RESUMO
Although MRI assessment of white matter lesions is essential for the clinical management of multiple sclerosis, the processes leading to the formation of lesions and underlying their subsequent MRI appearance are incompletely understood. We used proton MR spectroscopy to study the evolution of N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho), and myo-inositol (mI) in pre-lesional tissue, persistent and transient new lesions, as well as in chronic lesions, and related the results to quantitative MRI measures of T1-hypointensity and T2-volume. Within 10 patients with relapsing-remitting course, there were 180 regions-of-interest consisting of up to seven semi-annual follow-ups of normal-appearing white matter (NAWM, n = 10), pre-lesional tissue giving rise to acute lesions which resolved (n = 3) or persisted (n = 3), and of moderately (n = 9) and severely hypointense (n = 6) chronic lesions. Compared with NAWM, pre-lesional tissue had higher Cr and Cho, while compared with lesions, pre-lesional tissue had higher NAA. Resolving acute lesions showed similar NAA levels pre- and post-formation, suggesting no long-term axonal damage. In chronic lesions, there was an increase in mI, suggesting accumulating astrogliosis. Lesion volume was a better predictor of axonal health than T1-hypointensity, with lesions larger than 1.5 cm3 uniformly exhibiting very low (<4.5 millimolar) NAA concentrations. A positive correlation between longitudinal changes in Cho and in lesion volume in moderately hypointense lesions implied that lesion size is mediated by chronic inflammation. These and other results are integrated in a discussion on the steady-state metabolism of lesion evolution in multiple sclerosis, viewed in the context of conventional MRI measures. Hum Brain Mapp 38:4047-4063, 2017. © 2017 Wiley Periodicals, Inc.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Imageamento por Ressonância Magnética , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Adulto , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Colina/metabolismo , Creatina/metabolismo , Estudos Transversais , Progressão da Doença , Feminino , Seguimentos , Humanos , Inositol/metabolismo , Estudos Longitudinais , Masculino , Tamanho do Órgão , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Adulto JovemRESUMO
Total N-acetyl-aspartate + N-acetyl-aspartate-glutamate (NAA), total creatine (Cr) and total choline (Cho) proton MRS (1 H-MRS) signals are often used as surrogate markers in diffuse neurological pathologies, but spatial coverage of this methodology is limited to 1%-65% of the brain. Here we wish to demonstrate that non-localized, whole-head (WH) 1 H-MRS captures just the brain's contribution to the Cho and Cr signals, ignoring all other compartments. Towards this end, 27 young healthy adults (18 men, 9 women), 29.9 ± 8.5 years old, were recruited and underwent T1 -weighted MRI for tissue segmentation, non-localizing, approximately 3 min WH 1 H-MRS (TE /TR /TI = 5/10/940 ms) and 30 min 1 H-MR spectroscopic imaging (MRSI) (TE /TR = 35/2100 ms) in a 360 cm3 volume of interest (VOI) at the brain's center. The VOI absolute NAA, Cr and Cho concentrations, 7.7 ± 0.5, 5.5 ± 0.4 and 1.3 ± 0.2 mM, were all within 10% of the WH: 8.6 ± 1.1, 6.0 ± 1.0 and 1.3 ± 0.2 mM. The mean NAA/Cr and NAA/Cho ratios in the WH were only slightly higher than the "brain-only" VOI: 1.5 versus 1.4 (7%) and 6.6 versus 5.9 (11%); Cho/Cr were not different. The brain/WH volume ratio was 0.31 ± 0.03 (brain ≈ 30% of WH volume). Air-tissue susceptibility-driven local magnetic field changes going from the brain outwards showed sharp gradients of more than 100 Hz/cm (1 ppm/cm), explaining the skull's Cr and Cho signal losses through resonance shifts, line broadening and destructive interference. The similarity of non-localized WH and localized VOI NAA, Cr and Cho concentrations and their ratios suggests that their signals originate predominantly from the brain. Therefore, the fast, comprehensive WH-1 H-MRS method may facilitate quantification of these metabolites, which are common surrogate markers in neurological disorders.
