RESUMO
BACKGROUND: Huntington's disease (HD) patients often present with abnormal modulation of blood pressure and heart rate. We investigated whether cardiac autonomic innervation assessed by 123I-metaiodobenzylguanidine (MIBG) imaging is impaired in HD patients, in comparison with controls (Ctrl). METHODS: Fifteen patients (6 F and 9 M) were assessed by the motor section of the Unified HD Rating Scale, the Total Function Capacity, and the scale for outcomes in Parkinson's disease-autonomic (SCOPA-AUT) questionnaire. All patients and 10 Ctrl (5 F and 5 M) underwent 123I-MIBG imaging. From planar images, the early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates (WR) were calculated. RESULTS: We did not find significant differences in early and late H/M ratios and WR between the two groups. At individual level, three patients showed reduced early and/or late H/M ratios. The most common autonomic complaints were gastrointestinal and genitourinary disorders. SCOPA-AUT questionnaire score results positively correlated with the disease duration and WR. CONCLUSIONS: Our study indicates that myocardial postganglionic sympathetic innervation is essentially preserved or only minimally involved in HD. These findings suggest that the cardiovascular dysfunction might be mainly due to the impairment of brain areas associated with the regulation and modulation of the heart function.
Assuntos
Doenças do Sistema Nervoso Autônomo , Doença de Huntington , Imagem de Perfusão do Miocárdio , 3-Iodobenzilguanidina , Doenças do Sistema Nervoso Autônomo/diagnóstico por imagem , Coração/inervação , Humanos , Doença de Huntington/diagnóstico por imagem , Radioisótopos do Iodo , Compostos RadiofarmacêuticosRESUMO
PURPOSE: To evaluate the feasibility and sensitivity of multimodality PET/CT and MRI imaging for non-invasive characterization of brain microglial/macrophage activation occurring during the acute phase in a mouse model of relapsing remitting multiple sclerosis (RR-MS) using [18F]DPA-714, a selective radioligand for the 18-kDa translocator protein (TSPO), superparamagnetic iron oxide particles (SPIO), and ex vivo immunohistochemistry. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in female SJL/J mice by immunization with PLP139-151. Seven symptomatic EAE mice and five controls underwent both PET/CT and MRI studies between 11 and 14 days post-immunization. SPIO was injected i.v. in the same animals immediately after [18F]DPA-714 and MRI acquisition was performed after 24 h. Regional brain volumes were defined according to a mouse brain atlas on co-registered PET and SPIO-MRI images. [18F]DPA-714 standardized uptake value (SUV) ratios (SUVR), with unaffected neocortex as reference, and SPIO fractional volumes (SPIO-Vol) were generated. Both SUVR and SPIO-Vol values were correlated with the clinical score (CS) and among them. Five EAE and four control mice underwent immunohistochemical analysis with the aim of identifying activated microglia/macrophage and TSPO expressions. RESULTS: SUVR and SPIO-Vol values were significantly increased in EAE compared with controls in the hippocampus (p < 0.01; p < 0.02, respectively), thalamus (p < 0.02; p < 0.05, respectively), and cerebellum and brainstem (p < 0.02), while only SPIO-Vol was significantly increased in the caudate/putamen (p < 0.05). Both SUVR and SPIO-Vol values were positively significantly correlated with CS and among them in the same regions. TSPO/Iba1 and F4/80/Prussian blue staining immunohistochemistry suggests that increased activated microglia/macrophages underlay TSPO expression and SPIO uptake in symptomatic EAE mice. CONCLUSIONS: These preliminary results suggest that both activated microglia and infiltrated macrophages are present in vulnerable brain regions during the acute phase of PLP-EAE and contribute to disease severity. Both [18F]DPA-714-PET and SPIO-MRI appear suitable modalities for preclinical study of neuroinflammation in MS mice models.
