Jon Toledo | University of Pennsylvania (original) (raw)

Papers by Jon Toledo

Research paper thumbnail of Epidemiología descriptiva y analítica de la enfermedad de Alzheimer

Documento descargado de http://www.revistaalzheimer.com. Copia para uso personal, se prohíbe la t... more Documento descargado de http://www.revistaalzheimer.com. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato Palabras clave: demencia, enfermedad de Alzheimer, epidemiología, factores de riesgo, etiología.

Research paper thumbnail of Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy

Acta neuropathologica, Jan 10, 2015

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, b... more Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or ...

Research paper thumbnail of Correlating Cognitive Decline with White Matter Lesion and Brain Atrophy Magnetic Resonance Imaging Measurements in Alzheimer's Disease

Journal of Alzheimer's disease : JAD, Jan 27, 2015

Vascular risk factors are increasingly recognized as risks factors for Alzheimer's disease (A... more Vascular risk factors are increasingly recognized as risks factors for Alzheimer's disease (AD) and early conversion from mild cognitive impairment (MCI) to dementia. While neuroimaging research in AD has focused on brain atrophy, metabolic function, or amyloid deposition, little attention has been paid to the effect of cerebrovascular disease to cognitive decline. To investigate the correlation of brain atrophy and white matter lesions with cognitive decline in AD, MCI, and control subjects. Patients with AD and MCI, and healthy subjects were included in this study. Subjects had a baseline MRI scan, and baseline and follow-up neuropsychological battery (CERAD). Regional volumes were measured, and white matter lesion segmentation was performed. Correlations between rate of CERAD score decline and white matter lesion load and brain structure volume were evaluated. In addition, voxel-based correlations between baseline CERAD scores and atrophy and white matter lesion measures were...

Research paper thumbnail of Validation of the Erlangen Score Algorithm for the Prediction of the Development of Dementia due to Alzheimer's Disease in Pre-Dementia Subjects

Journal of Alzheimer's disease : JAD, Jan 9, 2015

In previous studies, a dichotomous stratification of subjects into "cerebrospinal fluid (CSF... more In previous studies, a dichotomous stratification of subjects into "cerebrospinal fluid (CSF) normal" and "CSF pathologic" was used to investigate the role of biomarkers in the prediction of progression to dementia in pre-dementia/mild cognitive impairment subjects. With the previously published Erlangen Score Algorithm, we suggested a division of CSF patterns into five groups, covering all possible CSF result combinations based on the presence of pathologic tau and/or amyloid-β CSF values. This study aimed to validate the Erlangen Score diagnostic algorithm based on the results of biomarkers analyses obtained in different patients cohorts, with different pre-analytical protocols, and with different laboratory analytical platforms. We evaluated the algorithm in two cohorts of pre-dementia subjects: the US-Alzheimer's Disease Neuroimaging Initiative and the German Dementia Competence Network. In both cohorts, the Erlangen scores were strongly associated with p...

Research paper thumbnail of Identifying amyloid pathology–related cerebrospinal fluid biomarkers for Alzheimer's disease in a multicohort study

Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 2015

The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1-42) measurement does not parallel t... more The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1-42) measurement does not parallel to cognitive changes in Alzheimer's disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important. Proteins were profiled using a multianalyte platform by Rules Based Medicine (MAP-RBM). Due to underlying heterogeneity and unbalanced sample size, we combined subjects (344 AD and 325 CN) from three cohorts: Alzheimer's Disease Neuroimaging Initiative, Penn Center for Neurodegenerative Disease Research of the University of Pennsylvania, and Knight Alzheimer's Disease Research Center at Washington University in St. Louis. We focused on samples whose cognitive and amyloid status was consistent. We performed linear regression (accounted for age, gender, number of APOE e4 alleles, and cohort variable) to identify amyloid-related proteins for symptomatic AD subjects in this largest ever CSF-based MAP-RBM study. ANOVA and Tukey's test were used to evaluate if these proteins were related to cognitive impairment changes as measured by mini-mental state examination (MMSE). Seven proteins were significantly associated with Aβ1-42 levels in the combined cohort (false discovery rate adjusted P < .05), of which lipoprotein a (Lp(a)), prolactin (PRL), resistin, and vascular endothelial growth factor (VEGF) have consistent direction of associations across every individual cohort. VEGF was strongly associated with MMSE scores, followed by pancreatic polypeptide and immunoglobulin A (IgA), suggesting they may be related to staging of AD. Lp(a), PRL, IgA, and tissue factor/thromboplastin have never been reported for AD diagnosis in previous individual CSF-based MAP-RBM studies. Although some of our reported analytes are related to AD pathophysiology, others' roles in symptomatic AD samples worth further explorations.

