Journal of Alzheimer's disease : JAD, Jan 27, 2015
We report a biomarker and genetic evaluation of four patients with cerebral amyloid angiopathy-re... more We report a biomarker and genetic evaluation of four patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) treated with corticosteroids. Patients presented with focal symptomatology and cognitive impairment. MRI revealed cortical microbleeds and asymmetrical hyperintense white matter lesions (WML). Cerebrospinal fluid (CSF) biomarker analyses showed increased anti-Aβ autoantibodies, t-Tau, and p-Tau and decreased Aβ 40 and Aβ 42. After treatment, focal symptomatology disappeared, and WML and anti-Aβ autoantibodies decreased. The APOEɛ4 allele was overrepresented. Florbetapir-PET showed cortical deposition with lower retention in swollen areas. In the case of suspected CAA-ri, both CSF anti-Aβ autoantibodies levels and Florbetapir-PET could provide highly useful data to guide the correct diagnosis, potentially avoiding brain biopsy.
Journal of Alzheimer's disease : JAD, Jan 10, 2015
Progranulin is implicated in frontotemporal dementia (FTD), but its role in other neurodegenerati... more Progranulin is implicated in frontotemporal dementia (FTD), but its role in other neurodegenerative disorders is unknown. To investigate the levels of progranulin (PGRN) in cerebrospinal fluid (CSF) in different neurodegenerative dementias and their correlation with levels in plasma in cognitively normal subjects. We measured PGRN in CSF in 229 patients with amnestic mild cognitive impairment, Alzheimer's disease dementia, sporadic FTD, dementia with Lewy bodies, corticobasal syndrome, or progressive supranuclear palsy. We also measured PGRN in CSF and plasma in 74 cognitively normal individuals. We examined the correlation between PGRN levels in CSF and diagnosis, cortical thickness, genetic factors and other CSF biomarkers. We also investigated the correlation between plasma and CSF levels of PGRN in cognitively normal individuals. CSF levels did not differ across diagnoses or correlate with cortical thickness. Polymorphism rs5848 in GRN influenced CSF PGRN levels, but APOEɛ4 ...
Alzheimer disease is the most common form of dementia in Western countries and the leading cause ... more Alzheimer disease is the most common form of dementia in Western countries and the leading cause of disability in the over-65 population. Apolipoprotein E (APOE) is a multifunctional protein implied in lipid metabolism and neurobiology. Polymorphisms of the APOE gene have been associated with a variety of medical disorders, from arteriosclerosis to AD. A high frequency of the APOE epsilon4 allele has been found in patients with AD and they seem to have a higher risk of developing the disease. Various authors have suggested a possible relationship between the efficacy of cholinesterase inhibitors and the presence of the APOE epsilon4 allele. The purpose of the present study was to compare prospectively the efficacy of rivastigmine in patients with mild to moderately severe AD presenting different polymorphisms of the APOE gene on chromosome 19 and to determine if there was a difference in the response to rivastigmine treatment in AD patients with the APOE epsilon4 allele (heterozygous or homozygous) versus patients who had other forms of APOE, such as epsilon2 and epsilon3. This was an open-label, nonrandomized, multicenter study in patients over 50 years of age diagnosed with mild to moderately severe AD. The results of the analysis of this study indicate that the presence of at least one APOE epsilon4 allele does not determine a difference in the response to treatment with rivastigmine. The data indicate that knowledge of the patient's genotype is not necessary for treatment with rivastigmine. It would be interesting in the future to analyze the interaction between these 2 factors using other available anticholinesterase drugs.
The tubulin alpha 4a (TUBA4A) gene has been recently associated with amyotrophic lateral sclerosi... more The tubulin alpha 4a (TUBA4A) gene has been recently associated with amyotrophic lateral sclerosis. Interestingly, some of the mutation carriers were also diagnosed with frontotemporal degeneration (FTD) or mild cognitive impairment. With the aim to investigate the role of TUBA4A in FTD, we screened TUBA4A in a series of 814 FTD patients from Spain. Our data did not disclose any nonsense or missense variant in the cohort, thus suggesting that TUBA4A mutations are not associated with FTD.
