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Research into hippocampal self-regulation abilities may help determine the clinical significance of hippocampal hyperactivity throughout the pathophysiological continuum of Alzheimer's disease. In this study, we aimed to identify the effects of amyloid-ß peptide 42 (amyloid-ß42) and phosphorylated tau on the patterns of functional connectomics involved in hippocampal downregulation. We identified 48 cognitively unimpaired participants (22 with elevated CSF amyloid-ß peptide 42 levels, 15 with elevated CSF phosphorylated tau levels, mean age of 62.705 ± 4.628 years), from the population-based 'Alzheimer's and Families' study, with baseline MRI, CSF biomarkers, APOE genotyping and neuropsychological evaluation. We developed a closed-loop, real-time functional MRI neurofeedback task with virtual reality and tailored it for training downregulation of hippocampal subfield cornu ammonis 1 (CA1). Neurofeedback performance score, cognitive reserve score, hippocampal volume, number of apolipoprotein ε4 alleles and sex were controlled for as confounds in all cross-sectional analyses. First, using voxel-wise multiple regression analysis and controlling for CSF biomarkers, we identified the effect of healthy ageing on eigenvector centrality, a measure of each voxel's overall influence based on iterative whole-brain connectomics, during hippocampal CA1 downregulation. Then, controlling for age, we identified the effects of abnormal CSF amyloid-ß42 and phosphorylated tau levels on eigenvector centrality during hippocampal CA1 downregulation. Across subjects, our main findings during hippocampal downregulation were: (i) in the absence of abnormal biomarkers, age correlated with eigenvector centrality negatively in the insula and midcingulate cortex, and positively in the inferior temporal gyrus; (ii) abnormal CSF amyloid-ß42 (<1098) correlated negatively with eigenvector centrality in the anterior cingulate cortex and primary motor cortex; and (iii) abnormal CSF phosphorylated tau levels (>19.2) correlated with eigenvector centrality positively in the ventral striatum, anterior cingulate and somatosensory cortex, and negatively in the precuneus and orbitofrontal cortex. During resting state functional MRI, similar eigenvector centrality patterns in the cingulate had previously been associated to CSF biomarkers in mild cognitive impairment and dementia patients. Using the developed closed-loop paradigm, we observed such patterns, which are characteristic of advanced disease stages, during a much earlier presymptomatic phase. In the absence of CSF biomarkers, our non-invasive, interactive, adaptive and gamified neuroimaging procedure may provide important information for clinical prognosis and monitoring of therapeutic efficacy. We have released the developed paradigm and analysis pipeline as open-source software to facilitate replication studies.
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Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Região CA1 Hipocampal/metabolismo , Neurorretroalimentação/métodos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Fatores Etários , Idoso , Doença de Alzheimer/complicações , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Disfunção Cognitiva/complicações , Disfunção Cognitiva/metabolismo , Conectoma , Estudos Transversais , Regulação para Baixo , Feminino , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos , Fosforilação , Software , Realidade VirtualRESUMO
White matter hyperintensities (WMH) have been extensively associated with cognitive impairment and reductions in gray matter volume (GMv) independently. This study explored whether WMH lesion volume mediates the relationship between cerebral patterns of GMv and cognition in 521 (mean age 57.7 years) cognitively unimpaired middle-aged individuals. Episodic memory (EM) was measured with the Memory Binding Test and executive functions (EF) using five WAIS-IV subtests. WMH were automatically determined from T2 and FLAIR sequences and characterized using diffusion-weighted imaging (DWI) parameters. WMH volume was entered as a mediator in a voxel-wise mediation analysis relating GMv and cognitive performance (with both EM and EF composites and the individual tests independently). The mediation model was corrected by age, sex, education, number of Apolipoprotein E (APOE)-ε4 alleles and total intracranial volume. We found that even at very low levels of WMH burden in the cohort (median volume of 3.2 mL), higher WMH lesion volume was significantly associated with a widespread pattern of lower GMv in temporal, frontal, and cerebellar areas. WMH mediated the relationship between GMv and EF, mainly driven by processing speed, but not EM. DWI parameters in these lesions were compatible with incipient demyelination and axonal loss. These findings lead to the reflection on the relevance of the control of cardiovascular risk factors in middle-aged individuals as a valuable preventive strategy to reduce or delay cognitive decline.
