RESUMO
INTRODUCTION: The impairment of nigrostriatal dopaminergic network is a core feature of dementia with Lewy bodies (DLB). The involvement and reconfiguration of extranigrostriatal dopaminergic circuitries in the DLB continuum is still theme of debate. We aim to investigate in vivo the dynamic changes of local and long-distance dopaminergic networks across DLB continuum. METHODS: Forty-nine patients (including 29 with dementia and 20 prodromal cases) and fifty-two controls entered the study. Each subject underwent a standardized clinical and neurological examination and performed Brain SPECT to measuring brain dopamine transporter (DAT) density. Spatially normalized images underwent the occipital-adjusted specific binding to obtain parametric data. The ANCOVA was applied to assess 123I-FP-CIT differences between pDLB, overt-DLB and CG, considering age, gender, and motor impairment as variables of no interest. Between-nodes correlation analysis measured molecular connectivity within the ventral and dorsal dopaminergic networks. RESULTS: Prodromal DLB and DLB patients showed comparable nigrostriatal deficits in basal ganglia regions compared with CG. Molecular connectivity analyses revealed extensive connectivity losses, more in ventral than in dorsal dopaminergic network in DLB dementia. Conversely, the prodromal group showed increased connectivity compared to CG, mostly putamen-thalamus-cortical and striatal-cortical connectivity. CONCLUSIONS: This study indicates a comparable basal ganglia deficit in nigrostriatal projections in DLB continuum and supports a different reorganization of extra-striatal dopaminergic connectivity in the prodromal phases of DLB. The shift from an increased to a decreased bilateral putamen-thalamus-cortex connectivity might be a hallmark of transition from prodromal to dementia DLB stages.
Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Humanos , Doença por Corpos de Lewy/metabolismo , Gânglios da Base/metabolismo , Corpo Estriado/metabolismo , Encéfalo/metabolismo , Tálamo/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Doença de Alzheimer/metabolismoRESUMO
OBJECTIVE: Neuroinflammation is considered a key driver for neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). SOD1 mutations cause about 20% of familial ALS, and related pathology might generate microglial activation triggering neurodegeneration. 11 C-PK11195 is the prototypical and most validated PET radiotracer, targeting the 18-kDa translocator protein which is overexpressed in activated microglia. In this study, we investigated microglia activation in asymptomatic (ASYM) and symptomatic (SYM) SOD1 mutated carriers, by using 11 C-PK11195 and PET imaging. METHODS: We included 20 subjects: 4 ASYM-carriers, neurologically normal, 6 SYM-carriers with probable ALS, and 10 healthy controls. A receptor parametric mapping procedure estimated 11 C-PK11195 binding potentials and voxel-wise statistical comparisons were performed at group and single-subject levels. RESULTS: Both the SYM- and ASYM-carriers showed significant microglia activation in cortical and subcortical structures, with variable patterns at individual level. Clusters of activation were present in occipital and temporal regions, cerebellum, thalamus, and medulla oblongata. Notably, SYM-carriers showed microglia activation also in supplementary and primary motor cortices and in the somatosensory regions. INTERPRETATION: In vivo neuroinflammation occurred in all SOD1 mutated cases since the presymptomatic stages, as shown by a significant cortical and subcortical microglia activation. The involvement of sensorimotor cortex became evident at the symptomatic disease stage. Although our data indicate the role of in vivo PET imaging for assessing resident microglia in the investigation of SOD1-ALS pathophysiology, further studies are needed to clarify the temporal and spatial dynamics of microglia activation and its relationship with neurodegeneration.
