The term cognitive reserve describes the capacity of the adult brain to minimise the clinical man... more The term cognitive reserve describes the capacity of the adult brain to minimise the clinical manifestation of a neurodegenerative process. The acquisition of cognitive reserve has been linked to the performance of certain intellectual and cognitive activities throughout the whole of the individual's life. To create a new cognitive reserve questionnaire (CRQ), to establish its relation with the cognitive functions and to obtain the standard values in the cognitively healthy elderly Spanish population. The sample consisted of 55 cognitively healthy controls and 53 patients with Alzheimer's disease. All the subjects were asked to complete the CRQ, which consists of eight items with several different possible answers, together with a brief neuropsychological battery. Age had no significant influence on the score obtained on the CRQ in either of the groups, yet the number of years of schooling did exert a significant effect. In both groups significant correlations were found bet...
To investigate the relationship between performance in language tests and levels of brain metabol... more To investigate the relationship between performance in language tests and levels of brain metabolites in two selected left temporal lobe regions. Ninety-five subjects were included: 26 controls, 30 amnestic mild cognitive impairment subjects, 27 Alzheimer's disease and 12 frontotemporal lobar degeneration (FTLD) patients. Language was assessed by a naming test: Boston Naming Test (BNT) and by a semantic verbal fluency test. Other cognitive functions: verbal and visual memory, visual perception, attention and executive function, and praxis were also assessed. Single voxel magnetic resonance spectroscopy was obtained in the left temporal pole (L-TPOLE), and in the left posterior temporoparietal region (L-TPAR). BNT scores were significantly associated with N-acetylaspartate/creatine ratios (r = 0.45; p < 0.001) and choline/creatine ratios (r = 0.33; p < 0.005) in the L-TPOLE. No significant associations were found between BNT and metabolite levels in the L-TPAR. No significant associations were found between the semantic verbal fluency test and other cognitive tests and metabolite levels either in the L-TPOLE or in the L-TPAR. Naming performance is related to metabolite levels in the anterior L-TPOLE.
The term 'posterior cortical atrophy' (PCA) refers to a neurodegenerative syndrome that i... more The term 'posterior cortical atrophy' (PCA) refers to a neurodegenerative syndrome that is characterised by progressive alteration of the higher visual-perceptual and/or visual-spatial functions, which often presents Alzheimer's disease (AD). To describe the value of neuropsychological tests in the differential diagnosis of patients with PCA versus patients with typical AD. The sample was made up of four patients with PCA, four patients with initial typical AD with no significant differences in the degree of cognitive impairment according to the Minimental State Examination and seven cognitively healthy controls. Subjects were administered a full neuropsychological battery of tests for memory, language, praxias, executive functions, and visual-perceptual and visual-spatial capacities. The statistical analysis was performed using the Mann-Whitney U test for non-parametric tests and independent samples. In the neuropsychological study, scores were significantly lower in th...
Most cases of early-onset Alzheimer's disease (EOAD) are sporadic. A minority of EOAD are cau... more Most cases of early-onset Alzheimer's disease (EOAD) are sporadic. A minority of EOAD are caused by specific genetic defects in PSEN1, PSEN2, or AβPP genes. Magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarker comparisons between sporadic and monogenic EOAD are practically inexistent. CSF and MRI data from 14 amnestic-onset sporadic EOAD (sEOAD) subjects were compared with data from 8 symptomatic PSEN1 mutation carriers (PSEN1) and 14 age-matched cognitively-preserved controls. CSF concentrations of amyloid-β (Aβ)(42), total tau (t-tau), and phosphorylated tau (p-tau) were determined. Cortical thickness (CTh) and grey matter loss were compared between groups and correlated with CSF biomarkers. PSEN1 had significantly lower CSF Aβ(42) levels compared to sEOAD (mean 244.8 pg/ml versus 381.4 pg/ml; p = 0.006), but no differences in t-tau or p-tau. Both sEOAD and PSEN1 showed widespread CTh loss in AD target areas when compared with controls. No differences were ...