Assuntos
Encéfalo/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Prótons , Adolescente , Adulto , Ácido Aspártico/análogos & derivados , Colina/metabolismo , Creatina/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Concentration of the neuronal marker, N-acetylaspartate (NAA), a quantitative metric for the health and density of neurons, is currently obtained by integration of the manually defined peak in whole-head proton ((1) H)-MRS. Our goal was to develop a full spectral modeling approach for the automatic estimation of the whole-brain NAA concentration (WBNAA) and to compare the performance of this approach with a manual frequency-range peak integration approach previously employed. MRI and whole-head (1) H-MRS from 18 healthy young adults were examined. Non-localized, whole-head (1) H-MRS obtained at 3 T yielded the NAA peak area through both manually defined frequency-range integration and the new, full spectral simulation. The NAA peak area was converted into an absolute amount with phantom replacement and normalized for brain volume (segmented from T1 -weighted MRI) to yield WBNAA. A paired-sample t test was used to compare the means of the WBNAA paradigms and a likelihood ratio test used to compare their coefficients of variation. While the between-subject WBNAA means were nearly identical (12.8 ± 2.5 mm for integration, 12.8 ± 1.4 mm for spectral modeling), the latter's standard deviation was significantly smaller (by ~50%, p = 0.026). The within-subject variability was 11.7% (±1.3 mm) for integration versus 7.0% (±0.8 mm) for spectral modeling, i.e., a 40% improvement. The (quantifiable) quality of the modeling approach was high, as reflected by Cramer-Rao lower bounds below 0.1% and vanishingly small (experimental - fitted) residuals. Modeling of the whole-head (1) H-MRS increases WBNAA quantification reliability by reducing its variability, its susceptibility to operator bias and baseline roll, and by providing quality-control feedback. Together, these enhance the usefulness of the technique for monitoring the diffuse progression and treatment response of neurological disorders.
Assuntos
Ácido Aspártico/análogos & derivados , Química Encefálica , Espectroscopia de Prótons por Ressonância Magnética/métodos , Adulto , Ácido Aspártico/análise , Automação , Encéfalo/anatomia & histologia , Simulação por Computador , Feminino , Humanos , Masculino , Neurônios/metabolismo , Tamanho do Órgão , Imagens de Fantasmas , Espectroscopia de Prótons por Ressonância Magnética/instrumentação , Prótons , Valores de ReferênciaRESUMO
To test the hypotheses that global decreased neuro-axonal integrity reflected by decreased N-acetylaspartate (NAA) and increased glial activation reflected by an elevation in its marker, the myo-inositol (mI), present in a CD8-depleted rhesus macaque model of HIV-associated neurocognitive disorders. To this end, we performed quantitative MRI and 16 × 16 × 4 multivoxel proton MRS imaging (TE/TR = 33/1400 ms) in five macaques pre- and 4-6 weeks post-simian immunodeficiency virus infection. Absolute NAA, creatine, choline (Cho), and mI concentrations, gray and white matter (GM and WM) and cerebrospinal fluid fractions were obtained. Global GM and WM concentrations were estimated from 224 voxels (at 0.125 cm(3) spatial resolution over ~35% of the brain) using linear regression. Pre- to post-infection global WM NAA declined 8%: 6.6 ± 0.4 to 6.0 ± 0.5 mM (p = 0.05); GM Cho declined 20%: 1.3 ± 0.2 to 1.0 ± 0.1 mM (p < 0.003); global mI increased 11%: 5.7 ± 0.4 to 6.5 ± 0.5 mM (p < 0.03). Global GM and WM brain volume fraction changes were statistically insignificant. These metabolic changes are consistent with global WM (axonal) injury and glial activation, and suggest a possible GM host immune response.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Substância Cinzenta/metabolismo , Depleção Linfocítica , Macaca mulatta/virologia , Espectroscopia de Prótons por Ressonância Magnética , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Substância Branca/metabolismo , Animais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Colina/metabolismo , Creatina/metabolismo , Feminino , Inositol/metabolismo , Macaca mulatta/imunologia , Masculino , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Marcadores de Spin , Substância Branca/patologiaRESUMO
Since approximately 5-10% of the ~50,000 tuberous sclerosis complex (TSC) patients in the US are "MRI-negative," our goal was to test the hypothesis that they nevertheless exhibit metabolic abnormalities. To test this, we used proton MR spectroscopy to obtain and compare gray and white matter (GM and WM) levels of the neuronal marker, N-acetylaspartate (NAA), the glial marker, myo-inositol (mI), and its associated creatine (Cr), and choline (Cho) between two "MRI-negative" female TSC patients (ages 5 and 43 years) and their matched controls. The NAA, Cr, Cho and mI concentrations, 9.8, 6.3, 1.4, and 5.7 mM, in the pediatric control were similar to those of the patients, whereas the adult patient revealed a 17% WM NAA decrease and 16% WM Cho increase from their published means for healthy adults - both outside their respective 90% prediction intervals. These findings suggest that longer disease duration and/or TSC2 gene mutation may cause axonal dysfunction and demyelination.