Assuntos
Encefalomielite Autoimune Experimental , Animais , Encefalomielite Autoimune Experimental/diagnóstico por imagem , Feminino , Ativação de Macrófagos , Macrófagos , Imageamento por Ressonância Magnética , Camundongos , Microglia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Pirazóis , PirimidinasRESUMO
PURPOSE: An appropriate healthy control dataset is mandatory to achieve good performance in voxel-wise analyses. We aimed at evaluating [18F]FDG PET brain datasets of healthy controls (HC), based on publicly available data, for the extraction of voxel-based brain metabolism maps at the single-subject level. METHODS: Selection of HC images was based on visual rating, after Cook's distance and jack-knife analyses, to exclude artefacts and/or outliers. The performance of these HC datasets (ADNI-HC and AIMN-HC) to extract hypometabolism patterns in single patients was tested in comparison with the standard reference HC dataset (HSR-HC) by means of Dice score analysis. We evaluated the performance and comparability of the different HC datasets in the assessment of single-subject SPM-based hypometabolism in three independent cohorts of patients, namely, ADD, bvFTD and DLB. RESULTS: Two-step Cook's distance analysis and the subsequent jack-knife analysis resulted in the selection of n = 125 subjects from the AIMN-HC dataset and n = 75 subjects from the ADNI-HC dataset. The average concordance between SPM hypometabolism t-maps in the three patient cohorts, as obtained with the new datasets and compared to the HSR-HC standard reference dataset, was 0.87 for the AIMN-HC dataset and 0.83 for the ADNI-HC dataset. Pattern expression analysis revealed high overall accuracy (> 80%) of the SPM t-map classification according to different statistical thresholds and sample sizes. CONCLUSIONS: The applied procedures ensure validity of these HC datasets for the single-subject estimation of brain metabolism using voxel-wise comparisons. These well-selected HC datasets are ready-to-use in research and clinical settings.
Assuntos
Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , HumanosRESUMO
PURPOSE: Moyamoya syndrome (MMS) is a rare intracranial arterial vasculopathy which can occur in neurofibromatosis type 1 (NF1) disease, representing a cause of cerebrovascular reserve (CVR) impairment, possibly leading to ischemic stroke. Here, we evaluated noninvasive imaging techniques used to assess CVR in MMS patients, describing clinical and imaging findings in patients affected by MMS-NF1. METHODS: Following strict inclusion and exclusion criteria, in this retrospective observational study, we evaluated imaging data of nine consecutive MMS-NF1 patients (M/F = 5/4, mean age: 12.6 ± 4.0). Subjects underwent a multimodal evaluation of cerebral vascular status, including intracranial arterial MR Angiography (MRA), MRI perfusion with dynamic susceptibility contrast (DSC) technique, and 99mTc-hexamethylpropyleneamine oxime (HMPAO) SPECT. RESULTS: In 8 out 9 patients (88.8%, 6/8 symptomatic), time-to-peak maps were correlated with the involved cerebral hemisphere, while in 6 out 9 patients (66.6%, 5/6 symptomatic), mean transit time (MTT) maps showed correspondence with the affected cerebrovascular territories. Cerebral blood flow (CBF) calculated using DSC perfusion failed to detect the hypoperfused regions instead identified by SPECT-CBF in all patients, while MTT maps overlapped with SPECT-CBF data in all cases and time-to-peak maps in 60.0%. CONCLUSIONS: Although SPECT imaging still represents the gold standard for CBF assessment, our results suggest that data obtained using DSC perfusion technique, and in particular MTT maps, might be a very useful and noninvasive tool for evaluating hemodynamic status in MMS-NF1 patients.