Assuntos
Amidas , Esclerose Lateral Amiotrófica , Encéfalo , Inflamação , Isoquinolinas , Microglia , Tomografia por Emissão de Pósitrons , Superóxido Dismutase-1/genética , Adulto , Idoso , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/imunologia , Encéfalo/metabolismo , Feminino , Heterozigoto , Humanos , Inflamação/diagnóstico por imagem , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Microglia/imunologia , Microglia/metabolismo , Pessoa de Meia-Idade , Sintomas ProdrômicosRESUMO
Transcranial magnetic stimulation was used to investigate corticospinal output changes in 10 professional piano players during motor imagery of triad chords in C major to be "mentally" performed with three fingers of the right hand (thumb, index, and little finger). Five triads were employed in the task; each composed by a stable 3rd interval (C4-E4) and a varying third note that could generate a 5th (G4), a 6th (A4), a 7th (B4), a 9th (D5), or a 10th (E5) interval. The 10th interval chord was thought to be impossible in actual execution for biomechanical reasons, as long as the thumb and the index finger remained fixed on the 3rd interval. Chords could be listened from loudspeakers, read on a staff, or listened and read at the same time while performing the imagery task. The corticospinal output progressively increased along with task demands in terms of mental representation of hand extension. The effects of audio, visual, or audiovisual musical stimuli were generally similar, unless motor imagery of kinetically impossible triads was required. A specific three-effector motor synergy was detected, governing the representation of the progressive mental extension of the hand. Results demonstrate that corticospinal facilitation in professional piano players can be modulated according to the motor plan, even if simply "dispatched" without actual execution. Moreover, specific muscle synergies, usually encoded in the motor cortex, emerge along the cross-modal elaboration of musical stimuli and in motor imagery of musical performances.
Assuntos
Percepção Auditiva/fisiologia , Imaginação/fisiologia , Córtex Motor/fisiologia , Destreza Motora/fisiologia , Tratos Piramidais/fisiologia , Percepção Visual/fisiologia , Adulto , Eletromiografia , Potencial Evocado Motor , Feminino , Humanos , Masculino , Músculo Esquelético/fisiologia , Estimulação Magnética Transcraniana , Adulto JovemRESUMO
PURPOSE: The aim of the study was to evaluate extrastriatal dopaminergic and serotonergic pathways in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB) using 123I-FP-CIT SPECT imaging. METHODS: The study groups comprised 56 PD patients without dementia, 41 DLB patients and 54 controls. Each patient underwent a standardized neurological examination and 123I-FP-CIT SPECT. Binding in nigrostriatal and extrastriatal regions of interest was calculated in each patient from spatially normalized images. The occipital-adjusted specific to nondisplaceable binding ratio (SBR) in the different regions was compared among the PD patients, DLB patients and controls adjusting for the effects of age, sex, disease duration and serotonergic/dopaminergic treatment. Covariance analysis was used to determine the correlates of local and long-distance regions with extrastriatal 123I-FP-CIT deficits. RESULTS: Both PD and DLB patients showed lower 123I-FP-CIT SPECT SBR in several regions beyond the nigrostriatal system, especially the insula, cingulate and thalamus. DLB patients showed significantly lower 123I-FP-CIT SBR in the thalamus than controls and PD patients. Thalamic and cingulate 123I-FP-CIT SBR deficits were correlated, respectively, with limbic serotonergic and widespread cortical monoaminergic projections only in DLB patients but exhibited only local correlations in PD patients and controls. CONCLUSION: PD and DLB patients both showed insular dopamine deficits, whereas impairment of thalamic serotonergic pathways was specifically associated with DLB. Longitudinal studies are necessary to determine the clinical value of the assessment of extrastriatal 123I-FP-CIT SPECT.