Recently, there has been an increased interest in the use of automatically segmented subfields of... more Recently, there has been an increased interest in the use of automatically segmented subfields of the human hippocampal formation derived from magnetic resonance imaging (MRI). However, little is known about the test-retest reproducibility of such measures, particularly in the context of multisite studies. Here, we report the reproducibility of automated Freesurfer hippocampal subfields segmentations in 65 healthy elderly enrolled in a consortium of 13 3T MRI sites (five subjects per site). Participants were scanned in two sessions (test and retest) at least one week apart. Each session included two anatomical 3D T1 MRI acquisitions harmonized in the consortium. We evaluated the test-retest reproducibility of subfields segmentation (i) to assess the effects of averaging two within-session T1 images and (ii) to compare subfields with whole hippocampus volume and spatial reliability. We found that within-session averaging of two T1 images significantly improved the reproducibility of ...
Early-onset cognitive impairment diagnosis is often challenging due to the overlapping symptoms b... more Early-onset cognitive impairment diagnosis is often challenging due to the overlapping symptoms between the different degenerative and non-degenerative conditions. We aimed to evaluate the usefulness of cerebrospinal fluid (CSF) biomarkers in early-onset cognitive impairment differential diagnosis, to assess their contribution to the diagnosis of Alzheimer's disease (AD) based on the new National Institute of Aging-Alzheimer's Association (NIA-AA) workgroup's recommendations and their capacity to predict subsequent decline in early-onset mild cognitive impairment (MCI). 37 controls and 120 patients (clinical onset <65 years) with diagnosis based on criteria available in 2009 (51 MCI, 42 AD, 10 frontotemporal dementia (FTD), 3 posterior cortical atrophy, and 14 primary progressive aphasia (PPA)) were included. In addition, all subjects were also reclassified according to the revised criteria for MCI, AD, FTD, and PPA, excluding CSF data. We assessed the impact of addin...
Familial Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;am... more Familial Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease provides the opportunity to investigate brain changes even before the symptoms onset. We performed a structural magnetic resonance imaging (MRI) study in 38 participants from families with presenilin 1 gene mutations: 11 symptomatic mutation carriers, 13 asymptomatic mutation carriers (AMC), with a mean of 16.22 years before the estimated appearance of symptoms, and 14 noncarriers. A subset of subjects was studied longitudinally 2 and 4 years after the first scan. We found decreased cortical thickness (CTh) and volume in cortical and subcortical structures in symptomatic mutation carriers, with progressive loss over time. In AMC, we found increased CTh and volume in temporoparietal regions and in precuneus-posterior cingulate compared with controls at baseline. Longitudinal studies in AMC, by contrast, showed accelerated rates of CTh loss in precuneus-posterior cingulate and superior parietal, right lateral temporal and left orbitofrontal, and middle frontal regions. These findings suggest that brain structure in presenilin 1 mutation carriers follows nonlinear trajectories, with regional increases during the very early presymptomatic period. Initial neuroinflammation and/or accumulation of amyloid species followed by neurodegeneration, or congenital morphometric differences, may explain the observed features.
Mutations in the presenilin 1 (PSEN1) gene are the most frequent cause of familial Alzheimer&... more Mutations in the presenilin 1 (PSEN1) gene are the most frequent cause of familial Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD), with at least 182 different mutations published to date. We report a 48-year-old woman (age at onset 47 years) who presented a progressive alteration of episodic memory, spatial disorientation, apathy, language disturbances and neglect of personal care. Her MMSE score was 20/30. The patient presented an unusually rapid deterioration and at 6 months follow-up her cognitive and functional status had worsened considerably (MMSE score of 11). Cranial MRI showed a bilateral atrophy with temporal and parietal predominance and the quantification of AD CSF biomarkers showed the typical AD signature. Family history evidenced an autosomal dominant pattern of inheritance. Mutational screening was performed by direct sequencing of exons 3-12 of PSEN1. The patient presented the 3/3 APOE genotype. Genetic analysis revealed a nucleotide substitution in exon 7 of PSEN1 gene, producing a missense mutation in codon 235 from leucine amino acid to arginine (L235R). This amino acid is conserved between presenilin-1 and presenilin-2 proteins. The L235R mutation had not been previously reported, although other mutations in the same residue have also been associated with familial early-onset AD, providing support for the importance of this residue for the presenilin-1 function.