Assuntos
Doença de Moyamoya , Neurofibromatose 1 , Adolescente , Circulação Cerebrovascular , Criança , Humanos , Imageamento por Ressonância Magnética , Doença de Moyamoya/complicações , Doença de Moyamoya/diagnóstico por imagem , Neurofibromatose 1/complicações , Neurofibromatose 1/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
BACKGROUND: Alzheimer's disease (AD) is the most common age-related dementia. Besides its typical presentation with amnestic syndrome at onset, atypical AD cases are being increasingly recognized, often in presenile age. OBJECTIVES: To provide an extensive clinical and genetic characterization of six AD patients carrying one or more singular features, including age of onset, atypical phenotype and disease progression rate. By reviewing the pertinent literature and accessing publicly available databases, we aimed to assess the frequency and the significance of the identified genetic variants. METHODS: Biomarkers of amyloid-ß deposition and neurodegeneration were used to establish the in vivo diagnosis of probable AD, in addition to neurological and neuropsychological evaluation, extensive laboratory assays and neuroradiological data. Considering the presenile onset of the majority of the cases, we hypothesized genetically determined AD and performed extensive genetic analyses by both Sanger sequencing and next generation sequencing (NGS). RESULTS: We disclosed two known missense variants, one in PSEN1 and the other in PSEN2, and a novel silent variant in PSEN2. Most notably, we identified several additional variants in other dementia-related genes by NGS. Some of them have never been reported in any control or disease databases, representing variants unique to our cases. CONCLUSIONS: This work underlines the difficulties in reaching a confident in vivo diagnosis in cases of atypical dementia. Moreover, a wider genetic analysis by NGS approach may prove to be useful in specific cases, especially when the study of the so-far known AD causative genes produces negative or conflicting results.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Testes Genéticos , Humanos , Mutação de Sentido Incorreto , Testes Neuropsicológicos , Presenilina-1/genética , Presenilina-2/genéticaRESUMO
PURPOSE: This joint practice guideline or procedure standard was developed collaboratively by the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). The goal of this guideline is to assist nuclear medicine practitioners in recommending, performing, interpreting, and reporting the results of dopaminergic imaging in parkinsonian syndromes. METHODS: Currently nuclear medicine investigations can assess both presynaptic and postsynaptic function of dopaminergic synapses. To date both EANM and SNMMI have published procedural guidelines for dopamine transporter imaging with single photon emission computed tomography (SPECT) (in 2009 and 2011, respectively). An EANM guideline for D2 SPECT imaging is also available (2009). Since the publication of these previous guidelines, new lines of evidence have been made available on semiquantification, harmonization, comparison with normal datasets, and longitudinal analyses of dopamine transporter imaging with SPECT. Similarly, details on acquisition protocols and simplified quantification methods are now available for dopamine transporter imaging with PET, including recently developed fluorinated tracers. Finally, [18F]fluorodopa PET is now used in some centers for the differential diagnosis of parkinsonism, although procedural guidelines aiming to define standard procedures for [18F]fluorodopa imaging in this setting are still lacking. CONCLUSION: All these emerging issues are addressed in the present procedural guidelines for dopaminergic imaging in parkinsonian syndromes.
Assuntos
Medicina Nuclear , Transtornos Parkinsonianos , Humanos , Imagem Molecular , Transtornos Parkinsonianos/diagnóstico por imagem , Cintilografia , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
BACKGROUND AND AIM: Neurodegeneration with brain iron accumulation (NBIA) and Wilson's disease (WD) is considered the prototype of neurodegenerative disorders characterised by the overloading of iron and copper in the central nervous system. Growing evidence has unveiled the involvement of these metals in brain cortical neurotransmission. Aim of this study was to assess cortical excitability profile due to copper and iron overload. METHODS: Three patients affected by NBIA, namely two patients with a recessive hereditary parkinsonism (PARK9) and one patient with aceruloplasminemia and 7 patients with neurological WD underwent transcranial magnetic stimulation (TMS) protocols to assess cortical excitability. Specifically, we evaluated the motor thresholds that reflect membrane excitability related to the voltage-gated sodium channels in the neurons of the motor system and the ease of activation of motor cortex via glutamatergic networks, and ad hoc TMS protocols to probe inhibitory-GABAergic (short interval intracortical inhibition, SICI; short-latency afferent inhibition, SAI; cortical silent period, CSP) and excitatory intracortical circuitry (intracortical facilitation, ICF). RESULTS: Patients with NBIA exhibited an abnormal prolongation of CSP respect to HC and WD patients. On the contrary, neurological WD displayed higher motor thresholds and reduced CSP and SICI. CONCLUSION: Hereditary conditions due to overload of copper and iron exhibited peculiar cortical excitability profiles that can help during differential diagnosis between these conditions. Moreover, such results can give us more clues about the role of metals in acquired neurodegenerative disorders, such as Parkinson disease, Alzheimer disease, and multiple sclerosis.
