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Find video protocols related to scientific articles indexed in Pubmed.
Feasibility of lumbar puncture in the study of cerebrospinal fluid biomarkers for Alzheimer's disease: a multicenter study in Spain.
J. Alzheimers Dis.
PUBLISHED: 10-31-2014
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Lumbar puncture (LP) is increasingly performed in memory units due to the usefulness of cerebrospinal fluid (CSF) biomarkers in the diagnosis of Alzheimer's disease. The feasibility of this procedure in this context, however, is controversial.
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Clinical profile of Alzheimer's disease: is the age of the patient a decisive factor? Results of the INFLUENCE study.
J. Alzheimers Dis.
PUBLISHED: 10-22-2014
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Epidemiological and clinical studies suggest that dementia patients aged ? 85 years are biologically different from those aged 65-84. This study aimed to assess whether patients (>85 years) have a distinct sociodemographic and clinical profile. Older patients had lower educational achievements, different carer relationships, and were more likely to take memantine/concomitant treatments and be institutionalized. Differences were observed with respect to concomitant disease/other risk factors (depression, dyslipidemia, cardiovascular disease, hypertension). Oldest patients had greater impairment (more severe Global Deterioration Scale stage, lower Mini-Mental State Examination scores). Greater concomitant drug use and younger carers associated with older patients suggest higher management and social costs.
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The clinical use of cerebrospinal fluid biomarker testing for Alzheimer's disease diagnosis: A consensus paper from the Alzheimer's Biomarkers Standardization Initiative.
Alzheimers Dement
PUBLISHED: 08-20-2014
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Cerebrospinal fluid (CSF) biomarkers ?-amyloid 1-42 (A?1-42), also expressed as A?1-42:A?1-40 ratio, T-tau, and P-tau181P, have proven diagnostic accuracy for mild cognitive impairment and Alzheimer's disease (AD). How to use, interpret, and disclose biomarker results drives the need for standardization.
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Cerebrospinal fluid level of YKL-40 protein in preclinical and prodromal Alzheimer's disease.
J. Alzheimers Dis.
PUBLISHED: 07-16-2014
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An increase in YKL-40 levels seems to correlate with disease severity and poor prognosis in many diseases, including several neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease (AD). Specifically, YKL-40 protein is increased in mild AD with respect to controls, both in cerebrospinal fluid (CSF) and plasma.
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Correlates of cerebrospinal fluid levels of oligomeric- and total-?-synuclein in premotor, motor and dementia stages of Parkinson's disease.
J. Neurol.
PUBLISHED: 07-04-2014
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High-oligomeric and low-total-?-synuclein cerebrospinal fluid (CSF) levels have been found in Parkinson's disease (PD), but with inconsistent or limited data, particularly on their clinical and structural correlates in earliest (premotor) or latest (dementia) PD stages. We determined CSF oligomeric- and total-?-synuclein in 77 subjects: 23 with idiopathic REM-sleep behaviour disorder (iRBD, a condition likely to include a remarkable proportion of subjects in the premotor stage of PD) and 41 with PD [21 non-demented (PDND) + 20 demented (PDD)], intended to reflect the premotor-motor-dementia PD continuum, along with 13 healthy controls. The study protocol also included the Unified PD Rating Scale motor-section (UPDRS-III), mini mental state examination (MMSE), neuropsychological cognitive testing, 3T brain MRI for cortical-thickness analyses, CSF ? and CSF A?. CSF oligomeric-?-synuclein was higher in PDND than iRBD and in PDD than iRBD and controls, and correlated with UPDRS-III, MMSE, semantic fluency and visuo-perceptive scores across the proposed premotor-motor-dementia PD continuum (iRBD + PDND + PDD). CSF total-?-synuclein positively correlated with age, CSF A?, and, particularly, CSF ?, tending towards lower levels in PD (but not iRBD) vs. controls only when controlling for CSF ?. Low CSF total-?-synuclein was associated with dysfunction in phonetic-fluency (a frontal-lobe function) in PD and with frontal cortical thinning in iRBD and PDND independently of CSF ?. Conversely, the associations of high (instead of low) CSF total-?-synuclein with posterior-cortical neuropsychological deficits in PD and with posterior cortical thinning in PDD were driven by high CSF ?. These findings suggest that CSF oligomeric- and total-?-synuclein have different clinical, neuropsychological and MRI correlates across the proposed premotor-motor-dementia PD continuum. CSF total-?-synuclein correlations with CSF ? and A? support the hypothesis of an interaction among these proteins in PD, with CSF ? probably influencing the presence of high (instead of low) CSF total-?-synuclein and its correlates mostly in the setting of PD-related dementia.
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TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis.
Sci Transl Med
PUBLISHED: 07-04-2014
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Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to Nasu-Hakola disease, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and FTD-like syndrome without bone involvement. TREM2 is an innate immune receptor preferentially expressed by microglia and is involved in inflammation and phagocytosis. Whether and how TREM2 missense mutations affect TREM2 function is unclear. We report that missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells. As a consequence of reduced shedding, TREM2 is virtually absent in the cerebrospinal fluid (CSF) and plasma of a patient with FTD-like syndrome. A decrease in soluble TREM2 was also observed in the CSF of patients with AD and FTD, further suggesting that reduced TREM2 function may contribute to increased risk for two neurodegenerative disorders.
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Five-year follow-up of substantia nigra echogenicity in idiopathic REM sleep behavior disorder.
Mov. Disord.
PUBLISHED: 06-30-2014
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Hyperechogenicity of the substantia nigra visualized by transcranial sonography occurs in most Parkinson's disease (PD) patients. Idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) subjects eventually develop PD and other synucleinopathies. This study was undertaken to evaluate whether in IRBD, transcranial sonography identifies subjects who convert to PD and other synucleinopathies, and whether substantia nigra echogenic size changes with time. It was a prospective study in which 55 IRBD patients underwent transcranial sonography at baseline and were invited to follow-up after 5 years. Patients were assessed by the same experienced sonographer who was blinded to clinical data and baseline transcranial sonography results, and used the same equipment and adjustments. Twenty-one (38.2%) subjects were diagnosed with a synucleinopathy (PD in 11, dementia with Lewy bodies in nine, and multiple system atrophy in one). Sensitivity of baseline substantia nigra hyperechogenicity for the development of a synucleinopathy was 42.1%, specificity 67.7%, positive predictive value 44.4%, negative predictive value 65.6%, and relative risk 1.29. No differences were detected between the first and second examination in mean size of the substantia nigra (0.20?±?0.09 cm(2) vs. 0.19?±?0.07 cm(2) ; P?=?0.777) and in percentage of patients with substantia nigra hyperechogenicity (33.3% vs. 42.8%, P?=?0.125). Transcranial sonography of the substantia nigra alone is not a useful tool to identify IRBD subjects at risk for the development of PD or a synucleinopathy after 5 years of follow-up. In IRBD, transcranial sonography cannot be used to monitor the degenerative process in the substantia nigra, because echogenicity size remains stable over time. © 2014 International Parkinson and Movement Disorder Society.
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Cost-effectiveness of the use of biomarkers in cerebrospinal fluid for Alzheimer's disease.