The aims of this study were to assess the criterion validity of Alzheimer's Disea... more The aims of this study were to assess the criterion validity of Alzheimer's Disease Assessment Scale (ADAS) and its cognitive subscale (ADAS-Cog) for the diagnosis of Alzheimer's disease (AD), and to determine their different cut-off scores and sensitivity and specificity values. In addition, we also attempted to study the possible correlations between cognitive scores (ADAS) and functional measures. 451 subjects were studied (254 controls, 86 subjects with mild cognitive impairment and 111 patients with AD). ADAS total score was obtained by adding the cognitive (ADAS-Cog) and non-cognitive (ADAS-Nocog) scales. Scores were adjusted for age and formal education. For assessing the possible correlation between cognitive and functional measures, the following instruments were administered: Rapid Disability Rating Scale-2 (RDRS-2), Blessed Dementia Rating Scale (BDRS) and the Interview for the Deterioration of Daily Living in Dementia (IDDD). ROC curves and Pearson correlation coefficient. ADAS best cut-off score for dementia was > or = 17 providing sensitivity and specificity values of 90.09% and 85.88 % respectively, while for the ADAS-Cog best cut-off score was > or = 12 with sensitivity and specificity values of 89.19 % and 88.53 % respectively. In both cases scores were adjusted for age and formal education. The area under the ROC curve was 0.95 and 0.94 respectively. Highly significant correlations were found for ADAS and 19 ADAS-Cog with the functional scales studied. Both, ADAS and ADAS-Cog report good validity in terms of sensitivity, specificity and as predictive value for AD. Moreover, significant correlations were found between the functional impairment observed in patients with AD and the overall scores achieved in the ADAS and ADAS-Cog.
To investigate CSF markers involved in amyloid precursor protein processing, neuronal damage, and... more To investigate CSF markers involved in amyloid precursor protein processing, neuronal damage, and neuroinflammation in the preclinical stages of Alzheimer disease (AD) and participants with suspected non-Alzheimer pathology (SNAP). We collected CSF from 266 cognitively normal volunteers participating in a cross-sectional multicenter study (the SIGNAL study) to investigate markers involved in amyloid precursor protein processing (Aβ42, sAPPβ, β-secretase activity), neuronal damage (total-tau [t-tau], phospho-tau [p-tau]), and neuroinflammation (YKL-40). We analyzed the relationship among biomarkers, clinical variables, and the APOE genotype, and compared biomarker levels across the preclinical stages of the National Institute on Aging-Alzheimer's Association classification: stage 0, 1, 2, 3, and SNAP. The median age in the whole cohort was 58.8 years (range 39.8-81.6). Participants in stages 2-3 and SNAP had higher levels of YKL-40 than those in stages 0 and 1. Participants with SNAP had higher levels of sAPPβ than participants in stage 0 and 1. No differences were found between stages 0, 1, and 2-3 in sAPPβ and β-secretase activity in CSF. Age correlated with t-tau, p-tau, and YKL-40. It also correlated with Aβ42, but only in APOE ε4 carriers. Aβ42 correlated positively with t-tau, sAPPβ, and YKL-40 in participants with normal Aβ42. Our findings suggest that inflammation in the CNS increases in normal aging and is intimately related to markers of neurodegeneration in the preclinical stages of AD and SNAP. sAPPβ and β-secretase activity are not useful diagnostic or staging markers in preclinical AD.
Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaque... more Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non-AD dementia. To use individual participant data meta-analysis to estimate the prevalence of amyloid positivity on PET in a wide variety of dementia syndromes. The MEDLINE and Web of Science databases were searched from January 2004 to April 2015 for amyloid PET studies. Case reports and studies on neurological or psychiatric diseases other than dementia were excluded. Corresponding authors of eligible cohorts were invited to provide individual participant data. Data were provided for 1359 participants with clinically diagnosed AD and 538 participants with non-AD dementia. The reference groups were 1849 healthy control participants (based on amyloid PET) and an independent sample of 1369 AD participants (based on autopsy). Estimated...