Research paper thumbnail of Retinal Nerve Fiber Layer Atrophy Is Associated With Visual Field Loss Over Time in Glaucoma Suspect and Glaucomatous Eyes

American Journal of Ophthalmology, 2013

PURPOSE: To compare prospectively detection of progressive retinal nerve fiber layer thickness (R... more PURPOSE: To compare prospectively detection of progressive retinal nerve fiber layer thickness (RNFL) atrophy identified using time-domain optical coherence tomography with visual field progression using standard automated perimetry in glaucoma suspect and preperimetric glaucoma patients or perimetric glaucoma patients. DESIGN: Prospective, longitudinal clinical trial. METHODS: Eligible eyes with 2 years or more of followup underwent time-domain optical coherence tomography and standard automated perimetry every 6 months. The occurrence of visual field progression was defined as the first follow-up visit reaching a significant (P < .05) negative visual field index slope over time. RNFL progression or improvement was defined as a significant negative or positive slope over time, respectively. Specificity was defined as the number of eyes with neither progression nor improvement, divided by the number of eyes without progression. Cox proportional hazard ratios were calculated using univariate and multivariate models with RNFL loss as a time-dependent covariate.

Research paper thumbnail of Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects

Brain : a journal of neurology, Jan 27, 2015

In a large multicentre sample of cognitively normal subjects, as a function of age, gender and AP... more In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal ...

Research paper thumbnail of Narrative Speech is Impaired in Multiple Sclerosis

Language is frequently impaired in multiple sclerosis (MS) in which, in addition to dysarthria an... more Language is frequently impaired in multiple sclerosis (MS) in which, in addition to dysarthria and loss of fluency, other language deficits might affect patients and impinge on their quality of life.

Research paper thumbnail of The Alzheimer’s Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans

Alzheimer's & Dementia, 2015

Introduction: We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progr... more Introduction: We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Ab 1-42 ), t-tau, and ptau 181 analytical performance, definition of Alzheimer's disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids. Methods: Review publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSFAb 1-42 , t-tau, and p-tau 181 data. Results: CSF AD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies.

Research paper thumbnail of Role of Brain Infarcts in Behavioral Variant Frontotemporal Dementia

Neurobiology of Aging, 2015

Diagnosing behavioral variant frontotemporal dementia (bvFTD) in patients with prior history of s... more Diagnosing behavioral variant frontotemporal dementia (bvFTD) in patients with prior history of stroke or with silent brain infarcts on neuroimaging studies can be challenging. Vascular changes in patients with bvFTD are not unusual, but bvFTD tends to be ruled out in the presence of cerebrovascular disease. We aimed to identify the clinical, cognitive, and risk factor profile of bvFTD with coexistent cerebrovascular disease (V-bvFTD). We compared demographic data, clinical diagnoses, vascular risk factors, functional status, and normalized neuropsychological z-scores between patients with V-bvFTD versus bvFTD without concomitant cerebrovascular disease (NV-bvFTD) from the National Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Coordinating Centre database. We included 391 neuropathologically-diagnosed cases of frontotemporal lobe degeneration. We excluded patients that were diagnosed with aphasic variants of frontotemporal dementia before death. Patients with V-bvFTD (n = 62) were older at the time of onset of cognitive decline (71.6 vs. 62.5 years, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) and death (78.7 vs. 69.6, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), more likely to be hypertensive (75.8% vs. 45.7%, p = 0.002) and to have a history of stroke (21.2% vs. 6.1%, p = 0.007) than those with NV-bvFTD (n = 329). V-bvFTD was often underdiagnosed, affected elderly patients, and had a similar cognitive profile as NV-bvFTD despite the presence of brain infarcts. In the whole cohort, we observed enhanced cognitive performance with increasing age quintiles despite larger proportions of cerebrovascular disease pathology, likely meaning that frontotemporal lobe degeneration-related primary neurodegeneration exerts a stronger impact on cognition than cerebrovascular disease. Coexisting cerebrovascular disease should not preclude the diagnosis of bvFTD.