Familial Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;am... more Familial Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease allows studies in the preclinical phases of the disease. We studied cerebrospinal fluid (CSF) amyloid β1-42 (Aβ1-42), total tau (t-tau) and phospho-tau181 (p-tau) levels in PSEN1 families and correlated the results with the genetic status, age and clinical stage. Thirteen subjects from 3 families with 2 PSEN1 mutations (L286P, M139T) were recruited from the genetic counseling program for familial dementia. Eight mutation carriers (MC) and 5 noncarriers (NC) underwent clinical and cognitive evaluations. CSF concentrations were obtained by ELISA methodology. Symptomatic MC presented reduced CSF Aβ1-42 (mean = 175 pg/ml) and elevated t-tau (mean = 635 pg/ml) compared to controls, but not asymptomatic MC (mean = 684 and 255 pg/ml, respectively) at a median of -12.8 years from the predicted disease onset (adjusted age). Aβ1-42 levels presented an inverse correlation with the adjusted age (r = -1, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0. 01) in asymptomatic MC, but not in symptomatic MC or NC. t-tau presented a trend towards a negative correlation with Mini Mental State Examination (MMSE; r = -0.949, p = 0.051) in symptomatic MC but not in asymptomatic MC. In the whole group of MC, t-tau presented a significant positive correlation with Clinical Dementia Rating sum of boxes (r = 0.913, p = 0.002) and a negative correlation with MMSE (r = -0.946, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). CSF Aβ1-42 levels correlate with time to disease onset in asymptomatic MC to reach floor levels when symptoms appear. CSF t-tau levels become elevated in symptomatic MC and correlate with clinical severity. These findings may suggest that the changes in Aβ1-42 precede t-tau elevation in PSEN1 MC.
Cerebrospinal fluid (CSF) biomarkers, such as Aβ(42), total-tau and phosphorylated-tau(181) refle... more Cerebrospinal fluid (CSF) biomarkers, such as Aβ(42), total-tau and phosphorylated-tau(181) reflect neuropathological changes of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD). We studied these biomarkers in 24 controls and 19 subjects with subjective memory complaints, and we distinguished different CSF profiles: normal (group 1, 55.8%), only pathologic Aβ(42) (group 2, 27.9%), pathologic Aβ(42) plus pathologic total-tau and/or phosphorylated-tau(181) (group 3, 7%), and only pathologic total-tau and phosphorylated-tau(181) (group 4, 9.3%). Group 2 could represent an earlier phase of preclinical AD than group 3, and group 4 an unknown etiology.
Journal of Clinical and Experimental Neuropsychology, 2008
The objective of this study was to obtain normative data for naming and semantic memory (SM) test... more The objective of this study was to obtain normative data for naming and semantic memory (SM) tests in the elderly Spanish population. A total of 121 Spanish-speaking senior citizens were assessed with the Boston Naming Test (BNT). Of these, 79 were assessed with the Semantic Fluency Test (Sem-Flu) and 72 with the Pyramids and Palm Trees Test (PPT). Mean scores were 49.6 (SD = 5.6) for the BNT, 49.6 (SD = 2.2) for the PPT, and 16.9 (SD = 4.9) for the Sem-Flu. All SM tests were significantly influenced by participants&amp;amp;amp;amp;amp;amp;#39; level of education (p &amp;amp;amp;amp;amp;amp;lt; .01). The BNT was also significantly influenced by gender. A significant positive association was found between naming and SM tests (p &amp;amp;amp;amp;amp;amp;lt; .01). Normative data for naming and SM tests could be useful in clinical assessment and research in Spanish-speaking dementia patients.
Cognitive reserve (CR) reflects the capacity of the brain to endure neuropathology in order to mi... more 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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;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. 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. 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. 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.