Several controlled clinical trials have demonstrated safety, tolerability, and efficacy of galant... more Several controlled clinical trials have demonstrated safety, tolerability, and efficacy of galantamine in patients with Alzheimer's disease (AD). We present an observational and multicenter study carried out in Spain. Its main objective was the assessment of the safety and tolerability of galantamine in the treatment of mild to moderately severe dementia of the Alzheimer type under real clinical conditions. The study had five visits over a 6-month period. Titration of galantamine was performed on a standard basis. All the adverse events (AE) reported were recorded. Serious AE were particularly considered. Effectiveness was also assessed covering cognitive, functional, behavioral and sleep domains. 723 patients were enrolled but 74 were excluded, a sample of 649 (71% women and 29% men) remaining. A total of 56.3% patients completed all visits. Baseline Mini-Mental mean score was 19,4 (SD: 4,7). Up to 400 AEs were collected from 29.3% of the patients. The commonest AEs were: nause...
The study aimed to investigate the Rapid Disability Rating Scale-2 (RDRS-2) in Alzheimer's di... more The study aimed to investigate the Rapid Disability Rating Scale-2 (RDRS-2) in Alzheimer's disease (AD). Test retest reliability, internal consistency, data of discriminant validity of the scale, correlations with other functional and cognitive measures were analyzed. 451 subjects were assessed: 254 healthy controls, 86 with cognitive impairment but no dementia (CIND) and 111 subjects diagnosed of AD. Total and subscales scores of the RDRS-2 were obtained. The total score is the sum of three subscales: activities of daily living, disability, and special problems. To establish its correlation with other functional scales and cognitive instruments, the following tools were applied: Blessed Dementia Rating Scale (BDRS), Interview for the Deterioration of Daily Living in Dementia (IDDD), Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) and the Mini-Mental State Examination (MMSE). lineal multivariate regression analysis. Crossvalidation. ROC curves. Intraclass coefficie...
The objective is to establish the existence of possible correlations between cognitive measures u... more The objective is to establish the existence of possible correlations between cognitive measures using the a-BT, and functional measures in a population of normal to moderately severe demented subjects. A sample of 107 subjects (42 healthy controls, 19 subjects with mild cognitive impairment and 46 patients with probable Alzheimer's disease) were included in the present study. The instruments of the cognitive measure used was the abbreviated Barcelona Test (a-BT), a test of general cognitive function. Apart from that, the following functional scales, evaluating activities of daily living, were used: Rapid Disability Rating Scale-2 (RDRS-2), Blessed Dementia Rating Scale (BDRS), and Interview for Deterioration in Daily living in Dementia (IDDD). The statistical procedures were the correlations between cognitive and functional measures using Pearson's correlation coefficient. The correlations obtained between the cognitive and all functional measures were all highly significant...
Rivastigmine transdermal patches for the treatment of Alzheimer's disease (AD) ha... more Rivastigmine transdermal patches for the treatment of Alzheimer's disease (AD) have potential benefits compared to capsules because of their sustained absorption through the skin, good local tolerability and reduction of gastrointestinal problems. To assess gastrointestinal and skin tolerability and the need for optimal dose titration of rivastigmine transdermal patches in Alzheimer's disease patients previously treated with oral rivastigmine. A multicenter, randomized, open-label study including patients with mild to moderate AD (DSM-IV) previously treated with rivastigmine capsules (6-12 mg/day) was conducted. Patients were randomized to: continue with capsules for 3 months (n=49) or switch to rivastigmine patch without titration (9.5mg/day for 3 months; n=48), or switch to rivastigmine patch with titration (4.6 mg/day for 1 month followed by 9.5mg/day for 2 months, n=43). Incidence of gastrointestinal adverse events was 6.1% in the group treated orally and 4.2% in the group treated with non-titrated patches (P=.908). Skin tolerability was good (n=15, 16.7%) without any serious adverse events registered. Patch treatment was considered very easy to use by 72% of patients compared with 30% in the group with oral treatment (P=.0005). 60% of patients were satisfied with the patch, while only 14% were satisfied with capsules (P<.0001). Rivastigmine patches have a tolerability profile similar to that shown by capsules, but are associated with greater patient satisfaction.