Research paper thumbnail of 2012GalbeteGXN

Research paper thumbnail of Prediction of Conversion from MCI to AD: Integration and Relative Values of Brain Atrophy Patterns, Clinical Scores, CSF Biomarkers, and APOE Genotype

PURPOSE We evaluate the individual, as well as relative and joint values of indices obtained from... more PURPOSE We evaluate the individual, as well as relative and joint values of indices obtained from MRI patterns of atrophy, cerebrospinal fluid (CSF) biomarkers, APOE genotype, and cognitive performance for prediction of clinical progression of MCI patients, on an individual person basis. METHOD AND MATERIALS The SPARE-AD index, a previously characterized imaging biomarker capturing spatial patterns of brain atrophy, was first tested for sensitivity and specificity as a biomarker of Alzheimer’s disease (AD), in a training set of 411 participants. SPARE-AD, and a related mild cognitive impairment (MCI)-specific index called SPARE-MCI, were then evaluated at baseline in 212 MCI patients who either converted to AD within 18 months or remained stable for at least 3 years. Baseline predictive value of SPARE-AD, SPARE-MCI, CSF biomarkers (total and phosphorylated tau and Aβ), MMSE, ADAS-Cog, and APOE genotype were then evaluated using a support vector machine classifier. RESULTS SPARE-AD o...

Research paper thumbnail of PART, a distinct tauopathy, different from classical sporadic Alzheimer disease

Acta neuropathologica, Jan 17, 2015

Research paper thumbnail of Mediterranean diet and cognitive function: The sun project

The journal of nutrition, health & aging, 2015

Our aim was to evaluate the association between adherence to the Mediterranean Diet (MedDiet) and... more Our aim was to evaluate the association between adherence to the Mediterranean Diet (MedDiet) and cognitive function in 823 participants (62 ± 6 years at baseline) from a Spanish prospective cohort (SUN project). A validated 136-item food frequency questionnaire was used to assess the adherence to the MedDiet at baseline. The 10-point (0 to 9) MedDiet Score was used to categorize adherence to MedDiet. Cognitive function was assessed twice at follow-up with a mean follow-up time between exposure and outcome assessment of 6 and 8y using the Telephone Interview of Cognitive Status-modified (TICS-m, range 0 to 54 points). ANCOVA models were used to assess the association between adherence to the MedDiet and cognitive decline. In the multivariable-adjusted analysis of 2-year changes, a higher cognitive decline was observed among participants with low or moderate baseline adherence to the MedDiet than among those with better adherence (adjusted difference = -0.56 points in TICS-m, 95% CI = -0.99 to -0.13). A higher adherence to the MedDiet might be associated with better cognitive function. However, observed differences were of small magnitude and further studies are needed to confirm this finding.