J. Alzheimers Dis.
PUBLISHED: 06-12-2014
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The use of cerebrospinal fluid (CSF) biomarkers could facilitate early detection of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) and the differential diagnosis between AD and non-AD dementias.
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Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria.
Lancet Neurol
PUBLISHED: 05-23-2014
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In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.
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Cognitive and neuroimaging profiles in mild cognitive impairment and Alzheimer's disease: data from the Spanish Multicenter Normative Studies (NEURONORMA Project).
J. Alzheimers Dis.
PUBLISHED: 04-11-2014
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The aim of this study was to characterize the neuropsychological and neuroimaging profiles of mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients, and to study the magnitude of the differences by comparing both outcomes with healthy subjects in a cross-sectional manner. Five hundred and thirty-five subjects (356 cognitively normal adults (CONT), 79 MCI, and 100 AD) were assessed with the NEURONORMA neuropsychological battery. Thirty CONT, 23 MCI, and 23 AD subjects from this sample were included in the neuroimaging substudy. Patients' raw cognitive scores were converted to age and education-adjusted scaled ones (range 2-18) using co-normed reference values. Medians were plotted to examine the cognitive profile. MRIs were processed by means of FreeSurfer. Effect size indices (Cohen's d) were calculated in order to compare the standardized differences between patients and healthy subjects. Graphically, the observed cognitive profiles for MCI and AD groups produced near to parallel lines. Verbal and visual memories were the most impaired domains in both groups, followed by executive functions and linguistic/semantic ones. The largest effect size between AD and cognitively normal subjects was found for the FCSRT (d = 4.05, AD versus CONT), which doubled the value obtained by the best MRI measure, the right hippocampus (d = 1.65, AD versus CONT). Our results support the notion of a continuum in cognitive profile between MCI and AD. Neuropsychological outcomes, in particular the FCSRT, are better than neuroimaging ones at detecting differences among subjects.
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Validation of the AD-CSF-index in autopsy-confirmed Alzheimer's disease patients and healthy controls.
J. Alzheimers Dis.
PUBLISHED: 04-08-2014
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The cerebrospinal fluid (CSF) biomarkers amyloid-? peptide of 42 amino acids (A?1-42), total tau-protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181P) are used to diagnose Alzheimer's disease (AD). In order to increase diagnostic power, several biomarker combinations have been proposed. In that sense, a new CSF biomarker index was developed, the AD-CSF-index, which has been validated in clinically diagnosed AD patients using electrochemoluminescence based Meso Scale Discovery and single-analyte ELISA kits. This study validated the AD-CSF-index in neuropathologically diagnosed AD patients, using both single-analyte ELISA and multi-analyte Luminex assays. CSF of 51 neuropathologically diagnosed AD patients and of 95 controls was analyzed by commercially available single-analyte ELISA-kits (INNOTEST, Innogenetics) and by a Research Use Only version of the multi-analyte Luminex xMAP assay (INNO-BIA AlzBio3, Innogenetics). Subsequently the AD-CSF-indices were calculated. Both T-tau and P-tau181P AD-CSF-indices were significantly increased in AD patients when compared to controls (p < 0.001). The diagnostic power of the indices was calculated using ROC analyses, resulting in excellent sensitivity and specificity values that systematically exceeded the 80% threshold for discriminating autopsy-confirmed AD patients from controls, independent of the analytical platform. The power to discriminate between AD and non-AD dementias was not included in this study and should be validated in the future. In conclusion, this study validated the AD-CSF-index in autopsy-confirmed AD patients and has shown that its excellent diagnostic accuracy is independent of the analytical platform.
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The Subjective Cognitive Decline Questionnaire (SCD-Q): a validation study.
J. Alzheimers Dis.
PUBLISHED: 03-15-2014
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Subjective cognitive decline (SCD) is gaining importance as a focus of investigation, but adequate tools are needed for its quantification.
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Usefulness of biomarkers in the diagnosis and prognosis of early-onset cognitive impairment.
J. Alzheimers Dis.
PUBLISHED: 03-01-2014
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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 adding the CSF data to the subject categorization according to the NIA-AA criteria. After inclusion of CSF results, 90% of amnestic and 82% of the non-amnestic AD presentation could be categorized as "high probability", while 3% of AD patients fit into the category "dementia probably not due to AD". All the 24 MCI patients who progressed to AD dementia and only 1/27 stable MCI presented pathological CSF at baseline. Only 4% of the FTD clinical diagnosis had pathological CSF levels. CSF biomarkers provide high diagnostic accuracy in a clinical context in differentiating AD, frontotemporal lobar degeneration, and controls in presenile subjects and can be used equally in amnestic and non-amnestic AD. Abnormal CSF-AD biomarker levels predict subsequent progression to AD dementia in subjects with early-onset MCI.
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Neuropathology of prodromal Lewy body disease.
Mov. Disord.
PUBLISHED: 01-31-2014
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Current evidence suggests that there is a prodromal stage in Parkinson disease characterized by a variety of nonmotor symptoms.
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White matter changes in preclinical Alzheimer's disease: a magnetic resonance imaging-diffusion tensor imaging study on cognitively normal older people with positive amyloid ? protein 42 levels.
Neurobiol. Aging
PUBLISHED: 01-21-2014
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The aim of this study was to use diffusion tensor imaging measures to determine the existence of white matter microstructural differences in the preclinical phases of Alzheimer's disease, assessing cognitively normal older individuals with positive amyloid ? protein (A?42) levels (CN_A?42+) on the basis of normal cognition and cerebrospinal fluid A?42 levels below 500 pg/mL. Nineteen CN_A?42+ and 19 subjects with A?42 levels above 500 pg/mL (CN_A?42-) were included. We encountered increases in axial diffusivity (AxD) in CN_A?42+ relative to CN_A?42- in the corpus callosum, corona radiata, internal capsule, and superior longitudinal fasciculus bilaterally, and also in the left fornix, left uncinate fasciculus, and left inferior fronto-occipital fasciculus. However, no differences were found in other diffusion tensor imaging indexes. Cognitive reserve scores were positively associated with AxD exclusively in the CN_A?42+ group. The finding of AxD alteration together with preserved fractional anisotropy, mean diffusivity, and radial diffusivity indexes in the CN_A?42+ group may indicate that, subtle axonal changes may be happening in the preclinical phases of Alzheimer's disease, whereas white matter integrity is still widely preserved.
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Identification of blood serum micro-RNAs associated with idiopathic and LRRK2 Parkinson's disease.
J. Neurosci. Res.
PUBLISHED: 01-21-2014
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Blood-cell-free circulating micro-RNAs (miRNAs) have been proposed as potential accessible biomarkers for neurodegenerative diseases such as Parkinson's disease (PD). Here we analyzed the serum levels of 377 miRNAs in a discovery set of 10 idiopathic Parkinson's disease (IPD) patients, 10 PD patients carriers of the LRRK2 G2019S mutation (LRRK2 PD), and 10 controls by using real-time quantitative PCR-based TaqMan MicroRNA arrays. We detected candidate differentially expressed miRNAs, which were further tested in a first validation set consisting of 20 IPD, 20 LRRK2 PD, and 20 control samples. We found four statistically significant miRNAs that were downregulated in either LRRK2 or IPD (miR-29a, miR-29c, miR-19a, and miR-19b). Subsequently, we validated these findings in a third set of samples consisting of 65 IPD and 65 controls and confirmed the association of downregulated levels of miR-29c, miR-29a, and miR-19b in IPD. Differentially expressed miRNAs are predicted to target genes belonging to pathways related to ECM-receptor interaction, focal adhesion, MAPK, Wnt, mTOR, adipocytokine, and neuron projection. Results from our exploratory study indicate that downregulated levels of specific circulating serum miRNAs are associated with PD and suggest their potential use as noninvasive biomarkers for PD. Future studies should further confirm the association of these miRNAs with PD.
