Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
1.
medRxiv ; 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38562801

RESUMO

Objective: To identify imaging subtypes of the cortico-basal syndrome (CBS) based solely on a data-driven assessment of MRI atrophy patterns, and investigate whether these subtypes provide information on the underlying pathology. Methods: We applied Subtype and Stage Inference (SuStaIn), a machine learning algorithm that identifies groups of individuals with distinct biomarker progression patterns, to a large cohort of 135 CBS cases (52 had a pathological or biomarker defined diagnosis) and 252 controls. The model was fit using volumetric features extracted from baseline T1-weighted MRI scans and validated using follow-up MRI. We compared the clinical phenotypes of each subtype and investigated whether there were differences in associated pathology between the subtypes. Results: SuStaIn identified two subtypes with distinct sequences of atrophy progression; four-repeat-tauopathy confirmed cases were most commonly assigned to the Subcortical subtype (83% of CBS-PSP and 75% of CBS-CBD), while CBS-AD was most commonly assigned to the Fronto-parieto-occipital subtype (81% of CBS-AD). Subtype assignment was stable at follow-up (98% of cases), and individuals consistently progressed to higher stages (100% stayed at the same stage or progressed), supporting the model's ability to stage progression. Interpretation: By jointly modelling disease stage and subtype, we provide data-driven evidence for at least two distinct and longitudinally stable spatiotemporal subtypes of atrophy in CBS that are associated with different underlying pathologies. In the absence of sensitive and specific biomarkers, accurately subtyping and staging individuals with CBS at baseline has important implications for screening on entry into clinical trials, as well as for tracking disease progression.

2.
Alzheimers Dement ; 16(1): 91-105, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914227

RESUMO

INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.


Assuntos
Cognição/fisiologia , Exercício Físico , Degeneração Lobar Frontotemporal , Atividades de Lazer , Testes Neuropsicológicos/estatística & dados numéricos , Idoso , Atrofia/patologia , Feminino , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
3.
Neuroimage Clin ; 23: 101822, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31003069

RESUMO

OBJECTIVE: We aimed to understand the impact of dopamine receptor D4 (DRD4) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD4dampened-variants with reduced functional potency would be associated with greater atrophy in regions with higher receptor density. Given that DRD4 is concentrated in anterior regions of the limbic and cortical forebrain we anticipated genotype effects in patients with a more rostral pattern of neurodegeneration. METHODS: 337 subjects, including healthy controls, patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) underwent genotyping, structural MRI, and cognitive/behavioral testing. We conducted whole-brain voxel-based morphometry to examine the relationship between DRD4 genotypes and brain atrophy patterns within and across groups. General linear modeling was used to evaluate relationships between genotype and cognitive/behavioral measures. RESULTS: DRD4 dampened-variants predicted gray matter atrophy in disease-specific regions of FTD in anterior cingulate, ventromedial prefrontal, orbitofrontal and insular cortices on the right greater than the left. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD. These results covaried with frontoinsular cortical atrophy. Peak atrophy patterned along regions of neuroanatomic vulnerability in FTD-spectrum disorders. In AD subjects and controls, genotype did not impact gray matter intensity. CONCLUSIONS: We conclude that DRD4 polymorphisms with reduced functional potency exacerbate neuronal injury in sites of higher receptor density, which intersect with syndrome-specific regions undergoing neurodegeneration in FTD.


Assuntos
Encéfalo/patologia , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Receptores de Dopamina D4/genética , Receptores de Dopamina D4/fisiologia , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Atrofia , Feminino , Demência Frontotemporal/psicologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Polimorfismo Genético , Síndrome
4.
Neuropathol Appl Neurobiol ; 45(1): 81-87, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30422329

RESUMO

Frontotemporal dementias (FTDs) are clinically, genetically and pathologically heterogeneous neurodegenerative disorders that affect the frontal and anterior temporal lobes of the brain. They are relatively common causes of young-onset dementia and usually present with behavioural disturbance (behavioural variant FTD) or language impairment (primary progressive aphasia), but there is also overlap with motor neurone disease and the atypical parkinsonian disorders, corticobasal syndrome and progressive supranuclear palsy. At post mortem, neuronal inclusions containing tau, TDP-43 or infrequently FUS protein are seen in most cases. However, a poor correlation between clinical syndrome and underlying pathology means that it is difficult to diagnose the underlying molecular basis using clinical criteria. At this point, biomarkers for the underlying pathology come into play. This paper provides a brief update on fluid biomarkers for FTDs that may be useful to dissect the underlying molecular changes in patients presenting with signs of frontal and/or temporal lobe dysfunction. The hope is that such biomarkers, together with genetics and imaging, would be useful in clinical trials of novel drug candidates directed against specific pathologies and, in the long run, helpful in clinical practice to select the most appropriate treatment at the right dose for individual patients.