Research paper thumbnail of TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord

Acta Neuropathologica, 2014

of columns of 9, 10, and 11 in cases with lower extremity onset. Severe TDP-43 lesions and neuron... more of columns of 9, 10, and 11 in cases with lower extremity onset. Severe TDP-43 lesions and neuronal loss were observed in stage 4 cases and sometimes included Onuf's nucleus. Notably, three cases displayed pTDP-43 aggregates in the midbrain oculomotor nucleus, which we had not seen previously even in cases with advanced (i.e., stage 4) pathology. pTDP-43 aggregates were observed in neurons of Clarke's column in 30.6 % of cases but rarely in the intermediolateral nucleus (IMl). gray matter oligodendroglial pTDP-43 inclusions were present in areas devoid of neuronal pTDP-43 aggregates and neuronal loss. Taken together, our findings indicate that (1) the dorsolateral motor nuclei columns of the cervical and lumbosacral anterior horn may be the earliest foci of pTDP-43 pathology in the spinal cord, (2) gray matter oligodendroglial involvement is an early event in the AlS disease process that possibly heralds subsequent involvement of neurons by pTDP-43 pathology, and (3) in some very advanced cases, there Abstract We examined the phosphorylated 43-kDa TAr DNA-binding protein (pTDP-43) inclusions as well as neuronal loss in full-length spinal cords and five selected regions of the central nervous system from 36 patients with amyotrophic lateral sclerosis (AlS) and 10 age-matched normal controls. The most severe neuronal loss and pTDP-43 lesions were seen in lamina IX motor nuclei columns 4, 6, and 8 of lower cervical segments and in columns 9-11 of lumbosacral segments. Severity of pTDP-43 pathology and neuronal loss correlated closely with gray and white matter oligodendroglial involvement and was linked to onset of disease, with severe involvement of columns 4, 6, and 8 of upper extremity onset cases and severe involvement J. Brettschneider, K. Arai, and K. Del Tredici contributed equally. H. Braak and J. Q. Trojanowski are Senior authors. Electronic supplementary material The online version of this article (eselsberg 45, 89081 Ulm, germany Acta Neuropathol 1 3

Research paper thumbnail of Lifestyle factors modify obesity risk linked to PPARG2 and FTO variants in an elderly population: a cross-sectional analysis in the SUN Project

Genes & Nutrition, 2012

Genetic factors may interact with lifestyle factors to modify obesity risk. FTO and PPARG2 are re... more Genetic factors may interact with lifestyle factors to modify obesity risk. FTO and PPARG2 are relevant obesogenes. Our aim was to explore the effect of Pro12Ala (rs1801282) of PPARG2 and rs9939609 of FTO, on obesity risk and to examine their interaction with lifestyle factors in an elderly population.

Research paper thumbnail of Primary age-related tauopathy (PART): a common pathology associated with human aging

Acta Neuropathologica, 2014

tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is... more tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

Research paper thumbnail of Classification of Sleep Disorders

CONTINUUM: Lifelong Learning in Neurology, 2007

Los trastornos del sueño son una patología muy frecuente tanto aislada, propia como tal, o asocia... more Los trastornos del sueño son una patología muy frecuente tanto aislada, propia como tal, o asociada a otros trastornos. Sin embargo, es una parte de la medicina relativamente nueva, dado que ha sido en los últimos 40 años cuando se ha trabajado realmente en ella, y se han producido los avances tanto diagnósticos como terapéuticos. Las clasificaciones de estas enfermedades han ido sufriendo cierta evolución, fijándose primero en los síntomas, y luego en las enfermedades. La nueva clasificación del 2005 vuelve a basarse en los síntomas. En ella se incluyen más de 90 enfermedades del sueño, y se intentan incluir tanto los síntomas, como las enfermedades propiamente del sueño y aquellas en las que los trastornos del sueño son fundamentales. Conocer y dominar esta completa clasificación es esencial para poder manejar adecuadamente estos pacientes.

Research paper thumbnail of Microglial Activation Correlates with Disease Progression and Upper Motor Neuron Clinical Symptoms in Amyotrophic Lateral Sclerosis

PLoS ONE, 2012

Background/Aims: We evaluated clinicopathological correlates of upper motor neuron (UMN) damage i... more Background/Aims: We evaluated clinicopathological correlates of upper motor neuron (UMN) damage in amyotrophic lateral sclerosis (ALS), and analyzed if the presence of the C9ORF72 repeat expansion was associated with alterations in microglial inflammatory activity.