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Taking stock: A multistakeholder perspective on improving the delivery of care and the development of treatments for Alzheimer's disease.
Alzheimers Dement
PUBLISHED: 01-14-2014
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Health-care stakeholders increasingly recognize that the scientific and economic challenges associated with Alzheimer's disease (AD) are simply too great for individual stakeholder groups to address solely from within their own silos. In the necessary spirit of collaboration, we present in this perspective a set of multicountry multistakeholder recommendations to improve the organization of existing AD and dementia care and the development of new treatments. In brief, the five recommendations are (1) health-care systems must make choices regarding the patient populations to be diagnosed and treated, (2) health-care systems should use an evidence-based standard of care, (3) increased collaboration between public and private institutions is needed to enhance research, (4) reimbursement end points need to be agreed on and validated, and (5) innovative business models should be used to spur the introduction of new medicines.
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Large APP locus duplication in a sporadic case of cerebral haemorrhage.
Neurogenetics
PUBLISHED: 01-14-2014
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We report a 54-year-old man who was admitted to the hospital because of acute neurological symptoms due to a cerebral haemorrhage. Postmortem brain examination revealed a lobar haemorrhage and advanced AD neuropathologic changes associated with severe cerebral amyloid angiopathy. Genetic study evidenced the presence of a large APP locus duplication (APPdup) in the patient and a PSEN1 p.E318G polymorphism in him and his older asymptomatic sibling. The APPdup spanned 14.5 Mb and blocks of segmental duplications were detected in the breakpoints. We propose the replication-based mechanism of Fork Stalling Template Switching (FoSTeS) to explain this APPdup rearrangement.
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A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease.
Alzheimers Dement
PUBLISHED: 01-09-2014
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There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.
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Increased Levels of Chitotriosidase and YKL-40 in Cerebrospinal Fluid from Patients with Alzheimer's Disease.
Dement Geriatr Cogn Dis Extra
PUBLISHED: 01-01-2014
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The cerebrospinal fluid (CSF) biomarkers total tau, abnormally phosphorylated tau and amyloid ? 1-42 are strongly associated with Alzheimer's disease (AD). Apart from the pathologic hallmarks that these biomarkers represent, other processes such as inflammation and microglial activation are present in the brains of patients with AD. New biomarkers related to these processes could be valuable for the diagnosis and follow-up of AD patients and for the evaluation of inflammation-related pathologies.
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Neurodegenerative disorder risk in idiopathic REM sleep behavior disorder: study in 174 patients.
PLoS ONE
PUBLISHED: 01-01-2014
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To estimate the risk for developing a defined neurodegenerative syndrome in a large cohort of idiopathic REM sleep behavior disorder (IRBD) patients with long follow-up.
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Plasma phosphorylated TDP-43 levels are elevated in patients with frontotemporal dementia carrying a C9orf72 repeat expansion or a GRN mutation.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 12-04-2013
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About a half of patients with frontotemporal dementia (FTD) has deposition of phosphorylated TDP-43 protein (pTDP-43) in the brain. We studied pTDP-43 and total TDP-43 levels in plasma and cerebrospinal fluid (CSF) in healthy controls and patients with FTD, including those carrying a repeat expansion in the C9orf72 gene or a mutation in GRN.
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Spanish Multicenter Normative Studies (NEURONORMA Project): Normative Data and Equivalence of Four BNT Short-Form Versions.
Arch Clin Neuropsychol
PUBLISHED: 11-11-2013
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The application of the Boston Naming Test (BNT) is time-consuming and shortened versions need to be developed for screening purposes. The aims of this study were to develop four equivalent 15-item forms of a Spanish adaptation of the BNT, to test the equivalence of the new versions in a clinical sample, and to provide normative data. The normative sample consisted of 340 subjects. The clinical sample included 172 patients (76 Mild Cognitive Impairment and 96 Alzheimers disease). An empirical procedure was used to develop the shortened versions. All new versions demonstrated satisfactory internal consistency. Pearsons coefficient analysis showed strong relationships among the four short-form versions as well as between each of them and the 60-item test. The inferential confidence interval method demonstrated the equivalence between the four shortened versions. Age and education affected the score of all short-form versions, but sex was found to be unrelated to the performance. Normative data were calculated for midpoint age groups. This paper proposes four 15-item equivalent versions that could be useful and time-saving tools for screening purposes.
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Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study.
Lancet Neurol
PUBLISHED: 04-03-2013
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We postulated that idiopathic rapid-eye-movement (REM) sleep behaviour disorder (IRBD) represents the prodromal phase of a Lewy body disorder and that, with sufficient follow-up, most cases would eventually be diagnosed with a clinical defined Lewy body disorder, such as Parkinsons disease (PD) or dementia with Lewy bodies (DLB).
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Donepezil treatment stabilizes functional connectivity during resting state and brain activity during memory encoding in Alzheimers disease.
J Clin Psychopharmacol
PUBLISHED: 02-21-2013
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Previous studies with functional magnetic resonance imaging (fMRI) demonstrated a differential brain activity and connectivity after treatment with donepezil in Alzheimers disease (AD) when compared to healthy elders. Importantly however, there are no available studies where the placebo or control group included comparable AD patients relative to the treated groups. Fifteen patients recently diagnosed of AD were randomized to treatment (n = 8) or to control group (n = 7); the former receiving daily treatment of donepezil during 3 months. At baseline and follow-up, both groups underwent resting-state as well as task-fMRI examinations, this latter assessing encoding of visual scenes. The treated group showed higher connectivity in areas of the default mode network, namely the right parahippocampal gyrus at follow-up resting-fMRI as compared to the control group. On the other hand, for the task-fMRI, the untreated AD group presented progressive increased activation in the left middle temporal gyrus and bilateral precuneus at the 3-month examination compared to baseline, whereas the treated group exhibited stable patterns of brain activity. Donepezil treatment is associated with stabilization of connectivity of medial temporal regions during resting state and of brain efficiency during a cognitive demand, on the whole reducing progressive dysfunctional reorganizations observed during the natural course of the disease.
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International Work Group criteria for the diagnosis of Alzheimer disease.
Med. Clin. North Am.
PUBLISHED: 02-16-2013
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Alzheimer-type biomarker changes are identifiable in asymptomatic and mildly symptomatic predementia phases of Alzheimer disease (AD) and AD dementia. The International Work Group (IWG) guidelines for diagnosis identify a unified spectrum of 3 phases. The classic clinical feature that indicates AD is an episodic memory defect of the amnestic type. IWG criteria require biomarker support for the diagnoses of AD at any clinical stage. Pathophysiologic and topographic biomarkers are recognized. These criteria are proposed to allow highly specific diagnosis of AD and assist in identifying patients for clinical trials of AD-related treatments and other types of AD research.