The term cognitive reserve describes the capacity of the adult brain to minimise the clinical man... more The term cognitive reserve describes the capacity of the adult brain to minimise the clinical manifestation of a neurodegenerative process. The acquisition of cognitive reserve has been linked to the performance of certain intellectual and cognitive activities throughout the whole of the individual's life. To create a new cognitive reserve questionnaire (CRQ), to establish its relation with the cognitive functions and to obtain the standard values in the cognitively healthy elderly Spanish population. The sample consisted of 55 cognitively healthy controls and 53 patients with Alzheimer's disease. All the subjects were asked to complete the CRQ, which consists of eight items with several different possible answers, together with a brief neuropsychological battery. Age had no significant influence on the score obtained on the CRQ in either of the groups, yet the number of years of schooling did exert a significant effect. In both groups significant correlations were found bet...
To investigate the relationship between performance in language tests and levels of brain metabol... more To investigate the relationship between performance in language tests and levels of brain metabolites in two selected left temporal lobe regions. Ninety-five subjects were included: 26 controls, 30 amnestic mild cognitive impairment subjects, 27 Alzheimer&#39;s disease and 12 frontotemporal lobar degeneration (FTLD) patients. Language was assessed by a naming test: Boston Naming Test (BNT) and by a semantic verbal fluency test. Other cognitive functions: verbal and visual memory, visual perception, attention and executive function, and praxis were also assessed. Single voxel magnetic resonance spectroscopy was obtained in the left temporal pole (L-TPOLE), and in the left posterior temporoparietal region (L-TPAR). BNT scores were significantly associated with N-acetylaspartate/creatine ratios (r = 0.45; p &lt; 0.001) and choline/creatine ratios (r = 0.33; p &lt; 0.005) in the L-TPOLE. No significant associations were found between BNT and metabolite levels in the L-TPAR. No significant associations were found between the semantic verbal fluency test and other cognitive tests and metabolite levels either in the L-TPOLE or in the L-TPAR. Naming performance is related to metabolite levels in the anterior L-TPOLE.
The term 'posterior cortical atrophy' (PCA) refers to a neurodegenerative syndrome that i... more The term 'posterior cortical atrophy' (PCA) refers to a neurodegenerative syndrome that is characterised by progressive alteration of the higher visual-perceptual and/or visual-spatial functions, which often presents Alzheimer's disease (AD). To describe the value of neuropsychological tests in the differential diagnosis of patients with PCA versus patients with typical AD. The sample was made up of four patients with PCA, four patients with initial typical AD with no significant differences in the degree of cognitive impairment according to the Minimental State Examination and seven cognitively healthy controls. Subjects were administered a full neuropsychological battery of tests for memory, language, praxias, executive functions, and visual-perceptual and visual-spatial capacities. The statistical analysis was performed using the Mann-Whitney U test for non-parametric tests and independent samples. In the neuropsychological study, scores were significantly lower in th...
Most cases of early-onset Alzheimer's disease (EOAD) are sporadic. A minority of EOAD are cau... more Most cases of early-onset Alzheimer's disease (EOAD) are sporadic. A minority of EOAD are caused by specific genetic defects in PSEN1, PSEN2, or AβPP genes. Magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarker comparisons between sporadic and monogenic EOAD are practically inexistent. CSF and MRI data from 14 amnestic-onset sporadic EOAD (sEOAD) subjects were compared with data from 8 symptomatic PSEN1 mutation carriers (PSEN1) and 14 age-matched cognitively-preserved controls. CSF concentrations of amyloid-β (Aβ)(42), total tau (t-tau), and phosphorylated tau (p-tau) were determined. Cortical thickness (CTh) and grey matter loss were compared between groups and correlated with CSF biomarkers. PSEN1 had significantly lower CSF Aβ(42) levels compared to sEOAD (mean 244.8 pg/ml versus 381.4 pg/ml; p = 0.006), but no differences in t-tau or p-tau. Both sEOAD and PSEN1 showed widespread CTh loss in AD target areas when compared with controls. No differences were ...