Research paper thumbnail of Improving Diagnostic Accuracy for Dementia: CSF Biomarker Cutoffs Based on Clinical and Neuropathological Criteria (IN3-1.010)

Research paper thumbnail of Epidemiología descriptiva y analítica de la enfermedad de Alzheimer

Documento descargado de http://www.revistaalzheimer.com. Copia para uso personal, se prohíbe la t... more Documento descargado de http://www.revistaalzheimer.com. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato Palabras clave: demencia, enfermedad de Alzheimer, epidemiología, factores de riesgo, etiología.

Research paper thumbnail of Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy

Acta neuropathologica, Jan 10, 2015

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, b... more Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or ...

Research paper thumbnail of Correlating Cognitive Decline with White Matter Lesion and Brain Atrophy Magnetic Resonance Imaging Measurements in Alzheimer's Disease

Journal of Alzheimer's disease : JAD, Jan 27, 2015

Vascular risk factors are increasingly recognized as risks factors for Alzheimer's disease (A... more Vascular risk factors are increasingly recognized as risks factors for Alzheimer's disease (AD) and early conversion from mild cognitive impairment (MCI) to dementia. While neuroimaging research in AD has focused on brain atrophy, metabolic function, or amyloid deposition, little attention has been paid to the effect of cerebrovascular disease to cognitive decline. To investigate the correlation of brain atrophy and white matter lesions with cognitive decline in AD, MCI, and control subjects. Patients with AD and MCI, and healthy subjects were included in this study. Subjects had a baseline MRI scan, and baseline and follow-up neuropsychological battery (CERAD). Regional volumes were measured, and white matter lesion segmentation was performed. Correlations between rate of CERAD score decline and white matter lesion load and brain structure volume were evaluated. In addition, voxel-based correlations between baseline CERAD scores and atrophy and white matter lesion measures were...

Research paper thumbnail of Validation of the Erlangen Score Algorithm for the Prediction of the Development of Dementia due to Alzheimer's Disease in Pre-Dementia Subjects

Journal of Alzheimer's disease : JAD, Jan 9, 2015

In previous studies, a dichotomous stratification of subjects into "cerebrospinal fluid (CSF... more In previous studies, a dichotomous stratification of subjects into "cerebrospinal fluid (CSF) normal" and "CSF pathologic" was used to investigate the role of biomarkers in the prediction of progression to dementia in pre-dementia/mild cognitive impairment subjects. With the previously published Erlangen Score Algorithm, we suggested a division of CSF patterns into five groups, covering all possible CSF result combinations based on the presence of pathologic tau and/or amyloid-β CSF values. This study aimed to validate the Erlangen Score diagnostic algorithm based on the results of biomarkers analyses obtained in different patients cohorts, with different pre-analytical protocols, and with different laboratory analytical platforms. We evaluated the algorithm in two cohorts of pre-dementia subjects: the US-Alzheimer's Disease Neuroimaging Initiative and the German Dementia Competence Network. In both cohorts, the Erlangen scores were strongly associated with p...

Research paper thumbnail of Identifying amyloid pathology–related cerebrospinal fluid biomarkers for Alzheimer's disease in a multicohort study

Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 2015

The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1-42) measurement does not parallel t... more The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1-42) measurement does not parallel to cognitive changes in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important. Proteins were profiled using a multianalyte platform by Rules Based Medicine (MAP-RBM). Due to underlying heterogeneity and unbalanced sample size, we combined subjects (344 AD and 325 CN) from three cohorts: Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Disease Neuroimaging Initiative, Penn Center for Neurodegenerative Disease Research of the University of Pennsylvania, and Knight Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Disease Research Center at Washington University in St. Louis. We focused on samples whose cognitive and amyloid status was consistent. We performed linear regression (accounted for age, gender, number of APOE e4 alleles, and cohort variable) to identify amyloid-related proteins for symptomatic AD subjects in this largest ever CSF-based MAP-RBM study. ANOVA and Tukey&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s test were used to evaluate if these proteins were related to cognitive impairment changes as measured by mini-mental state examination (MMSE). Seven proteins were significantly associated with Aβ1-42 levels in the combined cohort (false discovery rate adjusted P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05), of which lipoprotein a (Lp(a)), prolactin (PRL), resistin, and vascular endothelial growth factor (VEGF) have consistent direction of associations across every individual cohort. VEGF was strongly associated with MMSE scores, followed by pancreatic polypeptide and immunoglobulin A (IgA), suggesting they may be related to staging of AD. Lp(a), PRL, IgA, and tissue factor/thromboplastin have never been reported for AD diagnosis in previous individual CSF-based MAP-RBM studies. Although some of our reported analytes are related to AD pathophysiology, others&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; roles in symptomatic AD samples worth further explorations.