Assuntos
Biomarcadores/metabolismo , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/metabolismo , Humanos
5.
Cytokine ; 111: 481-489, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29908923

RESUMO

BACKGROUND: Quantification of biofluid cytokines is a rapidly growing area of translational research. However, comparability across the expanding number of available assay platforms for detection of the same proteins remains to be determined. We aimed to directly compare a panel of commonly measured cytokines in plasma of typically aging adults across two high sensitivity quantification platforms, Meso Scale Discovery high performance electrochemiluminiscence (HPE) and single-molecule immunosorbent assays (Simoa) by Quanterix. METHODS: 57 community-dwelling older adults completed a blood draw, neuropsychological assessment, and brain MRI as part of a healthy brain aging study. Plasma samples from the same draw dates were analyzed for IL-10, IP-10, IL-6, TNFα, and IL-1ß on HPE and Simoa, separately. Reliable detectability (coefficient of variance (CV) < 20% and outliers 3 interquartiles above the median removed), intra-assay precision, absolute concentrations, reproducibility across platforms, and concurrent associations with external variables of interest (e.g., demographics, peripheral markers of vascular health, and brain health) were examined. RESULTS: The proportion of cytokines reliably measured on HPE (87.7-93.0%) and Simoa (75.4-93.0%) did not differ (ps > 0.32), with the exception of IL-1ß which was only reliably measured using Simoa (68.4%). On average, CVs were acceptable at <8% across both platforms. Absolute measured concentrations were higher using Simoa for IL-10, IL-6, and TNFα (ps < 0.05). HPE and Simoa shared only small-to-moderate proportions of variance with one another on the same cytokine proteins (range: r = 0.26 for IL-10 to r = 0.64 for IL-6), though platform agreement did not dependent on cytokine concentrations. Cytokine ratios within each platform demonstrated similar relative patterns of up- and down-regulation across HPE and Simoa, though still significantly differed (ps < 0.001). Supporting concurrent validity, all 95% confidence intervals of the correlations between cytokines and external variables overlapped between the two platforms. Moreover, most associations were in expected directions and consistently so across platforms (e.g., IL-6 and TNFα), though with several notable exceptions for IP-10 and IL-10. CONCLUSIONS: HPE and Simoa showed comparable detectability and intra-assay precision measuring a panel of commonly examined cytokine proteins, with the exception of IL-1ß which was not reliably detected on HPE. However, Simoa demonstrated overall higher concentrations and the two platforms did not show agreement when directly compared against one another. Relative cytokine ratios and associations demonstrated similar patterns across platforms. Absolute cytokine concentrations may not be directly comparable across platforms, may be analyte dependent, and interpretation may be best limited to discussion of relative associations.


Assuntos
Biomarcadores/sangue , Biomarcadores/metabolismo , Citocinas/sangue , Citocinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunoensaio/métodos , Interleucina-10/sangue , Interleucina-10/metabolismo , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Interleucina-6/sangue , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo
6.
Neurology ; 78(21): 1663-9, 2012 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-22573634

RESUMO

OBJECTIVE: We sought to determine whether the Val(158)Met polymorphism in the catechol-O-methyltransferase (COMT) gene influences neurodegeneration within dopamine-innervated brain regions. METHODS: A total of 252 subjects, including healthy controls and patients with Alzheimer disease, behavioral variant frontotemporal dementia, and semantic dementia, underwent COMT genotyping and structural MRI. RESULTS: Whole-brain voxel-wise regression analyses revealed that COMT Val(158)Met Val allele dosage, known to produce a dose-dependent decrease in synaptic dopamine (DA) availability, correlated with decreased gray matter in the region of the ventral tegmental area (VTA), ventromedial prefrontal cortex, bilateral dorsal midinsula, left dorsolateral prefrontal cortex, and right ventral striatum. Unexpectedly, patients carrying a Met allele showed greater VTA volumes than age-matched controls. Gray matter intensities within COMT-related brain regions correlated with cognitive and behavioral deficits. CONCLUSIONS: The results are consistent with the hypothesis that increased synaptic DA catabolism promotes neurodegeneration within DA-innervated brain regions.