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Substância Cinzenta/diagnóstico por imagem , Tempo de Reação/fisiologia , Substância Branca/diagnóstico por imagem , Adulto , Idoso , Apolipoproteínas E/genética , Axônios/patologia , Mapeamento Encefálico , Cognição , Doenças Desmielinizantes/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Função Executiva , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Memória Episódica , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de WechslerRESUMO
BACKGROUND: Cardiovascular disease and dementia often coexist at advanced stages. Yet, longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health in midlife are scarce. We aimed to characterise the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in middle-aged asymptomatic individuals. METHODS: The Progression of Early Subclinical Atherosclerosis (PESA) study is a Spanish longitudinal observational cohort study of 4184 asymptomatic individuals aged 40-54 years (NCT01410318). Participants with subclinical atherosclerosis underwent longitudinal cerebral [18F]fluorodeoxyglucose ([18F]FDG)-PET, and annual percentage change in [18F]FDG uptake was assessed (primary outcome). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with three-dimensional vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess associations between outcomes and exposures. Additionally, blood-based biomarkers of neuropathology were quantified and mediation analyses were performed. Secondary analyses were corrected for multiple comparisons using the false discovery rate (FDR) approach. FINDINGS: This longitudinal study included a PESA subcohort of 370 participants (median age at baseline 49·8 years [IQR 46·1-52·2]; 309 [84%] men, 61 [16%] women; median follow-up 4·7 years [IQR 4·2-5·2]). Baseline scans took place between March 6, 2013, and Jan 21, 2015, and follow-up scans between Nov 24, 2017, and Aug 7, 2019. Persistent high risk of cardiovascular disease was associated with an accelerated decline of cortical [18F]FDG uptake compared with low risk (ß=-0·008 [95% CI -0·013 to -0·002]; pFDR=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (ß=0·198 [0·008 to 0·740]; pFDR=0·050). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in [18F]FDG uptake in Alzheimer's disease brain regions, not explained by cardiovascular risk (ß=-0·269 [95% CI -0·509 to -0·027]; p=0·029). INTERPRETATION: Middle-aged asymptomatic individuals with persistent high risk of cardiovascular disease and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life. FUNDING: Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, "la Caixa" Foundation.
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Aterosclerose , Doenças Cardiovasculares , Doenças das Artérias Carótidas , Doenças Neurodegenerativas , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/epidemiologia , Fluordesoxiglucose F18 , Estudos Longitudinais , Estudos Prospectivos , Fatores de Risco , Aterosclerose/epidemiologia , Fatores de Risco de Doenças Cardíacas , GlucoseRESUMO
Neurodegenerative and neuropsychiatric disorders (ND-NPs) are multifactorial, polygenic and complex behavioral phenotypes caused by brain abnormalities. Large-scale collaborative efforts have tried to identify the genetic architecture of these conditions. However, the specific and shared underlying molecular pathobiology of brain illnesses is not clear. Here, we examine transcriptome-wide characterization of eight conditions, using a total of 2,633 post-mortem brain samples from patients with Alzheimer's disease (AD), Parkinson's disease (PD), Progressive Supranuclear Palsy (PSP), Pathological Aging (PA), Autism Spectrum Disorder (ASD), Schizophrenia (Scz), Major Depressive Disorder (MDD), and Bipolar Disorder (BP)-in comparison with 2,078 brain samples from matched control subjects. Similar transcriptome alterations were observed between NDs and NPs with the top correlations obtained between Scz-BP, ASD-PD, AD-PD, and Scz-ASD. Region-specific comparisons also revealed shared transcriptome alterations in frontal and temporal lobes across NPs and NDs. Co-expression network analysis identified coordinated dysregulations of cell-type-specific modules across NDs and NPs. This study provides a transcriptomic framework to understand the molecular alterations of NPs and NDs through their shared- and specific gene expression in the brain.