Assuntos
Córtex Cerebral/diagnóstico por imagem , Neurônios Dopaminérgicos/metabolismo , Doença por Corpos de Lewy/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Neurônios Serotoninérgicos/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Compostos Radiofarmacêuticos/farmacocinética , Substância Negra/diagnóstico por imagem , Tálamo/diagnóstico por imagem , Tropanos/farmacocinéticaRESUMO
Embodied cognition theories of semantic memory still face the need for multiple sources of converging evidence in support of the involvement of sensory-motor systems in action-related knowledge. Previous studies showed that training manual actions improves semantic processing of verbs referring to the trained actions. The present work aimed to provide complementary evidence by measuring the brain plasticity effects of a cognitive training requiring sustained lexical-semantic processing of action-related verbs. We included two groups of participants, namely the Proximal Group (PG) and the Distal Group (DG), which underwent a 3-week training with verbs referring to actions involving the proximal and the distal upper limb musculature, respectively. Before and after training, we measured gray matter voxel brain morphometry based on T1 structural magnetic resonance imaging. By means of this 2 (Group: PG, DG) × 2 (Time: pre-, post-training) factorial design, we tested whether sustained cognitive experience with specific action-related verbs induces congruent brain plasticity modifications in target regions of interest pertaining to the action representation system. We found significant post- versus pre-training gray matter volume increases, specifically for PG in the left dorsal precentral gyrus, and for DG in the right cerebellar lobule VIIa. These preliminary results suggest that a cognitive training can induce structural plasticity modifications in brain regions specifically coding for the distal and proximal motor actions the trained verbs refer to.
Assuntos
Encéfalo/fisiologia , Cognição/fisiologia , Substância Cinzenta/fisiologia , Plasticidade Neuronal/fisiologia , Semântica , Comportamento Verbal/fisiologia , Estimulação Acústica , Adulto , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Tomada de Decisões , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Rememoração Mental , Estimulação Luminosa , Tempo de Reação/fisiologia , Ensino , Adulto JovemRESUMO
OBJECTIVE: Spinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients. METHODS: We enrolled 10 SCA38 patients, and carried out a double-blind randomized placebo-controlled study for 16 weeks, followed by an open-label study with overall 40-week DHA treatment. At baseline and at follow-up visit, patients underwent standardized clinical assessment, brain 18-fluorodeoxyglucose positron emission tomography, electroneurography, and ELOVL5 expression analysis. RESULTS: After 16 weeks, we showed a significant pre-post clinical improvement in the DHA group versus placebo, using the Scale for the Assessment and Rating of Ataxia (SARA; mean difference [MD] = +2.70, 95% confidence interval [CI] = +0.13 to + 5.27, p = 0.042). At 40-week treatment, clinical improvement was found significant by both SARA (MD = +2.2, 95% CI = +0.93 to + 3.46, p = 0.008) and International Cooperative Ataxia Rating Scale (MD = +3.8, 95% CI = +1.39 to + 6.41, p = 0.02) scores; clinical data were corroborated by significant improvement of cerebellar hypometabolism (statistical parametric mapping analyses, false discovery rate corrected). We also showed a decreased expression of ELOVL5 in patients' blood at 40 weeks as compared to baseline. No side effect was recorded. INTERPRETATION: DHA supplementation is a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism. Ann Neurol 2017;82:615-621.
Assuntos
Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ataxias Espinocerebelares/tratamento farmacológico , Adulto , Ataxinas/genética , Encéfalo/diagnóstico por imagem , Método Duplo-Cego , Eletromiografia , Feminino , Fluordesoxiglucose F18/farmacocinética , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Avaliação de Resultados em Cuidados de Saúde , Tomografia por Emissão de Pósitrons , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Resultado do TratamentoRESUMO
The Rey Auditory Verbal Learning Test (RAVLT) is widely used in clinical practice to evaluate verbal episodic memory. While there is evidence that RAVLT performance can be influenced by executive dysfunction, the way executive disorders affect the serial position curve (SPC) has not been yet explored. To this aim, we analysed immediate and delayed recall performances of 13 non-demented amyotrophic lateral sclerosis (ALS) patients with a specific mild executive dysfunction (ALSci) and compared their performances to those of 48 healthy controls (HC) and 13 cognitively normal patients with ALS. Moreover, to control for the impact of a severe dysexecutive syndrome and a genuine episodic memory deficit on the SPC, we enrolled 15 patients with a diagnosis of behavioural variant of frontotemporal dementia (bvFTD) and 18 patients with probable Alzheimer's disease (AD). Results documented that, compared to cognitively normal subjects, ALSci patients had a selective mid-list impairment for immediate recall scores. The bvFTD group obtained low performances with a selectively increased forgetting rate for terminal items, whereas the AD group showed a disproportionately large memory loss on the primary and middle part of the SPC for immediate recall scores and were severely impaired in the delayed recall trial. These results suggested that subtle executive dysfunctions might influence the recall of mid-list items, possibly reflecting deficiency in control strategies at retrieval of word lists, whereas severer dysexecutive syndrome might also affect the recall of terminal items possibly due to attention deficit or retroactive interference.