Assuntos
Ácido Aspártico/análogos & derivados , Encéfalo/metabolismo , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Esclerose Tuberosa/metabolismo , Adolescente , Adulto , Ácido Aspártico/metabolismo , Criança , Pré-Escolar , Colina/metabolismo , Creatina/metabolismo , Feminino , Humanos , Inositol/metabolismo , Masculino , Esclerose Tuberosa/patologia , Adulto JovemRESUMO
Non-human primates are often used as preclinical model systems for (mostly diffuse or multi-focal) neurological disorders and their experimental treatment. Due to cost considerations, such studies frequently utilize non-destructive imaging modalities, MRI and proton MR spectroscopy ((1) H MRS). Cost may explain why the inter- and intra-animal reproducibility of the (1) H MRS observed brain metabolites, are not reported. To this end, we performed test-retest three-dimensional brain (1) H MRS in five healthy rhesus macaques at 3 T. Spectra were acquired from 224 isotropic (0.5 cm)(3) = 125 µL voxels, over 28 cm(3) (â¼ 35%) of the brain, then individually phased, frequency aligned and summed into a spectrum representative of the entire volume of interest. This dramatically increases the metabolites' signal-to-noise ratios, while maintaining the (narrow) voxel linewidth. The results show that the average N-acetylaspartate, creatine, choline, and myo-inositol concentrations in the macaque brain are: 7.7 ± 0.5, 7.0 ± 0.5, 1.2 ± 0.1 and 4.0 ± 0.6 mM/g wet weight (mean ± standard deviation). Their inter-animal coefficients of variation (CV) are 4%, 4%, 6%, and 15%; and the longitudinal (intra-animal) CVs are lower still: 4%, 5%, 5%, and 4%, much better than the 22%, 33%, 36%, and 45% intra-voxel CVs, demonstrating the advantage of the approach and its utility for preclinical studies of diffuse neurological diseases in rhesus macaques.
Assuntos
Mapeamento Encefálico/métodos , Encéfalo/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Animais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Colina/metabolismo , Creatina/metabolismo , Imageamento Tridimensional , Inositol/metabolismo , Macaca mulatta , Modelos Animais , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Neurotoxicity related to the Abeta peptide is thought to be a primary mechanism of dysfunction in Alzheimer disease (AD). Although numerous imaging studies have observed brain dysfunction in AD, whether these imaged defects reflect Abeta-related neurotoxicity remains unknown. OBJECTIVE: To study Abeta-related neurotoxicity by means of functional imaging maps of the hippocampal formation in human patients and mouse models. DESIGN: Cross-sectional study comparing humans with AD and control subjects, cross-sectional study of J20 mice, a transgenic mouse model of AD, and a longitudinal study of flurbiprofen administration to transgenic mice. SETTING: Alzheimer disease research center. Subjects Eleven subjects with probable Alzheimer disease and 11 age-matched controls, plus J20 mice and wild-type littermates. INTERVENTIONS: In the first study, human subjects and controls underwent magnetic resonance imaging. In the second study, mice underwent imaging at 3, 6, 12, 15, and 21 months of age, for a total of 57 imaging experiments. In the third study, 12 J20 mice underwent imaging repeatedly over time; 6 received flurbiprofen to ameliorate Abeta-related neurotoxicity and 6 received vehicle control. MAIN OUTCOME MEASURES: Comparison of hippocampal functional maps. RESULTS: Among all hippocampal subregions, the entorhinal cortex was the dominant site of dysfunction observed in both human patients and J20 mice. Long-term administration of flurbiprofen rescued entorhinal cortex dysfunction in transgenic mice. CONCLUSION: Our results establish that the neurotoxicity related to the Abeta peptide can be captured in vivo by functional imaging and suggest hippocampal subregions most vulnerable to its toxic effects.
Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , Síndromes Neurotóxicas/patologia , Idoso de 80 Anos ou mais , Algoritmos , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Volume Sanguíneo/fisiologia , Mapeamento Encefálico , Circulação Cerebrovascular/fisiologia , Estudos Transversais , Inibidores de Ciclo-Oxigenase/uso terapêutico , Giro Denteado/patologia , Giro Denteado/fisiologia , Modelos Animais de Doenças , Progressão da Doença , Córtex Entorrinal/patologia , Córtex Entorrinal/fisiologia , Flurbiprofeno/uso terapêutico , Hipocampo/patologia , Hipocampo/fisiologia , Humanos , Imageamento por Ressonância Magnética , Camundongos , Camundongos Transgênicos , Testes Neuropsicológicos , Síndromes Neurotóxicas/tratamento farmacológicoRESUMO
The authors compared the frequency of structural and functional heart abnormalities assessed using transthoracic echocardiography among persons with Alzheimer's disease, vascular dementia, stroke, and healthy control subjects. Compared with controls, patients with Alzheimer's disease were more likely to have aortic valve thickening, aortic valve regurgitation, left ventricular wall motion abnormalities, left ventricular hypertrophy, and reduced ejection fraction. Persons with vascular dementia were more likely to have aortic valve regurgitation, but mitral valve thickening and tricuspid valve regurgitation were also more frequent. In the absence of dementia, persons with stroke differed from controls by more frequent mitral valve calcifications. With the increasing prevalence of Alzheimer's disease and vascular dementia, clinicians have to be more attentive to the presence of structural heart disease and its complications in persons with these conditions.
Assuntos
Doença de Alzheimer/fisiopatologia , Demência Vascular/fisiopatologia , Avaliação Geriátrica , Cardiopatias/epidemiologia , Fatores Etários , Idoso , Doença de Alzheimer/diagnóstico por imagem , Estudos de Casos e Controles , Demência Vascular/diagnóstico por imagem , Ecocardiografia , Feminino , Cardiopatias/diagnóstico por imagem , Humanos , Estudos Longitudinais , Masculino , Medicare , Cidade de Nova Iorque/epidemiologia , Prevalência , Medição de Risco , Acidente Vascular Cerebral/fisiopatologiaRESUMO
BACKGROUND AND PURPOSE: To assess the sensitivity of non-localized, whole-head 1H-MRS to an individual's serial changes in total-brain NAA, Glx, Cr and Cho concentrations - metabolite metrics often used as surrogate markers in neurological pathologies. MATERIALS AND METHODS: In this prospective study, four back-to-back (single imaging session) and three serial (successive sessions) non-localizing, ~3min 1H-MRS (TE/TR/TI=5/104/940ms) scans were performed on 18 healthy young volunteers: 9 women, 9 men: 29.9±7.6 [mean±standard deviation (SD)] years old. These were analyzed by calculating a within-subject coefficient of variation (CV=SD/mean) to assess intra- and inter-scan repeatability and prediction intervals. This study was Health Insurance Portability and Accountability Act compliant. All subjects gave institutional review board-approved written, informed consent. RESULTS: The intra-scan CVs for the NAA, Glx, Cr and Cho were: 3.9±1.8%, 7.3±4.6%, 4.0±3.4% and 2.5±1.6%, and the corresponding inter-scan (longitudinal) values were: 7.0±3.1%, 10.6±5.6%, 7.6±3.5% and 7.0±3.9%. This method is shown to have 80% power to detect changes of 14%, 27%, 26% and 19% between two serial measurements in a given individual. CONCLUSIONS: Subject to the assumption that in neurological disorders NAA, Glx, Cr and Cho changes represent brain-only pathology and not muscles, bone marrow, adipose tissue or epithelial cells, this approach enables us to quantify them, thereby adding specificity to the assessment of the total disease load. This will facilitate monitoring diffuse pathologies with faster measurement, more extensive (~90% of the brain) spatial coverage and sensitivity than localized 1H-MRS.