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Applying the IWG research criteria in clinical practice: feasibility and ethical issues.
Med. Clin. North Am.
PUBLISHED: 02-01-2013
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One of the strengths of the IWG criteria was to reconceptualize the diagnosis of AD, from a clinical-pathologic diagnosis to a clinical-biologic one, which can be performed in vivo. The diagnosis should, therefore, be implemented in the clinical stage of the disease, relying on the essence of the new IWG diagnostic criteria in the recognition of this dual aspect of AD: a specific clinical presentation that is related to a well-defined underlying pathology. Biomarkers measured by PET or CSF correlate with high sensitivity and specificity with AD pathologic features; episodic memory properly measured also presents high specificity to detect patients who develop AD dementia, and clinical studies have demonstrated that these criteria applied in a clinical setting present good specificity, making feasible a diagnosis in the prodromal stage of the disease. From an ethical perspective, the governing principle for early prodromal diagnosis should be autonomy, because the decision of wishing to know or not to know should be performed individually by a competent individual. Furthermore, the potential benefit of an early diagnosis may be mediated through an autonomous decision.
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A preliminary study of the whole-genome expression profile of sporadic and monogenic early-onset Alzheimers disease.
Neurobiol. Aging
PUBLISHED: 01-28-2013
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Alzheimers disease (AD) is the most common neurodegenerative dementia. Approximately 10% of cases present at an age of onset before 65 years old, which in turn can be monogenic familial AD (FAD) or sporadic early-onset AD (sEOAD). Mutations in PSEN1, PSEN2, and APP genes have been linked with FAD. The aim of our study is to describe the brain whole-genome RNA expression profile of the posterior cingulate area in sEOAD and FAD caused by PSEN1 mutations (FAD-PSEN1). Fourteen patients (7 sEOAD and 7 FAD-PSEN1) and 7 neurologically healthy control subjects were selected and whole-genome expression was measured using Affymetrix Human Gene 1.1 microarrays. We identified statistically significant expression changes in sEOAD and FAD-PSEN1 brains with respect to control subjects (3183 and 3350 differentially expressed genes [DEG] respectively, false discovery rate-corrected p < 0.05). Of them, 1916 DEG were common between the 2 comparisons. We did not identify DEG between sEOAD and FAD-PSEN1. Microarray data were validated through real-time quantitative polymerase chain reaction. In silico analysis of DEG revealed an alteration in biological pathways related to intracellular signaling pathways (particularly calcium signaling), neuroactive ligand-receptor interactions, axon guidance, and long-term potentiation in both groups of patients. In conclusion, the altered biological final pathways in sEOAD and FAD-PSEN1 are mainly related with cell signaling cascades, synaptic plasticity, and learning and memory processes. We hypothesize that these 2 groups of early-onset AD with distinct etiologies and likely different could present a neurodegenerative process with potential different pathways that might converge in a common and similar final stage of the disease.
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Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease.
Ann. Neurol.
PUBLISHED: 01-09-2013
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To identify a novel biochemical marker that precedes clinical symptoms in Alzheimer disease (AD).
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A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats.
Julie van der Zee, Ilse Gijselinck, Lubina Dillen, Tim Van Langenhove, Jessie Theuns, Sebastiaan Engelborghs, Stéphanie Philtjens, Mathieu Vandenbulcke, Kristel Sleegers, Anne Sieben, Veerle Bäumer, Githa Maes, Ellen Corsmit, Barbara Borroni, Alessandro Padovani, Silvana Archetti, Robert Perneczky, Janine Diehl-Schmid, Alexandre de Mendonça, Gábriel Miltenberger-Miltényi, Sónia Pereira, José Pimentel, Benedetta Nacmias, Silvia Bagnoli, Sandro Sorbi, Caroline Graff, Huei-Hsin Chiang, Marie Westerlund, Raquel Sánchez-Valle, Albert Lladó, Ellen Gelpi, Isabel Santana, Maria Rosário Almeida, Beatriz Santiago, Giovanni Frisoni, Orazio Zanetti, Cristian Bonvicini, Matthis Synofzik, Walter Maetzler, Jennifer Müller vom Hagen, Ludger Schöls, Michael T Heneka, Frank Jessen, Radoslav Matej, Eva Parobkova, Gabor G Kovacs, Thomas Strobel, Stayko Sarafov, Ivailo Tournev, Albena Jordanova, Adrian Danek, Thomas Arzberger, Gian Maria Fabrizi, Silvia Testi, Eric Salmon, Patrick Santens, Jean-Jacques Martin, Patrick Cras, Rik Vandenberghe, Peter Paul De Deyn, Marc Cruts, Christine Van Broeckhoven, Peter P De Deyn, Jennifer Müller Vom Hagen, Alfredo Ramírez, Delia Kurzwelly, Carmen Sachtleben, Wolfgang Mairer, Clara Firmo, Anna Antonell, Jose Molinuevo, Anne Kinhult Ståhlbom, Håkan Thonberg, Inger Nennesmo, Anne Börjesson-Hanson, Valentina Bessi, Irene Piaceri, Maria Helena Ribeiro, Maria Rosário Almeida, Catarina Oliveira, João Massano, Carolina Garret, Paula Pires, Adrian Danel, Gian Maria Fabrizi, Sergio Ferrari, Tiziana Cavallaro, .
Hum. Mutat.
PUBLISHED: 01-04-2013
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We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), 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 (7-24 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 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.
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Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset Alzheimers disease patients alter calcium homeostasis.
PLoS ONE
PUBLISHED: 01-01-2013
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Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimers disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca(2+)-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca(2+) permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca(2+) influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca(2+) influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß) production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca(2+) dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.
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Using artificial neural networks in clinical neuropsychology: high performance in mild cognitive impairment and Alzheimers disease.
J Clin Exp Neuropsychol
PUBLISHED: 12-14-2011
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Mild cognitive impairment (MCI) is a transitional state between normal aging and Alzheimer disease (AD). Artificial neural networks (ANNs) are computational tools that can provide valuable support to clinical decision making, classification, and prediction of cognitive functioning. The aims of this study were to develop, train, and explore and develop the ability of ANNs to differentiate MCI and AD, and to study the relevant variables in MCI and AD diagnosis. The sample consisted of 346 controls and 79 MCI and 97 AD patients. A linear discriminant analysis (LDA) and ANNs with 12 input neurons (10 subtests of a neuropsychological test, the abbreviated Barcelona Test; age; and education), 4 hidden neurons, and output neuron (diagnosis) were used to classify the patients. The ANNs were superior to LDA in its ability to classify correctly patients (100-98.33% vs. 96.4-80%, respectively) and showed better predictive performance. Semantic fluency, working and episodic memory and education showed up as the most significant and sensitive variables for classification. Our results indicate that ANNs have an excellent capacity to discriminate MCI and AD patients from healthy controls. These findings provide evidence that ANNs can be a useful tool for the analysis of neuropsychological profiles related to clinical syndromes.
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[Role of biomarkers in the early diagnosis of Alzheimers disease].