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Obsessive-compulsive disorder (OCD) emerges during childhood through young adulthood coinciding with the late phases of postnatal brain development when fine remodeling of brain anatomy takes place. Previous research has suggested the existence of subtle anatomical alterations in OCD involving focal volume variations in different brain regions including the frontal lobes and basal ganglia. We investigated whether anatomical changes might also involve variations in the shape of the frontobasal region. A total of 101 OCD patients and 101 control subjects were examined using magnetic resonance imaging. A cross-sectional image highly representative of frontal-basal ganglia anatomy was selected in each individual and 25 reliable anatomical landmarks were identified to assess shape changes. A pixel-wise morphing approach was also used to dynamically illustrate the findings. We found significant group differences for overall landmark position and for most individual landmarks delimiting the defined frontobasal region. OCD patients showed a deformation pattern involving shortening of the anterior-posterior dimension of the frontal lobes and basal ganglia, and enlargement of cerebrospinal fluid spaces around the frontal opercula. In addition, we observed significant correlation of brain tissue shape variation with frontal sinus size. Identification of a global change in the shape of the frontobasal region may further contribute to characterizing the nature of brain alterations in OCD. The coincidence of brain shape variations with morphological changes in the frontal sinus indicates a potential association of OCD to late development disturbances, as the frontal sinus macroscopically emerges during the transition between childhood and adulthood.
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Lobo Frontal/patologia , Transtorno Obsessivo-Compulsivo/patologia , Adolescente , Adulto , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Neuroplastic changes involved in latent pain sensitization after surgery are poorly defined. We assessed temporal changes in glucose brain metabolism in a postoperative rat model using positron emission tomography. We also investigated brain metabolism after naloxone administration. METHODS: Rats were given remifentanil anesthetic and underwent a plantar incision, with 1 mg/kg of (-)-naloxone subcutaneously administered on postoperative days 20 and 21. Using the von Frey test, mechanical thresholds were measured pre- and postoperatively at different time points in awake animals during F-fluorodeoxyglucose (F-FDG) uptake. Brain images were also obtained the day before mechanical testing, using a positron emission tomography R4 scanner (Concorde Microsystems, Siemens, Knoxville, TN). Differences in brain activity were assessed utilizing a statistical parametric mapping. RESULTS: Surgery induced minor changes in F-FDG uptake in the cerebellum, hippocampus, and posterior cortex, which extended to the thalamus, hypothalamus, and brainstem on days 6 and 7. Changes were still present on day 21. Maximal postoperative hypersensitivity was observed on day 2. The administration of (-)-naloxone on day 21 induced significant hypersensitivity, greatly enhancing the effect on F-FDG uptake. In sham-operated rats, naloxone induced changes limited to the striatum and the cerebellum. Nonnociceptive stimulation with von Frey filaments had no effect on F-FDG uptake. CONCLUSIONS: Surgery, remifentanil, and their combination induced long-lasting and significant metabolic changes in the pain brain matrix, with a positive correlation with hypersensitivity after naloxone. Changes in brain F-FDG precipitated by naloxone suggest that surgery under remifentanil anesthetic induces the greatest neuroplastic brain adaptations in opioid-related pathways involved in nociceptive processing and long-lasting pain sensitization.
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Encéfalo/metabolismo , Fluordesoxiglucose F18 , Glucose/metabolismo , Limiar da Dor , Dor/fisiopatologia , Tomografia por Emissão de Pósitrons , Complicações Pós-Operatórias/fisiopatologia , Compostos Radiofarmacêuticos , Animais , Masculino , Naloxona/farmacologia , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , RemifentanilRESUMO
In recent decades, our understanding of the molecular changes involved in neurodegenerative diseases has been transformed. Single-cell RNA sequencing and single-nucleus RNA sequencing technologies have been applied to provide cellular and molecular details of the brain at the single-cell level. This has expanded our knowledge of the central nervous system and provided insights into the molecular vulnerability of brain cell types and underlying mechanisms in neurodegenerative diseases. In this review, we highlight the recent advances and findings related to neurodegenerative diseases using these cutting-edge technologies.