Assuntos
Encéfalo/metabolismo , Espectroscopia de Prótons por Ressonância Magnética/métodos , Adolescente , Adulto , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Encéfalo/diagnóstico por imagem , Colina/metabolismo , Creatina/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Humanos , Masculino , Estudos Prospectivos , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto JovemRESUMO
OBJECTIVE: As ~40% of persons with HIV also suffer neurocognitive decline, we sought to assess metabolic dysfunction in the brains of simian immunodeficiency virus (SIV)-infected rhesus macaques, an advanced animal model, in structures involved in cognitive function. We test the hypothesis that SIV-infection produces proton-magnetic resonance spectroscopic imaging (H-MRSI)-observed decline in the neuronal marker, N-acetylaspartate (NAA), and elevations in the glial marker, myo-inositol (mI), and associated creatine (Cr) and choline (Cho) in these structures. DESIGN: Pre- and 4-6 weeks post-SIV infection (with CD8 T-lymphocyte depletion) was monitored with T2-weighted quantitative MRI and 16×16×4 multivoxel H-MRSI (TE/TR =â33/1400 ms) in the brains of five rhesus macaques. METHODS: Exploiting the high-resolution H-MRSI grid, we obtained absolute, cerebrospinal fluid partial volume-corrected NAA, Cr, Cho and mI concentrations from centrum semiovale, caudate nucleus, putamen, thalamus and hippocampus regions. RESULTS: Pre- to post-infection mean Cr increased in the thalamus: 7.2±0.4 to 8.0±0.8 mmol/l (+11%, P<0.05); mI increased in the centrum semiovale: 5.1±0.8 to 6.6±0.8 mmol/l, caudate: 5.7±0.7 to 7.3±0.5 mmol/l, thalamus: 6.8±0.8 to 8.5±0.8 mmol/l and hippocampus: 7.7±1.2 to 9.9±0.4 mmol/l (+29%, +27%, +24% and +29%, all P<0.05). NAA and Cho changes were not significant. CONCLUSION: SIV-infection appears to cause brain injury indirectly, through glial activation, while the deep gray matter structures' neuronal cell bodies are relatively spared. Treatment regimens to reduce gliosis may, therefore, prevent neuronal damage and its associated neurocognitive impairment.
Assuntos
Ácido Aspártico/análogos & derivados , Química Encefálica , Doenças do Sistema Nervoso Central/patologia , Inositol/análise , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Animais , Ácido Aspártico/análise , Líquido Cefalorraquidiano/química , Colina/análise , Creatina/análise , Feminino , Macaca mulatta , Imageamento por Ressonância Magnética , MasculinoRESUMO
N-acetylaspartate (NAA) is an index of neuronal integrity. We hypothesized that in healthy subjects its whole brain concentration (WBNAA) may be related to formal educational attainment, a common proxy for cognitive reserve. To test this hypothesis, 97 middle aged to elderly subjects (51-89 years old, 38% women) underwent brain magnetic resonance imaging and non-localizing proton spectroscopy. Their WBNAA was obtained by dividing their whole-head NAA amount by the brain volume. Intracranial volume and fractional brain volume, a metric of brain atrophy, were also determined. Each subject's educational attainment was the sum of his/her years of formal education. In the entire group higher education was associated with larger intracranial volume. The relationship between WBNAA and education was observed only in younger (51-70 years old) participants. In this group, education explained 21% of the variance in WBNAA. More WBNAA was related to more years of formal education in adults and younger elders. Prospective studies can determine whether this relationship reflects a true advantage from years of training versus innate characteristics predisposing a subject to higher achievements later in life. We propose that late-life WBNAA may be more affected by other factors acting at midlife and later.
Assuntos
Ácido Aspártico/análogos & derivados , Encéfalo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Ácido Aspártico/metabolismo , Atrofia/diagnóstico por imagem , Atrofia/metabolismo , Encéfalo/diagnóstico por imagem , Reserva Cognitiva , Escolaridade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , CintilografiaRESUMO
We hypothesize that normal aging implies neuronal durability, reflected by age-independent concentrations of their marker--the amino acid derivative N-acetylaspartate (NAA). To test this, we obtained the whole-brain and whole-head N-acetylaspartate concentrations (WBNAA and WHNAA) with proton magnetic resonance (MR) spectroscopy; and the fractional brain parenchyma volume (fBPV)--a metric of atrophy, by segmenting the magnetic resonance image (MRI) from 42 (18 male) healthy young (31.9 ± 5.8 years old) and 100 (64 male, 72.6 ± 7.3 years old) cognitively normal elderly. The 12.8 ± 1.9 mM WBNAA of the young was not significantly different from the 13.1 ± 3.1 mM in the elderly (p > 0.05). In contrast, both fBPV (87.3 ± 4.7% vs. 74.8 ± 4.8%) and WHNAA (11.1 ± 1.7 mM vs. 9.8 ± 2.4 mM) were significantly higher in the young (approximately 14%; p < 0.0001 for both). The similarity in mean WBNAA between 2 cohorts 4 decades of normal aging apart suggests that neuronal integrity is maintained across the lifespan. Clinically, WBNAA could be used as a marker for normal (hence, also abnormal) brain aging. In contrast, WHNAA and fBPV seem age-related suggesting that brain atrophy may occur without compromising the remaining tissue.