Assuntos
Esclerose Lateral Amiotrófica/complicações , Transtornos Cognitivos/etiologia , Função Executiva/fisiologia , Transtornos da Memória/etiologia , Rememoração Mental/fisiologia , Doenças Neurodegenerativas/complicações , Estimulação Acústica , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Transtornos Cognitivos/diagnóstico , Feminino , Humanos , Masculino , Transtornos da Memória/diagnóstico , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Testes Neuropsicológicos , Aprendizagem VerbalRESUMO
The auditory scene is a mental representation of individual sounds extracted from the summed sound waveform reaching the ears of the listeners. Musical contexts represent particularly complex cases of auditory scenes. In such a scenario, melody may be seen as the main object moving on a background represented by the accompaniment. Both melody and accompaniment vary in time according to harmonic rules, forming a typical texture with melody in the most prominent, salient voice. In the present sparse acquisition functional magnetic resonance imaging study, we investigated the interplay between melody and accompaniment in trained pianists, by observing the activation responses elicited by processing: (1) melody placed in the upper and lower texture voices, leading to, respectively, a higher and lower auditory salience; (2) harmonic violations occurring in either the melody, the accompaniment, or both. The results indicated that the neural activation elicited by the processing of polyphonic compositions in expert musicians depends upon the upper versus lower position of the melodic line in the texture, and showed an overall greater activation for the harmonic processing of melody over accompaniment. Both these two predominant effects were characterized by the involvement of the posterior cingulate cortex and precuneus, among other associative brain regions. We discuss the prominent role of the posterior medial cortex in the processing of melodic and harmonic information in the auditory stream, and propose to frame this processing in relation to the cognitive construction of complex multimodal sensory imagery scenes.
Assuntos
Percepção Auditiva/fisiologia , Encéfalo/fisiologia , Imageamento por Ressonância Magnética , Música , Adulto , Feminino , Humanos , Masculino , Processos Mentais/fisiologia , Adulto JovemRESUMO
The ability to learn language is a human trait. In adults and children, brain imaging studies have shown that auditory language activates a bilateral frontotemporal network with a left hemispheric dominance. It is an open question whether these activations represent the complete neural basis for language present at birth. Here we demonstrate that in 2-d-old infants, the language-related neural substrate is fully active in both hemispheres with a preponderance in the right auditory cortex. Functional and structural connectivities within this neural network, however, are immature, with strong connectivities only between the two hemispheres, contrasting with the adult pattern of prevalent intrahemispheric connectivities. Thus, although the brain responds to spoken language already at birth, thereby providing a strong biological basis to acquire language, progressive maturation of intrahemispheric functional connectivity is yet to be established with language exposure as the brain develops.