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Doença de Alzheimer , Doenças Neurodegenerativas , Doença de Parkinson , Encéfalo , Humanos , Doenças Neurodegenerativas/genéticaRESUMO
Global and regional changes in cerebral blood flow (CBF) can result in biased quantitative estimates of amyloid load by PET imaging. Therefore, the current simulation study assessed effects of these changes on amyloid quantification using a reference tissue approach for [18F]flutemetamol and [18F]florbetaben. Previously validated pharmacokinetic rate constants were used to simulate time-activity curves (TACs) corresponding to full dynamic and dual-time-window acquisition protocols. CBF changes were simulated by varying the tracer delivery (K1) from +25 to -25%. The standardized uptake value ratio (SUVr) was computed and TACs were fitted using reference Logan (RLogan) and the simplified reference tissue model (SRTM) to obtain the relative delivery rate (R1) and volume of distribution ratio (DVR). RLogan was least affected by CBF changes (χ2 = 583 p < 0.001, χ2 = 81 p < 0.001, for [18F]flutemetamol and [18F]florbetaben, respectively) and the extent of CBF sensitivity generally increased for higher levels of amyloid. Further, SRTM-derived R1 changes correlated well with simulated CBF changes (R2 > 0.95) and SUVr's sensitivity to CBF changes improved for later uptake-times, with the exception of [18F]flutemetamol cortical changes. In conclusion, RLogan is the preferred method for amyloid quantification of [18F]flutemetamol and [18F]florbetaben studies and SRTM could be additionally used for obtaining a CBF proxy.
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Compostos de Anilina/química , Benzotiazóis/química , Circulação Cerebrovascular/fisiologia , Compostos Radiofarmacêuticos/química , Estilbenos/química , Doença de Alzheimer/patologia , Compostos de Anilina/farmacologia , Benzotiazóis/farmacologia , Estudos de Casos e Controles , Circulação Cerebrovascular/efeitos dos fármacos , Radioisótopos de Flúor/química , Humanos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacologia , Estilbenos/farmacologiaRESUMO
Virtual reality is a trending, widely accessible, and contemporary technology of increasing utility to biomedical and health applications. However, most implementations of virtual reality environments are tailored to specific applications. We describe the complete development of a novel, open-source virtual reality environment that is suitable for multipurpose biomedical and healthcare applications. This environment can be interfaced with different hardware and data sources, ranging from gyroscopes to fMRI scanners. The developed environment simulates an immersive (first-person perspective) run in the countryside, in a virtual landscape with various salient features. The utility of the developed VR environment has been validated via two test applications: an application in the context of motor rehabilitation following injury of the lower limbs and an application in the context of real-time functional magnetic resonance imaging neurofeedback, to regulate brain function in specific brain regions of interest. Both applications were tested by pilot subjects that unanimously provided very positive feedback, suggesting that appropriately designed VR environments can indeed be robustly and efficiently used for multiple biomedical purposes. We attribute the versatility of our approach on three principles implicit in the design: selectivity, immersiveness, and adaptability. The software, including both applications, is publicly available free of charge, via a GitHub repository, in support of the Open Science Initiative. Although using this software requires specialized hardware and engineering know-how, we anticipate our contribution to catalyze further progress, interdisciplinary collaborations and replicability, with regards to the usage of virtual reality in biomedical and health applications.