Atraumatic convexal subarachnoid hemorrhage (cSAH) in elderly patients is a rare entity that has ... more Atraumatic convexal subarachnoid hemorrhage (cSAH) in elderly patients is a rare entity that has been associated with cerebral amyloid angiopathy (CAA) and intracerebral hematomas (ICH). To characterize this entity and to study these associations, 22 patients over 60 with cSAH were included in a multicenter ambispective cohort study. Clinical data, magnetic resonance imaging (MRI) studies, APOE genotyping, and cerebrospinal fluid (CSF) biomarkers were evaluated. Results were compared with data from healthy controls (HC), non-cSAH CAA patients (CAAo), and Alzheimer disease patients. Convexal subarachnoid hemorrhage presented with transient sensory or motor symptoms. At follow-up (median 30.7 months), 5 patients had died, 6 survivors showed functional disability (modified Rankins Scale (mRS)>2), and 12 cognitive impairment. Four patients had prior ICH and six had an ICH during follow-up. CSF-Aß40 and Aß42 levels were lower in cSAH and CAAo compared with HC. Convexal subarachnoid hemorrhage presented an APOE-ɛ2 overrepresentation and CAAo had an APOE-ɛ4 overrepresentation. On MRI, all patients fulfilled CAA-modified Boston criteria and 9 showed cortical ischemia in the surrounding cortex or the vicinity of superficial siderosis. The neuropathologic study, available in one patient, showed severe CAA and advanced Alzheimer-type pathology. Convexal subarachnoid hemorrhage in the elderly is associated with cognitive impairment and lobar ICH occurrence. Our findings support the existence of an underlying CAA pathology.Journal of Cerebral Blood Flow & Metabolism advance online publication, 4 March 2015; doi:10.1038/jcbfm.2015.25.
Amnestic mild cognitive impairment represents, in many cases, the earliest clinical phases of Alz... more Amnestic mild cognitive impairment represents, in many cases, the earliest clinical phases of Alzheimer disease. Anti-inflammatory agents have epidemiologic support as drugs potentially beneficial in Alzheimer disease. In vivo studies have shown that Triflusal and its active metabolite 2-hydroxy-4-trifluoromethyl-benzoic acid have potent anti-inflammatory actions in the central nervous system. We conducted a randomized, double-blind, placebo-controlled trial of Triflusal in patients with amnestic mild cognitive impairment. Subjects were randomly assigned to receive 900 mg of Triflusal or placebo for 18 months. The primary outcome was a change in Cognitive subscale of the Alzheimer Disease Assessment Scale; conversion to dementia was a secondary outcome. A slow rate of recruitment forced a premature cessation of the study. Two hundred and fifty-seven subjects were enrolled and followed-up for an average of 13 months. The significance level was not reached for the primary outcome even...
Proceedings of the National Academy of Sciences, 2006
Reelin is a glycoprotein that is essential for the correct cytoarchitectonic organization of the ... more Reelin is a glycoprotein that is essential for the correct cytoarchitectonic organization of the developing CNS. Its function in the adult brain is less understood, although it has been proposed that Reelin is involved in signaling pathways linked to neurodegeneration. Here we analyzed Reelin expression in brains and cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients and nondemented controls. We found a 40% increase in the Reelin protein levels in the cortex of AD patients compared with controls. Similar increases were detected at the Reelin mRNA transcriptional level. This expression correlates with parallel increases in CSF but not in plasma samples. Next, we examined whether CSF Reelin levels were also altered in neurological diseases, including frontotemporal dementia, progressive supranuclear palsy, and Parkinson's disease. The Reelin 180-kDa band increased in all of the neurodegenerative disorders analyzed. Moreover, the 180-kDa Reelin levels correlated positively with Tau protein in CSF. Finally, we studied the pattern of Reelin glycosylation by using several lectins and the anti-HNK-1 antibody. Glycosylation differed in plasma and CSF. Furthermore, the pattern of Reelin lectin binding differed between the CSF of controls and in AD. Our results show that Reelin is up-regulated in the brain and CSF in several neurodegenerative diseases and that CSF and plasma Reelin have distinct cellular origins, thereby supporting that Reelin is involved in the pathogenesis of a number of neurodegenerative diseases.
