Alzheimer disease. Neuropathologic examination showed abundant diffuse amyloid plaques mainly composed of amyloid-beta42 and widespread neurofibrillary pathology. Lewy bodies were found in the amygdala. Chinese hamster ovary cells transfected with this mutation showed a marked increase in the amyloid-beta42/40 ratio and APP C-terminal fragments and a decrease in APP intracellular domain production, suggesting reduced APP proteolysis by gamma-secretase. Taken together, these findings indicate that the APP I716F mutation is associated with the youngest age of onset for this locus and strengthen the inverse association between amyloid-beta42/40 ratio and age of onset. The mutation leads to a protein that is poorly processed by gamma-secretase. This loss of function may be an additional mechanism by which some mutations around the gamma-secretase cleavage site lead to familial Alzheimer disease.
Abstract: INTRODUCTION. Semantic dementia is characterised by a progressive loss of semantic content that initially affects the capacity to name things, and is associated with asymmetric atrophy of the anterior temporal lobes. In Alzheimer's disease (AD) with predominant compromise of language, anomia is also the main symptom. The study examined the capacity to relearn vocabulary of two patients, each exhibiting one of these two forms of degenerative anomia. CASE REPORTS. The two cases presented similar ages, gender, levels of schooling and degree of compromise. Their capacity to name a list of 40 pictures was evaluated at baseline, following 20 sessions of relearning, at one month and at six months. The patient with semantic dementia named 25/40 objects at baseline, 40/40 after relearning, 35/40 at one month and 27/40 at six months. The patient with AD named 29/40 at baseline, 30/40 after relearning, 29/40 at one month and 32/40 at six months. No intrusions were observed following relearning. CONCLUSIONS. The patient with semantic dementia was able to relearn all the vocabulary she was shown, even though she lost everything she had acquired after treatment was interrupted. The AD patient did not improve her naming capacity with therapy. These differences suggest that the learning and consolidation circuits are affected in different ways. Subjects with semantic dementia, but not those with AD, could benefit from word relearning strategies with this method.
Abstract: OBJECTIVE: Neuroimaging techniques are able to mark distinct structural and metabolic changes in patients at risk for Alzheimer's disease (AD). The objectives of the study were to compare regional grey matter density in prodromal Alzheimer's disease (Prd-AD), amnestic mild cognitive impairment (aMCI), mild AD patients and healthy aged controls, to study prospectively their clinical and neuropsychological evolution and to evaluate the accuracy of proposed Prd-AD criteria to detect AD conversion. METHODS: Twenty-seven controls, 16 aMCI, 32 Prd-AD and 34 probable mild AD were included. Evaluations were performed at baseline and annually during a 2-year prospective follow-up period. Focal grey matter density loss was calculated through voxel based morphometry analysis at baseline. Sensitivity, specificity, positive and negative predictive values of Prd-AD criteria were calculated. RESULTS: Pr-AD, compared to aMCI, had decreased grey matter density mainly in both hippocampi and inferior temporal cortex (p < 0.001). AD patients compared with Prd-AD, presented grey matter loss in the right posterior and lateral temporal, inferior frontal and parietal cortex and left posterior temporal (p < 0.001). After 2-year follow-up, Prd-AD patients presented higher cognitive decline and conversion rate to AD (83.3%) than aMCI (21.4%; p < 0.0001). The sensitivity of Prd-AD criteria to predict AD conversion in the group of amnestic patients was 89.3; specificity 68.7; positive predictive value 83.3 and negative predictive value 78.6. CONCLUSION: Magnetic resonance imaging provides evidence of more severe temporal grey matter loss in Prd-AD group than in a-MCI. The proposed criteria present good accuracy to predict AD conversion among amnestic patients.
Abstract: Cognitive reserve (CR) defines the capacity of the adult brain to cope with pathology in order to minimize symptomatology. Relevant lifetime social, cognitive and leisure activities represent measurable proxies of cognitive CR but its underlying structural and functional brain mechanisms remain poorly understood. We investigated the relationship between CR and regional gray matter volumes and brain activity (fMRI) during a working memory task in a sample of healthy elders. Participants with higher CR had larger gray matter volumes in frontal and parietal regions. Conversely, a negative correlation was observed between CR and fMRI signal in the right inferior frontal cortex, suggesting increased neural efficiency for higher CR individuals. This latter association however disappeared after adjusting for gray matter images in a voxel-based manner. Altogether, present results may reflect both general and specific anatomofunctional correlates of CR in the healthy elders. Thus, whereas heteromodal anterior and posterior gray matter regions correspond to passive (i.e. morphological) correlates of CR unrelated to functional brain activation during this particular cognitive task, the right inferior frontal area reveals interactions between active and passive components of CR related to the cognitive functions tested in the fMRI study.