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Pesquisa Biomédica/métodos , Realidade Virtual , Algoritmos , Gráficos por Computador , Retroalimentação Psicológica , Humanos , Processamento de Imagem Assistida por Computador , Traumatismos da Perna/reabilitação , Extremidade Inferior , Imageamento por Ressonância Magnética/métodos , Neurorretroalimentação , Projetos Piloto , Reabilitação/instrumentação , Reabilitação/métodos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Mechanisms of functional compensation throughout the progression of Alzheimer's disease (AD) remain largely underspecified. By investigating functional connectomics in relation to cerebrospinal fluid (CSF) biomarkers across the pathophysiological continuum of AD, we identify disease-stage-specific patterns of functional degradation and functional compensation. METHODS: Data from a sample of 96 participants, comprised of 49 controls, 11 preclinical AD subjects, 21 patients with mild cognitive impairment (MCI) due to AD and 15 patients with mild dementia due to AD, were analyzed. CSF ratio of phosphorylated tau protein over amyloid beta peptide 42 (p-tau/Aß42) was computed and used as a marker of progression along the AD continuum. Whole-brain, voxel-wise eigenvector centrality mapping (ECM) was computed from resting-state fMRI and regression against p-tau/Aß42 was performed. Surviving clusters were used as data-derived seeds in functional connectivity analyses and investigated in relation to memory performance scores (delayed free recall and memory alteration) via complementary regression models. To investigate disease-stage-specific effects, the whole-brain connectivity maps of each cluster were compared between progressive groups. RESULTS: Centrality in BA39-BA19 is negatively correlated with the p-tau/Aß42 ratio and associated to memory function impairment across the AD continuum. The thalamus, anterior cingulate (ACC), midcingulate (MCC) and posterior cingulate cortex (PCC) show the opposite effect. The MCC shows the highest increase in centrality as memory performance decays. In the asymptomatic preclinical group, MCC shows reduced functional connectivity (FC) with the left hippocampus and stronger FC with the precuneus (PCu). Additionally, BA39-BA19 show reduced FC with the cerebellum, compensated by stronger FC between cerebellum and PCC. In the MCI group, PCC shows reduced FC with PCu, compensated by stronger FC with the left pars orbitalis, insula and temporal pole, as well as by stronger FC of MCC with its anterior and ventral neighboring areas and the cerebellum. In the mild dementia group, extensive functional decoupling occurs across the entire autobiographical memory network and functional resilience ensues in posterior regions and the cerebellum. CONCLUSIONS: Functional decoupling in preclinical AD occurs predominantly in AD-vulnerable regions (e.g. hippocampus, cerebellar lobule VI / Crus I, visual cortex, frontal pole) and coupling between MCC and PCu, as well as between PCC and cerebellum, emerge as intrinsic mechanisms of functional compensation. At the MCI stage, the PCu can no longer compensate for hippocampal decoupling, but the compensatory role of the MCC and PCC ensue into the stage of dementia. These findings shed light on the neural mechanisms of functional compensation across the pathophysiological continuum of AD, highlighting the compensatory roles of several key brain areas.
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Doença de Alzheimer/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Conectoma/métodos , Progressão da Doença , Hipocampo/fisiopatologia , Processamento de Imagem Assistida por Computador/métodos , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Sintomas Prodrômicos , Proteínas tau/líquido cefalorraquidianoRESUMO
In brain structural segmentation, multi-atlas strategies are increasingly being used over single-atlas strategies because of their ability to fit a wider anatomical variability. Patch-based label fusion (PBLF) is a type of such multi-atlas approaches that labels each target point as a weighted combination of neighboring atlas labels, where atlas points with higher local similarity to the target contribute more strongly to label fusion. PBLF can be potentially improved by increasing the discriminative capabilities of the local image similarity measurements. We propose a framework to compute patch embeddings using neural networks so as to increase discriminative abilities of similarity-based weighted voting in PBLF. As particular cases, our framework includes embeddings with different complexities, namely, a simple scaling, an affine transformation, and non-linear transformations. We compare our method with state-of-the-art alternatives in whole hippocampus and hippocampal subfields segmentation experiments using publicly available datasets. Results show that even the simplest versions of our method outperform standard PBLF, thus evidencing the benefits of discriminative learning. More complex transformation models tended to achieve better results than simpler ones, obtaining a considerable increase in average Dice score compared to standard PBLF.