Rev Esp Geriatr Gerontol
PUBLISHED: 12-14-2011
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Alheimers disease is the most frequent cause of cognitive decline and behavioral abnormalities in adults. Diagnosis is currently made in the advanced phases. An an early diagnosis in the prodromal phase (or earlier if possible) is required for the prevention of this disease, its early management and the development of potential therapies that could alter its natural course. The syndromic concept of mild cognitive impairment (the presence of detectable and quantifiable deterioration in one of the cognitive domains but without affecting -or without substantially affecting- autonomic performance of instrumental function) and its variants has aided understanding of the predementia stages of Alheimers disease, even though its etiology may involve multiple factors. The use of biomarkers such as determination of the proteins involved in the disease in cerebrospinal fluid (A???-amyloid, total and phosphorylated tau) and measurement of the hippocampus and entorhinal cortex with magnetic resonance imaging and positron emission tomography (both glucose and amyloid measurements), alone or combined, could allow early and etiologic diagnosis. Patients with Alzheimers disease show reduced A???-amyloid levels and increased total and phosphorylated tau levels in cerebrospinal fluid.
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Serial dopamine transporter imaging of nigrostriatal function in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study.
Lancet Neurol
PUBLISHED: 07-28-2011
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Serial dopamine transporter (DAT) imaging in patients with Parkinsons disease (PD) and other synucleinopathies shows progressive nigrostriatal dopaminergic dysfunction. Because idiopathic rapid-eye-movement (REM) sleep behaviour disorder (IRBD) can precede the classic symptoms of PD and other synucleinopathies, we postulated that serial DAT imaging in patients with IRBD could be used to detect decline in striatal tracer uptake, indicating progressive nigrostriatal cell degeneration.
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Identifying earlier Alzheimers disease: insights from the preclinical and prodromal phases.
Neurodegener Dis
PUBLISHED: 06-22-2011
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Alzheimers disease (AD) has been traditionally conceptualized as a clinicopathological entity, its definite diagnosis requiring the presence of characteristic pathology together with a dementia clinical picture. The fact that certain AD biomarkers show an acceptable sensitivity and specificity to detect AD pathology has shifted the diagnostic paradigm towards a clinicobiological approach. The objective of this paper is to present recent data that show how cerebrospinal fluid (CSF) biomarkers behave in preclinical AD. These studies have been performed in presymptomatic subjects (PreS) and asymptomatic subjects at risk for the disease (AsymR). In brief, the results show in PreS subjects that CSF biomarkers present a positive correlation with time to disease onset to reach floor levels at symptom onset. In addition, memory performance presents distinct associations in the AD continuum, being related to A?(1-42) levels in AsymR subjects and to t-tau and p-tau in prodromal AD. Furthermore, an increase in cortical thickness of typical AD areas was observed when mean A?(1-42) levels were still within the normal range in PreS subjects, or they presented transitional values in AsymR subjects. Overall, these findings suggest that the preclinical stage is biologically active and that there may be structural changes when amyloid is starting its deposition.
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[Landscape test for assessing visual memory in Alzheimers disease].
Rev Neurol
PUBLISHED: 06-17-2011
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Visual episodic memory is affected in the early phases of Alzheimers disease (AD).
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Association between cerebrospinal fluid tau and brain atrophy is not related to clinical severity in the Alzheimers disease continuum.
Psychiatry Res
PUBLISHED: 05-04-2011
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We aimed to assess the association between core cerebrospinal fluid (CSF) biomarkers, regional brain atrophy and clinical severity in the Alzheimers disease (AD) continuum, as well as to investigate how cognitive reserve (CR) may modulate these putative associations. Forty-nine subjects (11 controls, 10 patients with subjective memory complaints, 19 with mild cognitive impairment and 9 mild AD) underwent lumbar puncture and high-resolution magnetic resonance imaging (MRI). CSF amyloid-?(1-42) (A?(1-42)), total tau (t-tau) and phosphorylated tau (p-tau(181)) were determined. Voxel-based morphometry (VBM) was applied and multiple regression analyses for the whole sample were carried out. Clinical severity was adjusted using the Clinical Dementia Rating Sum of Boxes score (CDR-SB). A negative correlation between t-tau levels and grey matter (GM) volume in temporo-parietal regions was found, regardless of CDR-SB score. In contrast, the negative correlation between p-tau(181) and GM volume was largely explained by clinical severity, except in the posterior cingulate cortex. CR did not significantly modify these correlations. A?(1-42) levels were not related to GM volume but were related to clinical severity, an association that was attenuated when CR was considered. In conclusion, the present findings reflect that t-tau CSF concentrations are associated with GM atrophy in neuropathologically relevant areas across the AD continuum, whereas the p-tau(181) association is largely dependent on the degree of clinical severity. The relationship between CSF A?(1-42) and clinical severity seems to be modulated by CR, suggesting that there may be subjects with pathological levels of A?(1-42) and high CR estimates who remain clinically asymptomatic.
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Cognitively preserved subjects with transitional cerebrospinal fluid ß-amyloid 1-42 values have thicker cortex in Alzheimers disease vulnerable areas.
Biol. Psychiatry
PUBLISHED: 02-15-2011
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Establishing the relationship between cerebrospinal fluid (CSF) ß-amyloid 1-42 (Aß) and cortical thickness (CTh) would represent a major step forward in the understanding of the Alzheimers disease (AD) process. We studied this relationship in a group of healthy control subjects and subjects with subjective memory complaints with preserved cognitive function at neuropsychological testing.
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[Cognitive reserve questionnaire. Scores obtained in a healthy elderly population and in one with Alzheimers disease].
Rev Neurol
PUBLISHED: 02-12-2011
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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 individuals life.
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A novel PSEN1 gene mutation (L235R) associated with familial early-onset Alzheimers disease.
Neurosci. Lett.
PUBLISHED: 01-18-2011
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Mutations in the presenilin 1 (PSEN1) gene are the most frequent cause of familial Alzheimers 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.
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Cerebrospinal fluid biomarkers in Alzheimers disease families with PSEN1 mutations.
Neurodegener Dis
PUBLISHED: 01-05-2011
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Familial Alzheimers disease allows studies in the preclinical phases of the disease. We studied cerebrospinal fluid (CSF) amyloid ?1-42 (A?1-42), 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.
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Applying the new research diagnostic criteria: MRI findings and neuropsychological correlations of prodromal AD.
Int J Geriatr Psychiatry
PUBLISHED: 01-04-2011
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We describe the neuroimaging characteristics of prodromal AD (PrdAD) patients diagnosed using the new research criteria in a clinical setting. In order to further characterize these patients, we also study the relationship between neuropsychology, CSF biomarkers and magnetic resonance imaging (MRI) findings.
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Spanish multicenter normative studies (Neuronorma project): norms for the abbreviated Barcelona Test.
Arch Clin Neuropsychol
PUBLISHED: 12-13-2010
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The abbreviated Barcelona Test (a-BT) is an instrument widely used in Spain and Latin American countries for general neuropsychological assessment. The purpose of the present study was to provide new norms for the a-BT as part of the Neuronorma project. The sample consisted of 346 healthy controls. Overlapping cell procedure and midpoint techniques were applied to develop the normative data. Age, education, and sex influences were studied. Results indicated that although age and education affected the score on this test, sex did not. Raw scores were transformed to age-adjusted scaled scores (SS(A)) based on percentile ranks. These SS(A) were also converted into age-education scaled scores using a linear regression model. Norms were presented on age-education scaled scores. Also, the a-BT cognitive profile was presented and should prove to be clinically useful for interpretation. These co-normed data will allow clinicians to compare scores from a-BT with all the tests included in the Neuronorma project.