Research paper thumbnail of Retinal Nerve Fiber Layer Atrophy Is Associated With Visual Field Loss Over Time in Glaucoma Suspect and Glaucomatous Eyes

American Journal of Ophthalmology, 2013

PURPOSE: To compare prospectively detection of progressive retinal nerve fiber layer thickness (R... more PURPOSE: To compare prospectively detection of progressive retinal nerve fiber layer thickness (RNFL) atrophy identified using time-domain optical coherence tomography with visual field progression using standard automated perimetry in glaucoma suspect and preperimetric glaucoma patients or perimetric glaucoma patients. DESIGN: Prospective, longitudinal clinical trial. METHODS: Eligible eyes with 2 years or more of followup underwent time-domain optical coherence tomography and standard automated perimetry every 6 months. The occurrence of visual field progression was defined as the first follow-up visit reaching a significant (P < .05) negative visual field index slope over time. RNFL progression or improvement was defined as a significant negative or positive slope over time, respectively. Specificity was defined as the number of eyes with neither progression nor improvement, divided by the number of eyes without progression. Cox proportional hazard ratios were calculated using univariate and multivariate models with RNFL loss as a time-dependent covariate.

Research paper thumbnail of Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects

Brain : a journal of neurology, Jan 27, 2015

In a large multicentre sample of cognitively normal subjects, as a function of age, gender and AP... more In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal ...

Research paper thumbnail of Narrative Speech is Impaired in Multiple Sclerosis

Language is frequently impaired in multiple sclerosis (MS) in which, in addition to dysarthria an... more Language is frequently impaired in multiple sclerosis (MS) in which, in addition to dysarthria and loss of fluency, other language deficits might affect patients and impinge on their quality of life.

Research paper thumbnail of The Alzheimer’s Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans

Alzheimer's & Dementia, 2015

Introduction: We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progr... more Introduction: We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Ab 1-42 ), t-tau, and ptau 181 analytical performance, definition of Alzheimer's disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids. Methods: Review publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSFAb 1-42 , t-tau, and p-tau 181 data. Results: CSF AD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies.

Research paper thumbnail of Role of Brain Infarcts in Behavioral Variant Frontotemporal Dementia

Neurobiology of Aging, 2015

Diagnosing behavioral variant frontotemporal dementia (bvFTD) in patients with prior history of s... more Diagnosing behavioral variant frontotemporal dementia (bvFTD) in patients with prior history of stroke or with silent brain infarcts on neuroimaging studies can be challenging. Vascular changes in patients with bvFTD are not unusual, but bvFTD tends to be ruled out in the presence of cerebrovascular disease. We aimed to identify the clinical, cognitive, and risk factor profile of bvFTD with coexistent cerebrovascular disease (V-bvFTD). We compared demographic data, clinical diagnoses, vascular risk factors, functional status, and normalized neuropsychological z-scores between patients with V-bvFTD versus bvFTD without concomitant cerebrovascular disease (NV-bvFTD) from the National Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Coordinating Centre database. We included 391 neuropathologically-diagnosed cases of frontotemporal lobe degeneration. We excluded patients that were diagnosed with aphasic variants of frontotemporal dementia before death. Patients with V-bvFTD (n = 62) were older at the time of onset of cognitive decline (71.6 vs. 62.5 years, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) and death (78.7 vs. 69.6, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), more likely to be hypertensive (75.8% vs. 45.7%, p = 0.002) and to have a history of stroke (21.2% vs. 6.1%, p = 0.007) than those with NV-bvFTD (n = 329). V-bvFTD was often underdiagnosed, affected elderly patients, and had a similar cognitive profile as NV-bvFTD despite the presence of brain infarcts. In the whole cohort, we observed enhanced cognitive performance with increasing age quintiles despite larger proportions of cerebrovascular disease pathology, likely meaning that frontotemporal lobe degeneration-related primary neurodegeneration exerts a stronger impact on cognition than cerebrovascular disease. Coexisting cerebrovascular disease should not preclude the diagnosis of bvFTD.