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Doença de Alzheimer/diagnóstico por imagem , Mapeamento Encefálico/métodos , Hipocampo/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Redes Neurais de Computação , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-IdadeRESUMO
Cerebral white matter hyperintensities are believed the consequence of small vessel disease and are associated with risk and progression of Alzheimer's disease. The É4 allele of the APOE gene is the major factor accountable for Alzheimer's disease heritability. However, the relationship between white matter hyperintensities and APOE genotype in healthy subjects remains controversial. We investigated the association between APOE-É4 and vascular risk factors with white matter hyperintensities, and explored their interactions, in a cohort of cognitively healthy adults (45-75 years). White matter hyperintensities were assessed with the Fazekas Scale from magnetic resonance images (575 participants: 74 APOE-É4 homozygotes, 220 heterozygotes and 281 noncarriers) and classified into normal (Fazekas < 2) and pathological (≥2). Stepwise logistic regression was used to study the association between pathological Fazekas and APOE genotype after correcting for cardiovascular and sociodemographic factors. APOE-É4 homozygotes, but not heterozygotes, bear a significantly higher risk (OR 3.432; 95% CI [1.297-9.082]; p = 0.013) of displaying pathological white matter hyperintensities. As expected, aging, hypertension and cardiovascular and dementia risk scales were also positively associated to pathological white matter hyperintensities, but these did not modulate the effect of APOE-É4/É4. In subjects at genetic risk of developing Alzheimer's disease, the control of modifiable risk factors of white matter hyperintensities is of particular relevance to reduce or delay dementia's onset.
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Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Leucoaraiose/diagnóstico por imagem , Leucoaraiose/genética , Substância Branca/diagnóstico por imagem , Idoso , Alelos , Doença de Alzheimer/epidemiologia , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/epidemiologia , Doenças de Pequenos Vasos Cerebrais/genética , Estudos de Coortes , Feminino , Genótipo , Voluntários Saudáveis , Heterozigoto , Humanos , Leucoaraiose/epidemiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de RiscoRESUMO
Several [18F]-FDG positron emission tomography (PET) studies in alcoholics have consistently reported decreases in overall brain glucose metabolism at rest and following acute alcohol administration. However, changes in cerebral glucose utilization associated with the transition to addiction are not well understood and require longitudinal translational imaging studies in animal models of alcoholism. Here, we studied brain glucose uptake in alcohol drinking rats in order to provide convergent evidence to what has previously been reported in human studies. Brain glucose metabolism was measured by [18F]-FDG microPET imaging in different male Wistar rat groups: short-term drinking (three months), long-term drinking (twelve months) and alcohol-naïve. Global and regional cerebral glucose uptake was measured at rest and following acute alcohol administration. We showed that alcohol significantly reduced the whole-brain glucose metabolism. This effect was most pronounced in the parietal cortex and cerebellum. Alcohol-induced decreases in brain [18F]-FDG uptake was most apparent in alcohol-naïve rats, less intense in short-term drinkers and absent in long-term drinkers. The latter finding indicates the occurrence of tolerance to the intoxicating effects of alcohol in long-term drinking individuals. In contrast, some regions, like the ventral striatum and entorhinal cortex, showed enhanced metabolic activity, an effect that did not undergo tolerance during long-term alcohol consumption. Our findings are comparable to those described in human studies using the same methodology. We conclude that [18F]-FDG PET studies in rat models of alcoholism provide good translation and can be used for future longitudinal studies investigating alterations in brain function during different stages of the addiction cycle.
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Alcoolismo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Tomografia por Emissão de Pósitrons , Alcoolismo/diagnóstico por imagem , Animais , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Modelos Animais de Doenças , Fluordesoxiglucose F18 , Masculino , Compostos Radiofarmacêuticos , Ratos WistarRESUMO
Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aß42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aß42 levels inversely correlated to VV/TIV in the whole study population (Aß42: râ=â-0.28; pâ<â0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: râ=â-0.15; p-tau: râ=â-0.13; both pâ<â0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aß42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aß42 levels.