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Córtex Auditivo/fisiologia , Idioma , Rede Nervosa/fisiologia , Fala/fisiologia , Estimulação Acústica/métodos , Adulto , Córtex Auditivo/anatomia & histologia , Mapeamento Encefálico , Feminino , Humanos , Recém-Nascido , Desenvolvimento da Linguagem , Aprendizagem/fisiologia , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Análise Multivariada , Rede Nervosa/anatomia & histologiaRESUMO
In adults, specific neural systems with right-hemispheric weighting are necessary to process pitch, melody, and harmony as well as structure and meaning emerging from musical sequences. It is not known to what extent the specialization of these systems results from long-term exposure to music or from neurobiological constraints. One way to address this question is to examine how these systems function at birth, when auditory experience is minimal. We used functional MRI to measure brain activity in 1- to 3-day-old newborns while they heard excerpts of Western tonal music and altered versions of the same excerpts. Altered versions either included changes of the tonal key or were permanently dissonant. Music evoked predominantly right-hemispheric activations in primary and higher order auditory cortex. During presentation of the altered excerpts, hemodynamic responses were significantly reduced in the right auditory cortex, and activations emerged in the left inferior frontal cortex and limbic structures. These results demonstrate that the infant brain shows a hemispheric specialization in processing music as early as the first postnatal hours. Results also indicate that the neural architecture underlying music processing in newborns is sensitive to changes in tonal key as well as to differences in consonance and dissonance.
Assuntos
Encéfalo/fisiologia , Dominância Cerebral/fisiologia , Lateralidade Funcional/fisiologia , Música , Estimulação Acústica/métodos , Adulto , Córtex Auditivo/anatomia & histologia , Córtex Auditivo/fisiologia , Percepção Auditiva/fisiologia , Encéfalo/anatomia & histologia , Mapeamento Encefálico , Feminino , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética/métodos , Masculino , Percepção da Altura Sonora/fisiologia , Gravidez , SomRESUMO
OBJECTIVE: To investigate the presence of sub-clinical cognitive dysfunction in non-demented patients with amyotrophic lateral sclerosis (ALS) using auditory event-related potentials (ERPs). METHODS: Ten subjects with ALS and 10 age- and sex-matched controls performed a passive three-stimulus paradigm with standard (80%), deviant (16%) and distracter (4%) stimuli. To quantify the mismatch component, the evoked response to the standard tones was subtracted from the corresponding deviant stimuli and novel response; the P3a component was obtained by subtracting the response to the standard tone from that to the novel stimuli. The amplitude and latency for the N1 component obtained with the standard stimuli were also measured. Clinical features, disability, cognitive status and depression were evaluated with standardised scales. RESULTS: There were no significant differences between patients and controls for latencies, while the N1, P3a and MMN (obtained by the subtraction Novel-Standard) were of lower amplitude in patients than in controls. In the patient group, the P3a latency correlated with months from disease onset and symptoms severity, measured with the amyotrophic lateral sclerosis severity scale. CONCLUSIONS: Our findings confirm the hypothesis of a sub-clinical cognitive impairment in non-demented ALS patients, suggesting pathological involvement beyond the motor areas. SIGNIFICANCE: ERPs seem to be a promising technique to detect the possible impairment of extra-motor sub-clinical dysfunction in ALS, and an appropriate technique for the cognitive follow-up, as passive tasks, not requiring motor responses, are particularly adequate in a disorder leading to severe loss of motor function.
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Esclerose Lateral Amiotrófica/fisiopatologia , Potenciais Evocados Auditivos/fisiologia , Estimulação Acústica/métodos , Idoso , Estudos de Casos e Controles , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Reação , Estatística como AssuntoRESUMO
Knowing how and when the degenerative process starts is important in neurodegenerative diseases. We have addressed this issue in fatal familial insomnia (FFI) measuring the cerebral metabolic rate of glucose (CMRglc) with 2-[18F]fluoro-2-deoxy-D-glucose PET in parallel with detailed clinical, neuropsychological examinations and polysomnography with EEG spectral analyses. Nine asymptomatic carriers of the D178N mutation, 10 non-carriers belonging to the same family, and 19 age-matched controls were studied over several years. The CMRglc as well as clinical and electrophysiological examinations were normal in all cases at the beginning of the study. Four of the mutation carriers developed typical FFI during the study but CMRglc and the clinical and electrophysiological examinations remained normal 63, 56, 32 and 21 months, respectively before disease onset. The carrier whose tests were normal 32 months before disease onset was re-examined 13 months before the onset. At that time, selective hypometabolism was detected in the thalamus while spectral-EEG analysis disclosed an impaired thalamic sleep spindle formation. Following clinical disease onset, CRMglc was reduced in the thalamus in all 3 patients examined. Our data indicate that the neurodegenerative process associated with FFI begins in the thalamus between 13 and 21 months before the clinical presentation of the disease.