Research paper thumbnail of 2012GalbeteGXN

Research paper thumbnail of Prediction of Conversion from MCI to AD: Integration and Relative Values of Brain Atrophy Patterns, Clinical Scores, CSF Biomarkers, and APOE Genotype

PURPOSE We evaluate the individual, as well as relative and joint values of indices obtained from... more PURPOSE We evaluate the individual, as well as relative and joint values of indices obtained from MRI patterns of atrophy, cerebrospinal fluid (CSF) biomarkers, APOE genotype, and cognitive performance for prediction of clinical progression of MCI patients, on an individual person basis. METHOD AND MATERIALS The SPARE-AD index, a previously characterized imaging biomarker capturing spatial patterns of brain atrophy, was first tested for sensitivity and specificity as a biomarker of Alzheimer’s disease (AD), in a training set of 411 participants. SPARE-AD, and a related mild cognitive impairment (MCI)-specific index called SPARE-MCI, were then evaluated at baseline in 212 MCI patients who either converted to AD within 18 months or remained stable for at least 3 years. Baseline predictive value of SPARE-AD, SPARE-MCI, CSF biomarkers (total and phosphorylated tau and Aβ), MMSE, ADAS-Cog, and APOE genotype were then evaluated using a support vector machine classifier. RESULTS SPARE-AD o...

Research paper thumbnail of PART, a distinct tauopathy, different from classical sporadic Alzheimer disease

Acta neuropathologica, Jan 17, 2015

Research paper thumbnail of Mediterranean diet and cognitive function: The sun project

The journal of nutrition, health & aging, 2015

Our aim was to evaluate the association between adherence to the Mediterranean Diet (MedDiet) and... more Our aim was to evaluate the association between adherence to the Mediterranean Diet (MedDiet) and cognitive function in 823 participants (62 ± 6 years at baseline) from a Spanish prospective cohort (SUN project). A validated 136-item food frequency questionnaire was used to assess the adherence to the MedDiet at baseline. The 10-point (0 to 9) MedDiet Score was used to categorize adherence to MedDiet. Cognitive function was assessed twice at follow-up with a mean follow-up time between exposure and outcome assessment of 6 and 8y using the Telephone Interview of Cognitive Status-modified (TICS-m, range 0 to 54 points). ANCOVA models were used to assess the association between adherence to the MedDiet and cognitive decline. In the multivariable-adjusted analysis of 2-year changes, a higher cognitive decline was observed among participants with low or moderate baseline adherence to the MedDiet than among those with better adherence (adjusted difference = -0.56 points in TICS-m, 95% CI = -0.99 to -0.13). A higher adherence to the MedDiet might be associated with better cognitive function. However, observed differences were of small magnitude and further studies are needed to confirm this finding.

Research paper thumbnail of TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord

Acta Neuropathologica, 2014

of columns of 9, 10, and 11 in cases with lower extremity onset. Severe TDP-43 lesions and neuron... more of columns of 9, 10, and 11 in cases with lower extremity onset. Severe TDP-43 lesions and neuronal loss were observed in stage 4 cases and sometimes included Onuf's nucleus. Notably, three cases displayed pTDP-43 aggregates in the midbrain oculomotor nucleus, which we had not seen previously even in cases with advanced (i.e., stage 4) pathology. pTDP-43 aggregates were observed in neurons of Clarke's column in 30.6 % of cases but rarely in the intermediolateral nucleus (IMl). gray matter oligodendroglial pTDP-43 inclusions were present in areas devoid of neuronal pTDP-43 aggregates and neuronal loss. Taken together, our findings indicate that (1) the dorsolateral motor nuclei columns of the cervical and lumbosacral anterior horn may be the earliest foci of pTDP-43 pathology in the spinal cord, (2) gray matter oligodendroglial involvement is an early event in the AlS disease process that possibly heralds subsequent involvement of neurons by pTDP-43 pathology, and (3) in some very advanced cases, there Abstract We examined the phosphorylated 43-kDa TAr DNA-binding protein (pTDP-43) inclusions as well as neuronal loss in full-length spinal cords and five selected regions of the central nervous system from 36 patients with amyotrophic lateral sclerosis (AlS) and 10 age-matched normal controls. The most severe neuronal loss and pTDP-43 lesions were seen in lamina IX motor nuclei columns 4, 6, and 8 of lower cervical segments and in columns 9-11 of lumbosacral segments. Severity of pTDP-43 pathology and neuronal loss correlated closely with gray and white matter oligodendroglial involvement and was linked to onset of disease, with severe involvement of columns 4, 6, and 8 of upper extremity onset cases and severe involvement J. Brettschneider, K. Arai, and K. Del Tredici contributed equally. H. Braak and J. Q. Trojanowski are Senior authors. Electronic supplementary material The online version of this article (eselsberg 45, 89081 Ulm, germany Acta Neuropathol 1 3

Research paper thumbnail of Lifestyle factors modify obesity risk linked to PPARG2 and FTO variants in an elderly population: a cross-sectional analysis in the SUN Project

Genes & Nutrition, 2012

Genetic factors may interact with lifestyle factors to modify obesity risk. FTO and PPARG2 are re... more Genetic factors may interact with lifestyle factors to modify obesity risk. FTO and PPARG2 are relevant obesogenes. Our aim was to explore the effect of Pro12Ala (rs1801282) of PPARG2 and rs9939609 of FTO, on obesity risk and to examine their interaction with lifestyle factors in an elderly population.

Research paper thumbnail of Primary age-related tauopathy (PART): a common pathology associated with human aging

Acta Neuropathologica, 2014

tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is... more tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

Research paper thumbnail of Classification of Sleep Disorders

CONTINUUM: Lifelong Learning in Neurology, 2007

Los trastornos del sueño son una patología muy frecuente tanto aislada, propia como tal, o asocia... more Los trastornos del sueño son una patología muy frecuente tanto aislada, propia como tal, o asociada a otros trastornos. Sin embargo, es una parte de la medicina relativamente nueva, dado que ha sido en los últimos 40 años cuando se ha trabajado realmente en ella, y se han producido los avances tanto diagnósticos como terapéuticos. Las clasificaciones de estas enfermedades han ido sufriendo cierta evolución, fijándose primero en los síntomas, y luego en las enfermedades. La nueva clasificación del 2005 vuelve a basarse en los síntomas. En ella se incluyen más de 90 enfermedades del sueño, y se intentan incluir tanto los síntomas, como las enfermedades propiamente del sueño y aquellas en las que los trastornos del sueño son fundamentales. Conocer y dominar esta completa clasificación es esencial para poder manejar adecuadamente estos pacientes.

Research paper thumbnail of Microglial Activation Correlates with Disease Progression and Upper Motor Neuron Clinical Symptoms in Amyotrophic Lateral Sclerosis

PLoS ONE, 2012

Background/Aims: We evaluated clinicopathological correlates of upper motor neuron (UMN) damage i... more Background/Aims: We evaluated clinicopathological correlates of upper motor neuron (UMN) damage in amyotrophic lateral sclerosis (ALS), and analyzed if the presence of the C9ORF72 repeat expansion was associated with alterations in microglial inflammatory activity.

Research paper thumbnail of Improving Diagnostic Accuracy for Dementia: CSF Biomarker Cutoffs Based on Clinical and Neuropathological Criteria (IN3-1.010)