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Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Ventrículos Cerebrais/diagnóstico por imagem , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Idoso , Algoritmos , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Área Sob a Curva , Atrofia , Biomarcadores/líquido cefalorraquidiano , Feminino , Hipocampo/diagnóstico por imagem , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Reconhecimento Automatizado de Padrão , Fragmentos de Peptídeos/líquido cefalorraquidiano , Curva ROC , Proteínas tau/líquido cefalorraquidianoRESUMO
INTRODUCTION: Repetitive administration of neuropsychological tests can lead to performance improvement merely due to previous exposure. The magnitude of such practice effects (PEs) may be used as a marker of subtle cognitive impairment because they are diminished in healthy individuals subsequently developing Alzheimer's disease (AD). METHODS: To explore the relationship between sociodemographic factors, AD family history (FH), and APOE ε4 status, and the magnitude of PE, four subtests of the Wechsler Adult Intelligence Scale-IV were administered twice to 400 middle-aged healthy individuals, most of them first-degree descendants of AD patients. RESULTS: PEs were observed in all measures. Sociodemographic variables did not show a uniform effect on PE. Baseline score was the strongest predictor of change, being inversely related to PE magnitude. Significant effects of the interaction term APOE ε4∗Age in processing speed and working memory were observed. DISCUSSION: PEs exert a relevant effect in cognitive outcomes at retest and, accordingly, they must be taken into consideration in clinical trials. The magnitude of PE in processing speed and working memory could be of special interest for the development of cognitive markers of preclinical AD.
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BACKGROUND: The Memory Binding Test (MBT) is emerging as a promising tool for the detection of subtle memory impairment suggestive of Alzheimer's disease (AD). For such a test to be widely accessed and used, the availability of both alternate forms and language adaptations is required. OBJECTIVES: To develop a thorough methodology for obtaining alternate forms (A and B) of the MBT in Spanish and Catalan and to assess their equivalence. METHOD: According to the original development of the test, frequency was taken as the lexical variable of reference for the Spanish and Catalan adaptations. A crossed design protocol by form and language was used to compare the MBT results in a sample of 290 cognitively normal middle-aged participants. Pairwise Intraclass Correlation Coefficients (ICCs) were calculated among the six possible combinations. RESULTS: The Spanish and Catalan lists of words for the MBT A and B resulting from the adaptation process as well as the original lists in English are presented. ICC indices for the comparisons between forms and languages ranged from 0.56 to 0.82. CONCLUSION: The MBT A and B in Spanish and Catalan showed similar outcomes and can be considered equivalent. Moreover, the thorough methodology presented here for the transcultural adaptation and equivalence study, could serve as a model for future adaptations of the MBT and other verbal tests.
Assuntos
Idioma , Transtornos da Memória/diagnóstico , Testes Neuropsicológicos , Estudos de Coortes , Feminino , Humanos , Aprendizagem , Masculino , Rememoração Mental , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Distribuição Aleatória , Espanha , TraduçõesRESUMO
BACKGROUND: Episodic memory testing is fundamental for the diagnosis of Alzheimer's disease (AD). Although the Free and Cued Selective Reminding Test (FCSRT) is widely used for this purpose, it may not be sensitive enough for early detection of subtle decline in preclinical AD. The Memory Binding Test (MBT) intends to overcome this limitation. OBJECTIVES: To analyze the test-retest reliability of the MBT and its convergent validity with the FCRST. METHODS: 36 cognitively healthy participants of the ALFA Study, aged 45 to 65, were included for the test-retest study and 69 for the convergent analysis. They were visited twice in a period of 6 ± 2 weeks. Test-retest reliability was determined by the calculation of the intra-class correlation coefficient (ICC). Score differences were studied by computing the mean percentage of score variation between visits and visualized by Bland-Altman plots. Convergent validity was determined by Pearson's correlations. RESULTS: ICC values in the test-retest reliability analysis of the MBT direct scores ranged from 0.64 to 0.76. Subjects showed consistent practice effects, with mean amounts of score increasing between 10% and 26%. Pearson correlation between MBT and FCSRT direct scores showed r values between 0.40 and 0.53. The FCSRT displayed ceiling effects not observed in the MBT. CONCLUSIONS: The MBT shows adequate test-retest reliability and overall moderate convergent validity with the FCSRT. Unlike the FCSRT, the MBT does not have ceiling effects and it may therefore be especially useful in longitudinal studies, facilitating the measurement of subtle memory performance decline and the detection of very early AD.