Assuntos
Encéfalo/metabolismo , Insônia Familiar Fatal/diagnóstico , Adulto , Idoso , Glicemia/metabolismo , Diagnóstico Precoce , Feminino , Fluordesoxiglucose F18 , Seguimentos , Heterozigoto , Humanos , Insônia Familiar Fatal/diagnóstico por imagem , Insônia Familiar Fatal/genética , Masculino , Pessoa de Meia-Idade , Mutação , Polissonografia , Tomografia por Emissão de Pósitrons , Príons/genética , Compostos Radiofarmacêuticos , Tálamo/metabolismoRESUMO
Observing actions made by others activates the cortical circuits responsible for the planning and execution of those same actions. This observation-execution matching system (mirror-neuron system) is thought to play an important role in the understanding of actions made by others. In an fMRI experiment, we tested whether this system also becomes active during the processing of action-related sentences. Participants listened to sentences describing actions performed with the mouth, the hand, or the leg. Abstract sentences of comparable syntactic structure were used as control stimuli. The results showed that listening to action-related sentences activates a left fronto-parieto-temporal network that includes the pars opercularis of the inferior frontal gyrus (Broca's area), those sectors of the premotor cortex where the actions described are motorically coded, as well as the inferior parietal lobule, the intraparietal sulcus, and the posterior middle temporal gyrus. These data provide the first direct evidence that listening to sentences that describe actions engages the visuomotor circuits which subserve action execution and observation.
Assuntos
Lobo Frontal/fisiologia , Córtex Motor/fisiologia , Rede Nervosa/fisiologia , Lobo Parietal/fisiologia , Estimulação Acústica/métodos , Adulto , Mapeamento Encefálico , Feminino , Lobo Frontal/irrigação sanguínea , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Masculino , Córtex Motor/irrigação sanguínea , Rede Nervosa/irrigação sanguínea , Oxigênio/sangue , Lobo Parietal/irrigação sanguínea , Estudos RetrospectivosRESUMO
Basal ganglia have been implicated in syntactic and phonological processes, but direct evidence has been scarce. Here, we used [11C]raclopride and positron emission tomography to measure modulations of the dopaminergic system induced by phonological or syntactic processing. Two significant effects were found. First, the level of accuracy in phonological processing significantly correlated with tracer binding potential in the left caudate nucleus. Second, the speed in phonological processing significantly correlated with tracer binding potential in the left putamen. Thus, a more accurate and fast phonological processing was associated with a reduced dopamine requirement in the left striatum. These findings show that the striatal dopaminergic system plays an essential role in grammatical processes that form the core of human language.
Assuntos
Estimulação Acústica/métodos , Gânglios da Base/metabolismo , Dopamina/metabolismo , Idioma , Adulto , Análise de Variância , Humanos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Ligação Proteica/fisiologia , Receptores de Dopamina D2/metabolismoRESUMO
The existence of a "critical period" for language acquisition is controversial. Bilingual subjects with variable age of acquisition (AOA) and proficiency level (PL) constitute a suitable model to study this issue. We used functional magnetic resonance imaging to investigate the effects of AOA and PL on neural correlates of grammatical and semantic judgments in Italian-German bilinguals who learned the second language at different ages and had different proficiency levels. While the pattern of brain activity for semantic judgment was largely dependent on PL, AOA mainly affected the cortical representation of grammatical processes. These findings support the view that both AOA and PL affect the neural substrates of second language processing, with a differential effect on grammar and semantics.