Journal of Alzheimer's disease : JAD, Jan 27, 2015
We report a biomarker and genetic evaluation of four patients with cerebral amyloid angiopathy-re... more We report a biomarker and genetic evaluation of four patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) treated with corticosteroids. Patients presented with focal symptomatology and cognitive impairment. MRI revealed cortical microbleeds and asymmetrical hyperintense white matter lesions (WML). Cerebrospinal fluid (CSF) biomarker analyses showed increased anti-Aβ autoantibodies, t-Tau, and p-Tau and decreased Aβ 40 and Aβ 42. After treatment, focal symptomatology disappeared, and WML and anti-Aβ autoantibodies decreased. The APOEɛ4 allele was overrepresented. Florbetapir-PET showed cortical deposition with lower retention in swollen areas. In the case of suspected CAA-ri, both CSF anti-Aβ autoantibodies levels and Florbetapir-PET could provide highly useful data to guide the correct diagnosis, potentially avoiding brain biopsy.
Journal of Alzheimer's disease : JAD, Jan 10, 2015
Progranulin is implicated in frontotemporal dementia (FTD), but its role in other neurodegenerati... more Progranulin is implicated in frontotemporal dementia (FTD), but its role in other neurodegenerative disorders is unknown. To investigate the levels of progranulin (PGRN) in cerebrospinal fluid (CSF) in different neurodegenerative dementias and their correlation with levels in plasma in cognitively normal subjects. We measured PGRN in CSF in 229 patients with amnestic mild cognitive impairment, Alzheimer's disease dementia, sporadic FTD, dementia with Lewy bodies, corticobasal syndrome, or progressive supranuclear palsy. We also measured PGRN in CSF and plasma in 74 cognitively normal individuals. We examined the correlation between PGRN levels in CSF and diagnosis, cortical thickness, genetic factors and other CSF biomarkers. We also investigated the correlation between plasma and CSF levels of PGRN in cognitively normal individuals. CSF levels did not differ across diagnoses or correlate with cortical thickness. Polymorphism rs5848 in GRN influenced CSF PGRN levels, but APOEɛ4 ...
Alzheimer disease is the most common form of dementia in Western countries and the leading cause ... more Alzheimer disease is the most common form of dementia in Western countries and the leading cause of disability in the over-65 population. Apolipoprotein E (APOE) is a multifunctional protein implied in lipid metabolism and neurobiology. Polymorphisms of the APOE gene have been associated with a variety of medical disorders, from arteriosclerosis to AD. A high frequency of the APOE epsilon4 allele has been found in patients with AD and they seem to have a higher risk of developing the disease. Various authors have suggested a possible relationship between the efficacy of cholinesterase inhibitors and the presence of the APOE epsilon4 allele. The purpose of the present study was to compare prospectively the efficacy of rivastigmine in patients with mild to moderately severe AD presenting different polymorphisms of the APOE gene on chromosome 19 and to determine if there was a difference in the response to rivastigmine treatment in AD patients with the APOE epsilon4 allele (heterozygous or homozygous) versus patients who had other forms of APOE, such as epsilon2 and epsilon3. This was an open-label, nonrandomized, multicenter study in patients over 50 years of age diagnosed with mild to moderately severe AD. The results of the analysis of this study indicate that the presence of at least one APOE epsilon4 allele does not determine a difference in the response to treatment with rivastigmine. The data indicate that knowledge of the patient's genotype is not necessary for treatment with rivastigmine. It would be interesting in the future to analyze the interaction between these 2 factors using other available anticholinesterase drugs.
The tubulin alpha 4a (TUBA4A) gene has been recently associated with amyotrophic lateral sclerosi... more The tubulin alpha 4a (TUBA4A) gene has been recently associated with amyotrophic lateral sclerosis. Interestingly, some of the mutation carriers were also diagnosed with frontotemporal degeneration (FTD) or mild cognitive impairment. With the aim to investigate the role of TUBA4A in FTD, we screened TUBA4A in a series of 814 FTD patients from Spain. Our data did not disclose any nonsense or missense variant in the cohort, thus suggesting that TUBA4A mutations are not associated with FTD.