Assuntos
Memória , Testes Psicológicos , Idoso , Doença de Alzheimer/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Reprodutibilidade dos TestesRESUMO
RATIONALE: The study of the different effects on brain metabolism between typical and atypical antipsychotics would aid in understanding their mechanisms of action. Clozapine is of special interest, since it is one of the most effective antipsychotic drugs and demonstrates a distinctive mechanism of action in pre-clinical studies with respect to typical neuroleptics. OBJECTIVE: To study the differences in cerebral activity induced by clozapine as compared to those produced by haloperidol. METHODS: [18F]Fluoro-deoxy-glucose (FDG)-positron emission tomography (PET) scans were obtained in the resting condition before and after 6 months of treatment with clozapine in 22 treatment-resistant patients with schizophrenia. Before inclusion, patients had been chronically treated with classical drugs, and all of them received haloperidol during the last month. Data were analyzed with statistical parametric mapping (SPM'99) methods, comparing pre-treatment and post-treatment conditions. The association between the changes in symptom scores and metabolism was also assessed to corroborate the functional relevance of possible metabolic changes. RESULTS: Clozapine decreased prefrontal and basal ganglia activity, and increased occipital metabolism, including primary and association visual areas. The change in negative symptoms was related with the decrease of basal ganglia activity; the improvement in disorganization related to the metabolic decrease in the motor area, and the change in positive symptoms was associated to the increase of activity in the visual area. CONCLUSIONS: These results show that haloperidol and clozapine produce different patterns of metabolic changes in schizophrenia. Compared to the haloperidol baseline, clozapine inhibited the metabolic activity of the prefrontal and motor cortical regions and basal ganglia and induced a higher activation of the visual cortex. The improvement in disorganization, negative and positive syndromes with clozapine may be respectively associated with metabolic changes in the motor area, basal ganglia, and visual cortex.
Assuntos
Antipsicóticos/farmacologia , Encéfalo/metabolismo , Clozapina/farmacologia , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/uso terapêutico , Clozapina/uso terapêutico , Feminino , Haloperidol/farmacologia , Haloperidol/uso terapêutico , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Esquizofrenia/metabolismoRESUMO
Magnetic resonance spectroscopy studies in schizophrenia have revealed consistently reduced N-acetyl aspartate (NAA) levels in chronic patients, but not in recent-onset patients. Studies on the relationship between this marker and disease duration have commonly been negative, although it is also true that they have been conducted in patients with long-standing disease. We compared NAA levels in the dorsolateral prefrontal cortex in 16 recent-onset patients (duration: 1.8+/-0.6 years), 19 chronic patients (duration: 9.7+/-6.1 years), and 20 healthy controls. We studied the NAA/creatine and choline/creatine ratios in the dorsolateral prefrontal cortex in both hemispheres, controlling for the effect of age. Chronic patients had significantly lower NAA/Cr ratios in the left hemisphere compared to recent-onset patients and healthy controls, with no difference in Cho/Cr ratio. There were no differences between controls and recent-onset patients. There was a significant inverse relationship between left-side NAA/Cr and disease duration, suggesting that prefrontal NAA levels may progressively decrease in schizophrenia. Taken within the context of the existing literature, these results indicate that this process may be limited to the early years following the onset of the disease. Therefore, reduced prefrontal levels of NAA may be limited to chronic schizophrenia patients.