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[Early diagnosis of Alzheimers disease: the prodromal and preclinical phase].
Rev Neurol
PUBLISHED: 10-07-2010
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Because Alzheimers disease (AD) needs to be treated as soon as possible after onset, its early detection has become one of the core areas of research in the field of neurodegenerative diseases.
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Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study [corrected].
Lancet Neurol
PUBLISHED: 09-16-2010
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Patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) may develop neurodegenerative conditions associated with substantia nigra dysfunction such as Parkinsons disease. In patients with Parkinsons disease, ¹²³I-2?-carbomethoxy-3?-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (¹²³I-FP-CIT) SPECT detects striatal dopamine dysfunction resulting from nigral pathology whereas transcranial sonography (TCS) shows increased substantia nigra echogenic size, even before parkinsonism is clinically evident. We postulated that these neuroimaging changes could occur in a proportion of IRBD individuals who might then be at increased risk for development of a neurodegenerative disorder associated with substantia nigra dysfunction.
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Different profiles of Alzheimers disease cerebrospinal fluid biomarkers in controls and subjects with subjective memory complaints.
J Neural Transm
PUBLISHED: 08-20-2010
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Cerebrospinal fluid (CSF) biomarkers, such as A?(42), total-tau and phosphorylated-tau(181) reflect neuropathological changes of Alzheimers 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 A?(42) (group 2, 27.9%), pathologic A?(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.
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Neuropsychological profile of prodromal Alzheimers disease (Prd-AD) and their radiological correlates.
Arch Gerontol Geriatr
PUBLISHED: 03-17-2010
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This study describes the cognitive profile of Prd-AD, the neuropsychological tests that may predict progression to dementia, and to study their brain structural correlates. We enrolled 24 stable amnesics who did not develop dementia after two years follow-up; 27 patients were considered as Prd-AD, in the initial visit, since they fulfilled NINCDS-ADRDA criteria after two years; 31 Alzheimers disease (AD) patients and 27 controls (CTR). Structural magnetic resonance imaging (MRI), as well as a neuropsychological battery was performed at the initial visit. The key findings were: Prd-AD patients were characterized by prominent episodic memory dysfunction and minimal semantic memory and executive dysfunction. Semantic fluency test (Sem-Flu), delayed text memory test (Del-text-mem) and memory alteration test (M@T) (including both episodic and semantic memory), together with trail making test A (TMT-A), resulted significant predictors for dementia development in this group of amnesic patients. This optimal predictive model obtained an estimated accuracy of 53% after two years follow-up. M@T and semantic Sem-Flu test performance presented high correlation with decreased gray matter density in the left lateral temporal lobe. We conclude that Prd-AD is characterized by prominent episodic memory dysfunction and minimal semantic memory and executive dysfunction which are related with left medial, inferior and lateral temporal density loss, predominantly in the left side.
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[Relearning vocabulary. A comparative analysis between a case of dementia and Alzheimers disease with predominant compromise of language].
Rev Neurol
PUBLISHED: 02-11-2010
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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 Alzheimers 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.
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Multiple DTI index analysis in normal aging, amnestic MCI and AD. Relationship with neuropsychological performance.
Neurobiol. Aging
PUBLISHED: 02-03-2010
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White matter (WM) damage has been reported in Alzheimers Disease (AD) and Mild Cognitive Impairment (MCI) in diffusion tensor imaging (DTI) studies. It is, however, unknown how the investigation of multiple tensor indexes in the same patients, can differentiate them from normal aging or relate to patients cognition. Forty-six individuals (15 healthy, 16 a-MCI and 15 AD) were included. Voxel-based tract based spatial-statistics (TBSS) was used to obtain whole-brain maps of main WM bundles for fractional anisotropy (FA), radial diffusivity (DR), axial diffusivity (DA) and mean diffusivity (MD). FA reductions were evidenced among AD patients with posterior predominance. A-MCI patients displayed reduced mean FA in these critical regions, compared to healthy elders. MD increases were widespread in both groups of patients. Interestingly, a-MCI patients exhibited DR increases in overlapping areas of FA shrinkages in AD, whereas DA increases were only observed in AD. Gray matter atrophy explained most DTI differences, except those regarding MD in both groups as well as DR increases in posterior associative pathways among a-MCI cases. FA values were the only DTI measure significantly related to memory performance among patients. Present findings suggest that most DTI-derived changes in AD and a-MCI are largely secondary to gray matter atrophy. Notably however, specific DR signal increases in posterior parts of the inferior fronto-occipital and longitudinal fasciculi may reflect early WM compromise in preclinical dementia, which is independent of atrophy. Finally, global measures of integrity, particularly orientation coherence (FA) of diffusion, appear to be more closely related to the cognitive profile of our patients than indexes reflecting water movement parallel (DA) and perpendicular (DR) to the primary diffusion direction.
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Electroencephalographic slowing heralds mild cognitive impairment in idiopathic REM sleep behavior disorder.
Sleep Med.
PUBLISHED: 01-28-2010
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Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) may show electroencephalographic (EEG) slowing reflecting cortical dysfunction and are at risk for developing neurological conditions characterized by cognitive dysfunction including mild cognitive impairment (MCI), dementia with Lewy bodies and Parkinsons disease with associated dementia. We hypothesized that those IRBD patients who later developed MCI had pronounced cortical EEG slowing at presentation.
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Medial temporal lobe correlates of memory screening measures in normal aging, MCI, and AD.
J Geriatr Psychiatry Neurol
PUBLISHED: 12-22-2009
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This article aimed to study the correlations for both the Memory Impairment Screen (MIS) and the Free and Cued Selective Reminding Test (FCSRT) with regard to the volumetric measures of hippocampal formation and entorhinal cortex and to explore the effect size of these measures.
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Brain structure and function related to cognitive reserve variables in normal aging, mild cognitive impairment and Alzheimers disease.
Neurobiol. Aging
PUBLISHED: 08-22-2009
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Cognitive reserve (CR) is the brains capacity to cope with cerebral damage to minimize clinical manifestations. The passive model considers head or brain measures as anatomical substrates of CR, whereas the active model emphasizes the use of brain networks effectively. Sixteen healthy subjects, 12 amnestic mild cognitive impairment (MCI) and 16 cases with mild Alzheimers disease (AD) were included to investigate the relationships between proxies of CR and cerebral measures considered in the passive and active models. CR proxies were inferred premorbid IQ (WAIS Vocabulary test), education-occupation, a questionnaire of intellectual and social activities and a composite CR measure. MRI-derived whole-brain volumes and brain activity by functional MRI during a visual encoding task were obtained. Among healthy elders, higher CR was related to larger brains and reduced activity during cognitive processing, suggesting more effective use of cerebral networks. In contrast, higher CR was associated with reduced brain volumes in MCI and AD and increased brain function in the latter, indicating more advanced neuropathology but that active compensatory mechanisms are still at work in higher CR patients. The right superior temporal gyrus (BA 22) and the left superior parietal lobe (BA 7) showed greatest significant differences in direction of slope with CR and activation between controls and AD cases. Finally, a regression analysis revealed that fMRI patterns were more closely related to CR proxies than brain volumes. Overall, inverse relationships for healthy and pathological aging groups emerged between brain structure and function and CR variables.