Assuntos
Catecol O-Metiltransferase/genética , Córtex Cerebral/patologia , Demência/patologia , Dopamina/fisiologia , Idoso , Alelos , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Córtex Cerebral/metabolismo , Demência/etiologia , Dopamina/genética , Feminino , Demência Frontotemporal/etiologia , Demência Frontotemporal/patologia , Degeneração Lobar Frontotemporal/etiologia , Degeneração Lobar Frontotemporal/patologia , Genótipo , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Metionina/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Valina/genética
7.
Neurology ; 78(23): 1824-31, 2012 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-22573640

RESUMO

OBJECTIVE: To create and validate a simple, standardized version of the antisaccade (AS) task that requires no specialized equipment for use as a measure of executive function in multicenter clinical studies. METHODS: The bedside AS (BAS) task consisted of 40 pseudorandomized AS trials presented on a laptop computer. BAS performance was compared with AS performance measured using an infrared eye tracker in normal elders (NE) and individuals with mild cognitive impairment (MCI) or dementia (n = 33). The neuropsychological domain specificity of the BAS was then determined in a cohort of NE, MCI, and dementia (n = 103) at UCSF, and the BAS was validated as a measure of executive function in a 6-center cohort (n = 397) of normal adults and patients with a variety of brain diseases. RESULTS: Performance on the BAS and laboratory AS task was strongly correlated and BAS performance was most strongly associated with neuropsychological measures of executive function. Even after controlling for disease severity and processing speed, BAS performance was associated with multiple assessments of executive function, most strongly the informant-based Frontal Systems Behavior Scale. CONCLUSIONS: The BAS is a simple, valid measure of executive function in aging and neurologic disease.


Assuntos
Encefalopatias/fisiopatologia , Função Executiva/fisiologia , Testes Neuropsicológicos/normas , Movimentos Sacádicos/fisiologia , Idoso , Envelhecimento/fisiologia , Disfunção Cognitiva/fisiopatologia , Estudos de Coortes , Demência/fisiopatologia , Medições dos Movimentos Oculares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
Neurology ; 76(5): 475-83, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21282594

RESUMO

OBJECTIVE: To derive an algorithm for genetic testing of patients with frontotemporal lobar degeneration (FTLD). METHODS: A literature search was performed to review the clinical and pathologic phenotypes and family history associated with each FTLD gene. RESULTS: Based on the literature review, an algorithm was developed to allow clinicians to use the clinical and neuroimaging phenotypes of the patient and the family history and autopsy information to decide whether or not genetic testing is warranted, and if so, the order for appropriate tests. CONCLUSIONS: Recent findings in genetics, pathology, and imaging allow clinicians to use the clinical presentation of the patient with FTLD to inform genetic testing decisions.


Assuntos
Algoritmos , Degeneração Lobar Frontotemporal/diagnóstico , Degeneração Lobar Frontotemporal/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Testes Genéticos/normas , Proteínas do Tecido Nervoso/genética , Adulto , Idoso , Análise Mutacional de DNA/métodos , Análise Mutacional de DNA/normas , Árvores de Decisões , Diagnóstico Diferencial , Feminino , Degeneração Lobar Frontotemporal/fisiopatologia , Testes Genéticos/economia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Fenótipo
9.
Neurology ; 69(3): 283-90, 2007 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-17636066

RESUMO

OBJECTIVE: To compare the in vivo uptake of two amyloid-binding PET agents, PIB and FDDNP, in human subjects with a prion protein (PrP) gene (PRNP) mutation that produces a clinical syndrome similar to Alzheimer disease (AD). BACKGROUND: Amyloid imaging with specific PET ligands offers great promise for early detection and differential diagnosis of AD. Genetic forms of prion disease can present with clinical features that resemble AD, and at autopsy may show deposition of mutant PrP-amyloid. FDDNP binds to PrP-amyloid in postmortem human specimens, but has not been reported in vivo in prion disease. The ability of PIB to bind PrP-amyloid is not known. METHODS: Two brothers with a 6 octapeptide repeat insertion mutation (6-OPRI) in the PRNP gene underwent clinical, structural MRI, and FDG-PET evaluations. One brother received a PIB-PET evaluation, while the other received an FDDNP-PET scan. PET results were compared with five normal subjects and five individuals with AD scanned with either agent. RESULTS: PIB uptake was similar to controls in one brother, while FDDNP uptake was intermediate between AD and controls in the other brother. CONCLUSIONS: Different amyloid-binding agents may have differential sensitivity to prion-related brain pathology. A combination of amyloid imaging agents may be useful in the diagnosis of early-onset dementia.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Amiloide/análise , Tomografia por Emissão de Pósitrons/métodos , Doenças Priônicas/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Mutação , Doenças Priônicas/diagnóstico , Doenças Priônicas/genética
10.
Neurology ; 67(7): 1265-7, 2006 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-17030763

RESUMO

The neurocognitive features of juvenile-onset Huntington disease (HD) are not well understood. We present three patients with onset of HD symptoms before age 10 years in whom speech delay was the first symptom. Speech delay predated motor symptoms by at least 2 years, and language function was consistently impaired on formal testing. Screening for speech delay is particularly important in children with a family history of HD.