Abstract: The 14-3-3 protein test has been shown to support the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) when associated with an adequate clinical context, and a high differential potential for the diagnosis of sporadic CJD has been attributed to other cerebrospinal fluid (CSF) proteins such as tau protein, S100b and neuron specific enolase (NSE). So far there has been only limited information available about biochemical markers in genetic transmissible spongiform encephalopathies (gTSE), although they represent 10-15% of human TSEs. In this study, we analyzed CSF of 174 patients with gTSEs for 14-3-3 (n = 166), tau protein (n = 78), S100b (n = 46) and NSE (n = 50). Levels of brain-derived proteins in CSF varied in different forms of gTSE. Biomarkers were found positive in the majority of gCJD (81%) and insert gTSE (69%), while they were negative in most cases of fatal familial insomnia (13%) and Gerstmann-Sträussler-Scheinker syndrome (10%). Disease duration and codon 129 genotype influence the findings in a different way than in sporadic CJD.
Abstract: INTRODUCTION: Cognitive reserve (CR) reflects the capacity of the brain to endure neuropathology in order to minimize clinical manifestations. Previous studies showed that CR modulates the patterns of brain activity in both healthy and clinical populations. In the present study we sought to determine whether reorganizations of functional brain resources linked to CR could already be observed in amnestic mild cognitive impairment (a-MCI) and mild Alzheimer's disease (AD) patients when performing a task corresponding to an unaffected cognitive domain. We further investigated if activity in regions showing task-induced deactivations, usually identified as pertaining to the default-mode network (DMN), was also influenced by CR. METHODS: Fifteen healthy elders, 15 a-MCI and 15 AD patients underwent functional magnetic resonance imaging (fMRI) during a speech comprehension task. Differences in the regression of slopes between CR proxies and blood-oxygen-level dependent (BOLD) signals across clinical groups were investigated for activation and deactivation areas. Correlations between significant fMRI results and a language comprehension test were also computed. RESULTS: Among a-MCI and AD we observed positive correlations between CR measures and BOLD signals in task-induced activation areas directly processing speech, as well as greater deactivations in regions of the DMN. These relationships were inverted in healthy elders. We found no evidence that these results were mediated by gray matter volumes. Increased activity in left frontal areas and decreased activity in the anterior cingulate were related to better language comprehension in clinical evaluations. CONCLUSIONS: The present findings provide evidence that the neurofunctional reorganizations related to CR among a-MCI and AD patients can be seen even when considering a preserved cognitive domain, being independent of gray matter atrophy. Areas showing both task-induced activations and deactivations are modulated by CR in an opposite manner when considering healthy elders versus patients. Brain reorganizations facilitated by CR may reflect behavioral compensatory mechanisms.
Abstract: Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in patients with early-onset (<65years) Alzheimer's disease (AD). We performed a screening for mutations in the coding regions of presenilins, as well as exons 16 and 17 of the APP gene in a total of 231 patients from the Iberian peninsular with a clinical diagnosis of early-onset AD (mean age at onset of 52.9 years; range 31-64). We found three novel mutations in PSEN1, one novel mutation in PSEN2, and a novel mutation in the APP gene. Four previously described mutations in PSEN1 were also found. The same analysis was carried in 121 elderly healthy controls from the Iberian peninsular, and a set of 130 individuals from seven African populations belonging to the Centre d'Etude du Polymorphisme Humain-Human Genome Diversity Panel (CEPH-HGDP), in order to determine the extent of normal variability in these genes. Interestingly, in the latter series, we found five new non-synonymous changes in all three genes and a presenilin 2 variant (R62H) that has been previously related to AD. In some of these mutations, the pathologic consequence is uncertain and needs further investigation. To address this question we propose and use a systematic algorithm to classify the putative pathology of AD mutations.