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Spanish Multicenter Normative Studies (NEURONORMA Project): norms for the Stroop color-word interference test and the Tower of London-Drexel.
Arch Clin Neuropsychol
PUBLISHED: 08-06-2009
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As part of the NEURONORMA project, we provide age- and education-adjusted norms for the Stroop color-word interference test (SCWT)-Golden version and the Tower of London-Drexel University version (TOL(DX)). The sample consists of 344 and 347 participants, respectively, who are cognitively normal, community dwelling, and ranging in age from 50 to 90 years. Tables are provided to convert raw scores to age-adjusted scaled scores. These were further converted into education-adjusted scaled scores by applying regression-based adjustments. Demographic variables, age, and education significantly affect scores of the SWCT and TOL(DX), sex, however, was found to be unrelated to performance in this sample. The normative data presented here were obtained from the same study sample as all the other NEURONORMA tests. In addition, the same statistical procedures for data analyses were applied. These co-normed data allow clinicians to compare scores from one test with all tests.
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Spanish Multicenter Normative Studies (NEURONORMA Project): norms for the Rey-Osterrieth complex figure (copy and memory), and free and cued selective reminding test.
Arch Clin Neuropsychol
PUBLISHED: 08-06-2009
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The Rey-Osterrieth complex figure (ROCF) and the free and cued selective reminding test (FCSRT) are frequently used in clinical practice. The ROCF assesses visual perception, constructional praxis, and visuospatial memory, and the FCSRT assesses verbal learning and memory. As part of the Spanish Normative Studies (NEURONORMA), we provide age- and education-adjusted norms for the ROCF (copy and memory) and for the FCSRT. The sample consists of 332 and 340 participants, respectively, who are cognitively normal, community dwelling, and ranging in age from 50 to 94 years. Tables are provided to convert raw scores to age-adjusted scaled scores. These were further converted into education-adjusted scaled scores by applying regression-based adjustments. Although age and education affected the score of the ROCF and FCSRT, sex was found to be unrelated in this normal sample. The normative data presented here were obtained from the same study sample as all other NEURONORMA norms and the same statistical procedures were applied. These co-normed data will allow clinicians to compare scores from one test with all the tests included in the project.
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Spanish Multicenter Normative Studies (NEURONORMA Project): norms for verbal span, visuospatial span, letter and number sequencing, trail making test, and symbol digit modalities test.
Arch Clin Neuropsychol
PUBLISHED: 08-05-2009
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As part of the Spanish Multicenter Normative Studies (NEURONORMA project), we provide age- and education-adjusted norms for the following instruments: verbal span (digits), visuospatial span (Corsis test), letter-number sequencing (WAIS-III), trail making test, and symbol digit modalities test. The sample consists of 354 participants who are cognitively normal, community-dwelling, and age ranging from 50 to 90 years. Tables are provided to convert raw scores to age-adjusted scaled scores. These were further converted into education-adjusted scaled scores by applying regression-based adjustments. The current norms should provide clinically useful data for evaluating elderly Spanish people. These data may be of considerable use for comparisons with other normative studies. Limitations of these normative data are mainly related to the techniques of recruitment and stratification employed.
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Spanish Multicenter Normative Studies (NEURONORMA Project): norms for the visual object and space perception battery-abbreviated, and judgment of line orientation.
Arch Clin Neuropsychol
PUBLISHED: 08-01-2009
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This study forms part of the Spanish Multicenter Normative Studies (NEURONORMA project). Normative data for people aged over 49 years are presented for selected tasks of the visual object and space perception battery (VOSP) and for the judgment of line orientation (JLO) test. Age-adjusted norms were derived from a sample of 341 participants who are cognitively normal and community-dwelling. Age- and education-adjusted norms are also provided. Years of education were modeled on age-scaled scores to derive regression equations that were applied for further demographic adjustments. The normative information provided here should prove useful for characterizing and interpreting individual test performances as well as comparing the scores from these tests with any other test using NEURONORMA norms.
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Spanish Multicenter Normative Studies (NEURONORMA Project): norms for verbal fluency tests.
Arch Clin Neuropsychol
PUBLISHED: 08-01-2009
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Lexical fluency tests are frequently used in clinical practice to assess language and executive function. As part of the Spanish multicenter normative studies (NEURONORMA project), we provide age- and education-adjusted norms for three semantic fluency tasks (animals, fruit and vegetables, and kitchen tools), three formal lexical tasks (words beginning with P, M, and R), and three excluded letter fluency tasks (excluded A, E, and S). The sample consists of 346 participants who are cognitively normal, community dwelling, and ranging in age from 50 to 94 years. Tables are provided to convert raw scores to age-adjusted scaled scores. These were further converted into education-adjusted scaled scores by applying regression-based adjustments. The current norms should provide clinically useful data for evaluating elderly Spanish people. These data may also be of considerable use for comparisons with other international normative studies. Finally, these norms should help improve the interpretation of verbal fluency tasks and allow for greater diagnostic accuracy.
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Spanish Multicenter Normative Studies (NEURONORMA Project): norms for Boston naming test and token test.
Arch Clin Neuropsychol
PUBLISHED: 08-01-2009
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As part of the Spanish Multicenter Normative Studies (NEURONORMA project), we provide age- and education-adjusted norms for the Boston naming test and Token test. The sample consists of 340 and 348 participants, respectively, who are cognitively normal, community-dwelling, and ranging in age from 50 to 94 years. Tables are provided to convert raw scores to age-adjusted scaled scores. These were further converted into education-adjusted scaled scores by applying regression-based adjustments. Age and education affected the score of the both tests, but sex was found to be unrelated to naming and verbal comprehension efficiency. Our norms should provide clinically useful data for evaluating elderly Spaniards. The normative data presented here were obtained from the same study sample as all the other NEURONORMA norms and the same statistical procedures for data analyses were applied. These co-normed data allow clinicians to compare scores from one test with all tests.
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Midbrain hyperechogenicity in idiopathic REM sleep behavior disorder.
Mov. Disord.
PUBLISHED: 08-01-2009
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Recent studies have reported an increased risk to develop Parkinsons disease (PD) in patients with idiopathic RBD (iRBD). Midbrain hyperechogenicity is a common transcranial sonography (TCS) finding in PD and has been suggested as a PD risk-marker in nonparkinsonian subjects. The objective of this study is to assess midbrain echogenicity by TCS in patients with iRBD and compare the findings with the healthy controls. TCS was performed in 55 iRBD patients and in 165 age and sex-matched controls. The area of echogenicity in the SN region in the iRBD group was significantly increased compared with the control group (P < 0.001). About 19 (37.3%) of patients with iRBD were found to have SN hyperechogenicity when compared with 16 (10.7%) of the controls (P < 0.001). This is the first case-control study assessing midbrain echogenicity in a large iRBD cohort compared to age- and sex-matched healthy individuals. The finding of an increased prevalence of hyperechogenicity in a subgroup of individuals with a priori increased risk for PD supports the potential role of hyperechogenicity as a risk marker for PD. The prospective follow-up of this iRBD cohort is needed to establish if those with midbrain hyperechogenicity will go on to develop clinically defined PD or not.