Assuntos
Doença de Huntington/complicações , Doença de Huntington/diagnóstico , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Prognóstico
11.
Neurology ; 64(8): 1431-4, 2005 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-15851736

RESUMO

An elevated serum homocysteine level is a risk factor for the development of cognitive impairment. Reported is a late-onset case of hyperhomocystinemia due to a vitamin B12 metabolic deficit (cobalamin C) with cognitive impairment, primarily in frontal/executive function. After homocysteine-lowering therapy, the patient's functional and neuropsychological status improved in conjunction with a decrease in leukoariosis on his MRI scan. These findings suggest that homocysteine-related cognitive impairment may be partially reversible.


Assuntos
Transtornos Cognitivos/etiologia , Confusão/etiologia , Homocisteína/sangue , Hiper-Homocisteinemia/complicações , Leucoaraiose/etiologia , Convulsões/etiologia , Adulto , Anticoagulantes/uso terapêutico , Betaína/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/metabolismo , Confusão/tratamento farmacológico , Confusão/metabolismo , Progressão da Doença , Quimioterapia Combinada , Ácido Fólico/uso terapêutico , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Lobo Frontal/fisiopatologia , Homocisteína/antagonistas & inibidores , Humanos , Hiper-Homocisteinemia/tratamento farmacológico , Hiper-Homocisteinemia/fisiopatologia , Leucoaraiose/diagnóstico , Leucoaraiose/tratamento farmacológico , Imageamento por Ressonância Magnética , Masculino , Ácido Metilmalônico/sangue , Ácido Metilmalônico/metabolismo , Indução de Remissão , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Resultado do Tratamento , Vitamina B 12/metabolismo , Vitamina B 12/uso terapêutico , Vitamina B 6/uso terapêutico
12.
Neurology ; 61(11): 1485-91, 2003 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-14663029

RESUMO

OBJECTIVE: To explore the structural neuroimaging correlates of visual constructive impairment in patients with mild to moderate Alzheimer disease (AD). BACKGROUND: There is considerable heterogeneity in the non-memory cognitive deficits associated with AD. Structural neuroimaging with MRI is an important diagnostic tool that is gaining acceptance as a surrogate measure of brain pathology in AD treatment trials. Most MRI measurements have focused on medial temporal lobe or global cortical atrophy, which may not reflect some important clinical features of AD. METHODS: Thirty-two patients with probable AD were stratified into two groups based on their relative performance on a visual constructive task, the copy of a modified Rey-Osterrieth figure (Rey). The two groups did not differ in basic demographic features or in neuropsychological performance, other than on the visual constructive task. MRI measurements of hippocampal volume, cortical gray matter volume, and focal cortical gray matter loss were performed in the patients and a group of 71 age-matched, normal controls. RESULTS: Both groups showed significant, bilateral hippocampal as well as cortical gray matter volume loss relative to controls. The more spatially impaired AD group (SAD) had more right than left cortical gray matter loss, whereas the opposite was true in the less spatially impaired group (NSAD). The SAD group had significantly less gray matter in the right inferior temporal gyrus relative to the NSAD group. Atrophy of this region was correlated with performance on the Rey task in all patients with AD. CONCLUSIONS: Right inferotemporal atrophy may serve as a neuroimaging marker of visual constructive impairment in mild to moderate AD. Heterogeneous cortical atrophy is a common feature of AD.


Assuntos
Doença de Alzheimer/patologia , Lobo Temporal/patologia , Transtornos da Visão/patologia , Idoso , Doença de Alzheimer/diagnóstico , Atrofia , Córtex Cerebral/patologia , Feminino , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos da Visão/diagnóstico
13.
J Neurophysiol ; 82(6): 3367-77, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10601468

RESUMO

Peptide growth factors such as the neurotrophins and fibroblast growth factors have potent effects on synaptic transmission, development, and cell survival. We report that chronic (hours) treatment with basic fibroblast growth factor (FGF-2) potentiates Ca(2+)-dependent N-methyl-D-aspartate (NMDA) receptor inactivation in cultured hippocampal neurons. This effect is specific for the NMDA-subtype of ionotropic glutamate receptor and FGF-2. The potentiated inactivation requires ongoing protein synthesis during growth factor treatment and the activity of protein phosphatase 2B (PP2B or calcineurin) during agonist application. These results suggest a mechanism by which FGF-2 receptor signaling may regulate neuronal survival and synaptic plasticity.


Assuntos
Cálcio/fisiologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Actinina/fisiologia , Animais , Calcineurina/metabolismo , Canais de Cálcio/fisiologia , Células Cultivadas , Estimulação Elétrica , Eletrofisiologia , Hipocampo/citologia , Imuno-Histoquímica , Ativação do Canal Iônico/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Técnicas de Patch-Clamp , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...