The aims of this study were to assess the criterion validity of Alzheimer's Disea... more The aims of this study were to assess the criterion validity of Alzheimer's Disease Assessment Scale (ADAS) and its cognitive subscale (ADAS-Cog) for the diagnosis of Alzheimer's disease (AD), and to determine their different cut-off scores and sensitivity and specificity values. In addition, we also attempted to study the possible correlations between cognitive scores (ADAS) and functional measures. 451 subjects were studied (254 controls, 86 subjects with mild cognitive impairment and 111 patients with AD). ADAS total score was obtained by adding the cognitive (ADAS-Cog) and non-cognitive (ADAS-Nocog) scales. Scores were adjusted for age and formal education. For assessing the possible correlation between cognitive and functional measures, the following instruments were administered: Rapid Disability Rating Scale-2 (RDRS-2), Blessed Dementia Rating Scale (BDRS) and the Interview for the Deterioration of Daily Living in Dementia (IDDD). ROC curves and Pearson correlation coefficient. ADAS best cut-off score for dementia was > or = 17 providing sensitivity and specificity values of 90.09% and 85.88 % respectively, while for the ADAS-Cog best cut-off score was > or = 12 with sensitivity and specificity values of 89.19 % and 88.53 % respectively. In both cases scores were adjusted for age and formal education. The area under the ROC curve was 0.95 and 0.94 respectively. Highly significant correlations were found for ADAS and 19 ADAS-Cog with the functional scales studied. Both, ADAS and ADAS-Cog report good validity in terms of sensitivity, specificity and as predictive value for AD. Moreover, significant correlations were found between the functional impairment observed in patients with AD and the overall scores achieved in the ADAS and ADAS-Cog.
To investigate CSF markers involved in amyloid precursor protein processing, neuronal damage, and... more To investigate CSF markers involved in amyloid precursor protein processing, neuronal damage, and neuroinflammation in the preclinical stages of Alzheimer disease (AD) and participants with suspected non-Alzheimer pathology (SNAP). We collected CSF from 266 cognitively normal volunteers participating in a cross-sectional multicenter study (the SIGNAL study) to investigate markers involved in amyloid precursor protein processing (Aβ42, sAPPβ, β-secretase activity), neuronal damage (total-tau [t-tau], phospho-tau [p-tau]), and neuroinflammation (YKL-40). We analyzed the relationship among biomarkers, clinical variables, and the APOE genotype, and compared biomarker levels across the preclinical stages of the National Institute on Aging-Alzheimer's Association classification: stage 0, 1, 2, 3, and SNAP. The median age in the whole cohort was 58.8 years (range 39.8-81.6). Participants in stages 2-3 and SNAP had higher levels of YKL-40 than those in stages 0 and 1. Participants with SNAP had higher levels of sAPPβ than participants in stage 0 and 1. No differences were found between stages 0, 1, and 2-3 in sAPPβ and β-secretase activity in CSF. Age correlated with t-tau, p-tau, and YKL-40. It also correlated with Aβ42, but only in APOE ε4 carriers. Aβ42 correlated positively with t-tau, sAPPβ, and YKL-40 in participants with normal Aβ42. Our findings suggest that inflammation in the CNS increases in normal aging and is intimately related to markers of neurodegeneration in the preclinical stages of AD and SNAP. sAPPβ and β-secretase activity are not useful diagnostic or staging markers in preclinical AD.
Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaque... more Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non-AD dementia. To use individual participant data meta-analysis to estimate the prevalence of amyloid positivity on PET in a wide variety of dementia syndromes. The MEDLINE and Web of Science databases were searched from January 2004 to April 2015 for amyloid PET studies. Case reports and studies on neurological or psychiatric diseases other than dementia were excluded. Corresponding authors of eligible cohorts were invited to provide individual participant data. Data were provided for 1359 participants with clinically diagnosed AD and 538 participants with non-AD dementia. The reference groups were 1849 healthy control participants (based on amyloid PET) and an independent sample of 1369 AD participants (based on autopsy). Estimated...