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Interactions of cognitive reserve with regional brain anatomy and brain function during a working memory task in healthy elders.
Biol Psychol
PUBLISHED: 05-09-2009
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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.
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Cognitive reserve modulates task-induced activations and deactivations in healthy elders, amnestic mild cognitive impairment and mild Alzheimers disease.
Cortex
PUBLISHED: 04-20-2009
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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 Alzheimers 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.
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Voxel based morphometry features and follow-up of amnestic patients at high risk for Alzheimers disease conversion.
Int J Geriatr Psychiatry
PUBLISHED: 03-05-2009
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Neuroimaging techniques are able to mark distinct structural and metabolic changes in patients at risk for Alzheimers disease (AD). The objectives of the study were to compare regional grey matter density in prodromal Alzheimers 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.
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APOE status modulates the changes in network connectivity induced by brain stimulation in non-demented elders.
PLoS ONE
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Behavioral consequences of a brain insult represent an interaction between the injury and the capacity of the rest of the brain to adapt to it. We provide experimental support for the notion that genetic factors play a critical role in such adaptation. We induced a controlled brain disruption using repetitive transcranial magnetic stimulation (rTMS) and show that APOE status determines its impact on distributed brain networks as assessed by functional MRI (fMRI).Twenty non-demented elders exhibiting mild memory dysfunction underwent two fMRI studies during face-name encoding tasks (before and after rTMS). Baseline task performance was associated with activation of a network of brain regions in prefrontal, parietal, medial temporal and visual associative areas. APOE ?4 bearers exhibited this pattern in two separate independent components, whereas ?4-non carriers presented a single partially overlapping network. Following rTMS all subjects showed slight ameliorations in memory performance, regardless of APOE status. However, after rTMS APOE ?4-carriers showed significant changes in brain network activation, expressing strikingly similar spatial configuration as the one observed in the non-carrier group prior to stimulation. Similarly, activity in areas of the default-mode network (DMN) was found in a single component among the ?4-non bearers, whereas among carriers it appeared disaggregated in three distinct spatiotemporal components that changed to an integrated single component after rTMS.Our findings demonstrate that genetic background play a fundamental role in the brain responses to focal insults, conditioning expression of distinct brain networks to sustain similar cognitive performance.
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Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease.
Acta Neuropathol.
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Autosomal-dominant Alzheimer disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studies from families with ADAD have been critical to support the amyloid cascade hypothesis of Alzheimer disease (AD), the basis for the current development of amyloid-based disease-modifying therapies in sporadic AD (SAD). However, whether the pathological changes in APP processing in the CNS in ADAD are similar to those observed in SAD remains unclear. In this study, we measured ?-site APP-cleaving enzyme (BACE) protein levels and activity, APP and APP C-terminal fragments in brain samples from subjects with ADAD carrying APP or PSEN1 mutations (n = 18), patients with SAD (n = 27) and age-matched controls (n = 22). We also measured sAPP? and BACE protein levels, as well as BACE activity, in CSF from individuals carrying PSEN1 mutations (10 mutation carriers and 7 non-carrier controls), patients with SAD (n = 32) and age-matched controls (n = 11). We found that in the brain, the pattern in ADAD was characterized by an increase in APP ?-C-terminal fragment (?-CTF) levels despite no changes in BACE protein levels or activity. In contrast, the pattern in SAD in the brain was mainly characterized by an increase in BACE levels and activity, with less APP ?-CTF accumulation than ADAD. In the CSF, no differences were found between groups in BACE activity or expression or sAPP? levels. Taken together, these data suggest that the physiopathological events underlying the chronic A? production/clearance imbalance in SAD and ADAD are different. These differences should be considered in the design of intervention trials in AD.
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Recommendations to standardize preanalytical confounding factors in Alzheimers and Parkinsons disease cerebrospinal fluid biomarkers: an update.
Biomark Med
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Early diagnosis of neurodegenerative disorders such as Alzheimers (AD) or Parkinsons disease (PD) is needed to slow down or halt the disease at the earliest stage. Cerebrospinal fluid (CSF) biomarkers can be a good tool for early diagnosis. However, their use in clinical practice is challenging due to the high variability found between centers in the concentrations of both AD CSF biomarkers (A?42, total tau and phosphorylated tau) and PD CSF biomarker (?-synuclein). Such a variability has been partially attributed to different preanalytical procedures between laboratories, thus highlighting the need to establish standardized operating procedures. Here, we merge two previous consensus guidelines for preanalytical confounding factors in order to achieve one exhaustive guideline updated with new evidence for A?42, total tau and phosphorylated tau, and ?-synuclein. The proposed standardized operating procedures are applicable not only to novel CSF biomarkers in AD and PD, but also to biomarkers for other neurodegenerative disorders.
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Randomized, double-blind, parallel-group, 48-week study for efficacy and safety of a higher-dose rivastigmine patch (15 vs. 10 cm²) in Alzheimers disease.
Dement Geriatr Cogn Disord
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Determine whether patients with Alzheimers disease demonstrating functional and cognitive decline, following 24-48 weeks of open-label treatment with 9.5 mg/24 h (10 cm(2)) rivastigmine patch, benefit from a dose increase in a double-blind (DB) comparative trial of two patch doses.
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[A new approach to the Alzheimers disease diagnosis with biomarkers: description of the AD-CSF-Index].
Rev Neurol
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Studies with cerebrospinal fluid (CSF) biomarkers in patients with confirmed Alzheimers disease (AD) pathology have shown that decreased levels of Abeta(1-42) and increased levels of tau and p-tau, are a specific feature of the AD type pathology.
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The amyloid-? isoform pattern in cerebrospinal fluid in familial PSEN1 M139T- and L286P-associated Alzheimers disease.
Mol Med Rep
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There are several familial forms of Alzheimers disease (AD) most of which are caused by mutations in the genes that encode the presenilin enzymes involved in the production of amyloid-? (A?) from the amyloid precursor protein (APP). In AD, A? forms fibrils that are deposited in the brain as plaques. Much of the fibrillar A? found in the plaques consists of the 42 amino acid form of A? (A?1-42) and it is now widely accepted that A? is related to the pathogenesis of AD and that A? may both impair memory and be neurotoxic. In human cerebrospinal fluid (CSF) several C- and N-terminally truncated A? isoforms have been detected and their relative abundance pattern is thought to reflect the production and clearance of A?. By using immunoprecipitation and mass spectrometry, we have previously demonstrated that carriers of the familial AD (FAD)-associated PSEN1 A431E mutation have low CSF levels of C-terminally truncated A? isoforms shorter than A?1-40. Here we replicate this finding in symptomatic carriers of the FAD-causing PSEN1 L286P mutation. Furthermore, we show that preclinical carriers of the PSEN1 M139T mutation may overexpress A?1-42 suggesting that this particular mutation may cause AD by stimulating ?-secretase-mediated cleavage at amino acid 42 in the A? sequence.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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