Recently, there has been an increased interest in the use of automatically segmented subfields of... more Recently, there has been an increased interest in the use of automatically segmented subfields of the human hippocampal formation derived from magnetic resonance imaging (MRI). However, little is known about the test-retest reproducibility of such measures, particularly in the context of multisite studies. Here, we report the reproducibility of automated Freesurfer hippocampal subfields segmentations in 65 healthy elderly enrolled in a consortium of 13 3T MRI sites (five subjects per site). Participants were scanned in two sessions (test and retest) at least one week apart. Each session included two anatomical 3D T1 MRI acquisitions harmonized in the consortium. We evaluated the test-retest reproducibility of subfields segmentation (i) to assess the effects of averaging two within-session T1 images and (ii) to compare subfields with whole hippocampus volume and spatial reliability. We found that within-session averaging of two T1 images significantly improved the reproducibility of ...
Early-onset cognitive impairment diagnosis is often challenging due to the overlapping symptoms b... more Early-onset cognitive impairment diagnosis is often challenging due to the overlapping symptoms between the different degenerative and non-degenerative conditions. We aimed to evaluate the usefulness of cerebrospinal fluid (CSF) biomarkers in early-onset cognitive impairment differential diagnosis, to assess their contribution to the diagnosis of Alzheimer's disease (AD) based on the new National Institute of Aging-Alzheimer's Association (NIA-AA) workgroup's recommendations and their capacity to predict subsequent decline in early-onset mild cognitive impairment (MCI). 37 controls and 120 patients (clinical onset <65 years) with diagnosis based on criteria available in 2009 (51 MCI, 42 AD, 10 frontotemporal dementia (FTD), 3 posterior cortical atrophy, and 14 primary progressive aphasia (PPA)) were included. In addition, all subjects were also reclassified according to the revised criteria for MCI, AD, FTD, and PPA, excluding CSF data. We assessed the impact of addin...
Familial Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;am... more Familial Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease provides the opportunity to investigate brain changes even before the symptoms onset. We performed a structural magnetic resonance imaging (MRI) study in 38 participants from families with presenilin 1 gene mutations: 11 symptomatic mutation carriers, 13 asymptomatic mutation carriers (AMC), with a mean of 16.22 years before the estimated appearance of symptoms, and 14 noncarriers. A subset of subjects was studied longitudinally 2 and 4 years after the first scan. We found decreased cortical thickness (CTh) and volume in cortical and subcortical structures in symptomatic mutation carriers, with progressive loss over time. In AMC, we found increased CTh and volume in temporoparietal regions and in precuneus-posterior cingulate compared with controls at baseline. Longitudinal studies in AMC, by contrast, showed accelerated rates of CTh loss in precuneus-posterior cingulate and superior parietal, right lateral temporal and left orbitofrontal, and middle frontal regions. These findings suggest that brain structure in presenilin 1 mutation carriers follows nonlinear trajectories, with regional increases during the very early presymptomatic period. Initial neuroinflammation and/or accumulation of amyloid species followed by neurodegeneration, or congenital morphometric differences, may explain the observed features.
Mutations in the presenilin 1 (PSEN1) gene are the most frequent cause of familial Alzheimer&... more Mutations in the presenilin 1 (PSEN1) gene are the most frequent cause of familial Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD), with at least 182 different mutations published to date. We report a 48-year-old woman (age at onset 47 years) who presented a progressive alteration of episodic memory, spatial disorientation, apathy, language disturbances and neglect of personal care. Her MMSE score was 20/30. The patient presented an unusually rapid deterioration and at 6 months follow-up her cognitive and functional status had worsened considerably (MMSE score of 11). Cranial MRI showed a bilateral atrophy with temporal and parietal predominance and the quantification of AD CSF biomarkers showed the typical AD signature. Family history evidenced an autosomal dominant pattern of inheritance. Mutational screening was performed by direct sequencing of exons 3-12 of PSEN1. The patient presented the 3/3 APOE genotype. Genetic analysis revealed a nucleotide substitution in exon 7 of PSEN1 gene, producing a missense mutation in codon 235 from leucine amino acid to arginine (L235R). This amino acid is conserved between presenilin-1 and presenilin-2 proteins. The L235R mutation had not been previously reported, although other mutations in the same residue have also been associated with familial early-onset AD, providing support for the importance of this residue for the presenilin-1 function.