Several controlled clinical trials have demonstrated safety, tolerability, and efficacy of galant... more Several controlled clinical trials have demonstrated safety, tolerability, and efficacy of galantamine in patients with Alzheimer's disease (AD). We present an observational and multicenter study carried out in Spain. Its main objective was the assessment of the safety and tolerability of galantamine in the treatment of mild to moderately severe dementia of the Alzheimer type under real clinical conditions. The study had five visits over a 6-month period. Titration of galantamine was performed on a standard basis. All the adverse events (AE) reported were recorded. Serious AE were particularly considered. Effectiveness was also assessed covering cognitive, functional, behavioral and sleep domains. 723 patients were enrolled but 74 were excluded, a sample of 649 (71% women and 29% men) remaining. A total of 56.3% patients completed all visits. Baseline Mini-Mental mean score was 19,4 (SD: 4,7). Up to 400 AEs were collected from 29.3% of the patients. The commonest AEs were: nause...
The study aimed to investigate the Rapid Disability Rating Scale-2 (RDRS-2) in Alzheimer's di... more The study aimed to investigate the Rapid Disability Rating Scale-2 (RDRS-2) in Alzheimer's disease (AD). Test retest reliability, internal consistency, data of discriminant validity of the scale, correlations with other functional and cognitive measures were analyzed. 451 subjects were assessed: 254 healthy controls, 86 with cognitive impairment but no dementia (CIND) and 111 subjects diagnosed of AD. Total and subscales scores of the RDRS-2 were obtained. The total score is the sum of three subscales: activities of daily living, disability, and special problems. To establish its correlation with other functional scales and cognitive instruments, the following tools were applied: Blessed Dementia Rating Scale (BDRS), Interview for the Deterioration of Daily Living in Dementia (IDDD), Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) and the Mini-Mental State Examination (MMSE). lineal multivariate regression analysis. Crossvalidation. ROC curves. Intraclass coefficie...
The objective is to establish the existence of possible correlations between cognitive measures u... more The objective is to establish the existence of possible correlations between cognitive measures using the a-BT, and functional measures in a population of normal to moderately severe demented subjects. A sample of 107 subjects (42 healthy controls, 19 subjects with mild cognitive impairment and 46 patients with probable Alzheimer's disease) were included in the present study. The instruments of the cognitive measure used was the abbreviated Barcelona Test (a-BT), a test of general cognitive function. Apart from that, the following functional scales, evaluating activities of daily living, were used: Rapid Disability Rating Scale-2 (RDRS-2), Blessed Dementia Rating Scale (BDRS), and Interview for Deterioration in Daily living in Dementia (IDDD). The statistical procedures were the correlations between cognitive and functional measures using Pearson's correlation coefficient. The correlations obtained between the cognitive and all functional measures were all highly significant...
Rivastigmine transdermal patches for the treatment of Alzheimer's disease (AD) ha... more Rivastigmine transdermal patches for the treatment of Alzheimer's disease (AD) have potential benefits compared to capsules because of their sustained absorption through the skin, good local tolerability and reduction of gastrointestinal problems. To assess gastrointestinal and skin tolerability and the need for optimal dose titration of rivastigmine transdermal patches in Alzheimer's disease patients previously treated with oral rivastigmine. A multicenter, randomized, open-label study including patients with mild to moderate AD (DSM-IV) previously treated with rivastigmine capsules (6-12 mg/day) was conducted. Patients were randomized to: continue with capsules for 3 months (n=49) or switch to rivastigmine patch without titration (9.5mg/day for 3 months; n=48), or switch to rivastigmine patch with titration (4.6 mg/day for 1 month followed by 9.5mg/day for 2 months, n=43). Incidence of gastrointestinal adverse events was 6.1% in the group treated orally and 4.2% in the group treated with non-titrated patches (P=.908). Skin tolerability was good (n=15, 16.7%) without any serious adverse events registered. Patch treatment was considered very easy to use by 72% of patients compared with 30% in the group with oral treatment (P=.0005). 60% of patients were satisfied with the patch, while only 14% were satisfied with capsules (P<.0001). Rivastigmine patches have a tolerability profile similar to that shown by capsules, but are associated with greater patient satisfaction.