Familial Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;am... more Familial Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease allows studies in the preclinical phases of the disease. We studied cerebrospinal fluid (CSF) amyloid β1-42 (Aβ1-42), total tau (t-tau) and phospho-tau181 (p-tau) levels in PSEN1 families and correlated the results with the genetic status, age and clinical stage. Thirteen subjects from 3 families with 2 PSEN1 mutations (L286P, M139T) were recruited from the genetic counseling program for familial dementia. Eight mutation carriers (MC) and 5 noncarriers (NC) underwent clinical and cognitive evaluations. CSF concentrations were obtained by ELISA methodology. Symptomatic MC presented reduced CSF Aβ1-42 (mean = 175 pg/ml) and elevated t-tau (mean = 635 pg/ml) compared to controls, but not asymptomatic MC (mean = 684 and 255 pg/ml, respectively) at a median of -12.8 years from the predicted disease onset (adjusted age). Aβ1-42 levels presented an inverse correlation with the adjusted age (r = -1, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0. 01) in asymptomatic MC, but not in symptomatic MC or NC. t-tau presented a trend towards a negative correlation with Mini Mental State Examination (MMSE; r = -0.949, p = 0.051) in symptomatic MC but not in asymptomatic MC. In the whole group of MC, t-tau presented a significant positive correlation with Clinical Dementia Rating sum of boxes (r = 0.913, p = 0.002) and a negative correlation with MMSE (r = -0.946, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). CSF Aβ1-42 levels correlate with time to disease onset in asymptomatic MC to reach floor levels when symptoms appear. CSF t-tau levels become elevated in symptomatic MC and correlate with clinical severity. These findings may suggest that the changes in Aβ1-42 precede t-tau elevation in PSEN1 MC.
Cerebrospinal fluid (CSF) biomarkers, such as Aβ(42), total-tau and phosphorylated-tau(181) refle... more Cerebrospinal fluid (CSF) biomarkers, such as Aβ(42), total-tau and phosphorylated-tau(181) reflect neuropathological changes of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD). We studied these biomarkers in 24 controls and 19 subjects with subjective memory complaints, and we distinguished different CSF profiles: normal (group 1, 55.8%), only pathologic Aβ(42) (group 2, 27.9%), pathologic Aβ(42) plus pathologic total-tau and/or phosphorylated-tau(181) (group 3, 7%), and only pathologic total-tau and phosphorylated-tau(181) (group 4, 9.3%). Group 2 could represent an earlier phase of preclinical AD than group 3, and group 4 an unknown etiology.
Journal of Clinical and Experimental Neuropsychology, 2008
The objective of this study was to obtain normative data for naming and semantic memory (SM) test... more The objective of this study was to obtain normative data for naming and semantic memory (SM) tests in the elderly Spanish population. A total of 121 Spanish-speaking senior citizens were assessed with the Boston Naming Test (BNT). Of these, 79 were assessed with the Semantic Fluency Test (Sem-Flu) and 72 with the Pyramids and Palm Trees Test (PPT). Mean scores were 49.6 (SD = 5.6) for the BNT, 49.6 (SD = 2.2) for the PPT, and 16.9 (SD = 4.9) for the Sem-Flu. All SM tests were significantly influenced by participants&amp;amp;amp;amp;amp;amp;#39; level of education (p &amp;amp;amp;amp;amp;amp;lt; .01). The BNT was also significantly influenced by gender. A significant positive association was found between naming and SM tests (p &amp;amp;amp;amp;amp;amp;lt; .01). Normative data for naming and SM tests could be useful in clinical assessment and research in Spanish-speaking dementia patients.
Cognitive reserve (CR) reflects the capacity of the brain to endure neuropathology in order to mi... more 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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;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. 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. 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. 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.
Uploads
Papers by Beatriz Bosch