Atraumatic convexal subarachnoid hemorrhage (cSAH) in elderly patients is a rare entity that has ... more Atraumatic convexal subarachnoid hemorrhage (cSAH) in elderly patients is a rare entity that has been associated with cerebral amyloid angiopathy (CAA) and intracerebral hematomas (ICH). To characterize this entity and to study these associations, 22 patients over 60 with cSAH were included in a multicenter ambispective cohort study. Clinical data, magnetic resonance imaging (MRI) studies, APOE genotyping, and cerebrospinal fluid (CSF) biomarkers were evaluated. Results were compared with data from healthy controls (HC), non-cSAH CAA patients (CAAo), and Alzheimer disease patients. Convexal subarachnoid hemorrhage presented with transient sensory or motor symptoms. At follow-up (median 30.7 months), 5 patients had died, 6 survivors showed functional disability (modified Rankins Scale (mRS)>2), and 12 cognitive impairment. Four patients had prior ICH and six had an ICH during follow-up. CSF-Aß40 and Aß42 levels were lower in cSAH and CAAo compared with HC. Convexal subarachnoid hemorrhage presented an APOE-ɛ2 overrepresentation and CAAo had an APOE-ɛ4 overrepresentation. On MRI, all patients fulfilled CAA-modified Boston criteria and 9 showed cortical ischemia in the surrounding cortex or the vicinity of superficial siderosis. The neuropathologic study, available in one patient, showed severe CAA and advanced Alzheimer-type pathology. Convexal subarachnoid hemorrhage in the elderly is associated with cognitive impairment and lobar ICH occurrence. Our findings support the existence of an underlying CAA pathology.Journal of Cerebral Blood Flow & Metabolism advance online publication, 4 March 2015; doi:10.1038/jcbfm.2015.25.
Amnestic mild cognitive impairment represents, in many cases, the earliest clinical phases of Alz... more Amnestic mild cognitive impairment represents, in many cases, the earliest clinical phases of Alzheimer disease. Anti-inflammatory agents have epidemiologic support as drugs potentially beneficial in Alzheimer disease. In vivo studies have shown that Triflusal and its active metabolite 2-hydroxy-4-trifluoromethyl-benzoic acid have potent anti-inflammatory actions in the central nervous system. We conducted a randomized, double-blind, placebo-controlled trial of Triflusal in patients with amnestic mild cognitive impairment. Subjects were randomly assigned to receive 900 mg of Triflusal or placebo for 18 months. The primary outcome was a change in Cognitive subscale of the Alzheimer Disease Assessment Scale; conversion to dementia was a secondary outcome. A slow rate of recruitment forced a premature cessation of the study. Two hundred and fifty-seven subjects were enrolled and followed-up for an average of 13 months. The significance level was not reached for the primary outcome even...
Proceedings of the National Academy of Sciences, 2006
Reelin is a glycoprotein that is essential for the correct cytoarchitectonic organization of the ... more Reelin is a glycoprotein that is essential for the correct cytoarchitectonic organization of the developing CNS. Its function in the adult brain is less understood, although it has been proposed that Reelin is involved in signaling pathways linked to neurodegeneration. Here we analyzed Reelin expression in brains and cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients and nondemented controls. We found a 40% increase in the Reelin protein levels in the cortex of AD patients compared with controls. Similar increases were detected at the Reelin mRNA transcriptional level. This expression correlates with parallel increases in CSF but not in plasma samples. Next, we examined whether CSF Reelin levels were also altered in neurological diseases, including frontotemporal dementia, progressive supranuclear palsy, and Parkinson's disease. The Reelin 180-kDa band increased in all of the neurodegenerative disorders analyzed. Moreover, the 180-kDa Reelin levels correlated positively with Tau protein in CSF. Finally, we studied the pattern of Reelin glycosylation by using several lectins and the anti-HNK-1 antibody. Glycosylation differed in plasma and CSF. Furthermore, the pattern of Reelin lectin binding differed between the CSF of controls and in AD. Our results show that Reelin is up-regulated in the brain and CSF in several neurodegenerative diseases and that CSF and plasma Reelin have distinct cellular origins, thereby supporting that Reelin is involved in the pathogenesis of a number of neurodegenerative diseases.
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Papers by rafael blesa