Assuntos
Ceruloplasmina/deficiência , Excitabilidade Cortical/fisiologia , Degeneração Hepatolenticular/fisiopatologia , Distúrbios do Metabolismo do Ferro/fisiopatologia , Distrofias Neuroaxonais/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Transtornos Parkinsonianos/fisiopatologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Magnética Transcraniana , Adulto JovemRESUMO
In May 2017 some representatives of the Italian nuclear medicine and neurological communities spontaneously met to discuss the issues emerged during the first two years of routine application of amyloid PET with fluorinated radiopharmaceuticals in the real world. The limitations of a binary classification of scans, the possibility to obtain early images as a surrogate marker of regional cerebral bloos flow, the need for (semi-)quantification and, thus, the opportunity of ranking brain amyloidosis, the correlation with Aß42 levels in the cerebrospinal fluid, the occurrence and biological meaning of uncertain/boderline scans, the issue of incidental amyloidosis, the technical pittfalls leading to false negative/positive results, the position of the tool in the diagnostic flow-chart in the national reality, are the main topics that have been discussed. Also, a card to justify the examination to be filled by the dementia specialist and a card for the nuclear medicine physician to report the exam in detail have been approved and are available in the web, which should facilitate the creation of a national register, as previewed by the 2015 intersocietal recommendation on the use of amyloid PET in Italy. The content of this discussion could stimulate both public institutions and companies to support further research on these topics.
Assuntos
Amiloide/metabolismo , Idioma , Tomografia por Emissão de Pósitrons/estatística & dados numéricos , Humanos , Processamento de Imagem Assistida por Computador , Itália , Traçadores RadioativosRESUMO
Simultaneously evaluating resting-state brain glucose metabolism and intrinsic functional activity has potential to impact the clinical neurosciences of Alzheimer Disease (AD). Indeed, integrating such combined information obtained in the same physiological setting may clarify how impairments in neuroenergetic and neuronal function interact and contribute to the mechanisms underlying AD. The present study used this multimodality approach to investigate, by means of a hybrid PET/MR scanner, the coupling between glucose consumption and intrinsic functional activity in 23 patients with AD-related cognitive impairment ranging from amnestic mild cognitive impairment (MCI) to mild-moderate AD (aMCI/AD), in comparison with a group of 23 healthy elderly controls. Between-group (Controlsâ¯>â¯Patients) comparisons were conducted on data from both imaging modalities using voxelwise 2-sample t-tests, corrected for partial-volume effects, head motion, age, gender and multiple tests. FDG-PET/fMRI relationships were assessed within and across subjects using Spearman partial correlations for three different resting-state fMRI (rs-fMRI) metrics sensitive to AD: fractional amplitude of low frequency fluctuations (fALFF), regional homogeneity (ReHo) and group independent component analysis with dual regression (gICA-DR). FDG and rs-fMRI metrics distinguished aMCI/AD from controls according to spatial patterns analogous to those found in stand-alone studies. Within-subject correlations were comparable across the three rs-fMRI metrics. Correlations were overall high in healthy controls (ρâ¯=â¯0.80⯱â¯0.04), but showed a significant 17% reduction (pâ¯<â¯0.05) in aMCI/AD patients (ρâ¯=â¯0.67⯱â¯0.05). Positive across-subject correlations were overall moderate (ρâ¯=â¯0.33⯱â¯0.07) and consistent across rs-fMRI metrics. These were confined around AD-target posterior regions for metrics of functional connectivity (ReHo and gICA-DR). In contrast, FDG/fALFF correlations were distributed in the frontal gyrus, thalami and caudate nuclei. Taken together, these results support the presence of bioenergetic coupling between glucose utilization and rapid transmission of neural information in healthy ageing, which is substantially reduced in aMCI/AD, suggesting that abnormal glucose utilization is in some way linked to communication breakdown among brain regions impacted by the underlying pathological process.
Assuntos
Envelhecimento/fisiologia , Doença de Alzheimer/diagnóstico por imagem , Amnésia/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Conectoma/métodos , Glucose/metabolismo , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Adulto , Idoso , Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Amnésia/metabolismo , Amnésia/fisiopatologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Imagem MultimodalRESUMO
BACKGROUND: In-vivo imaging of dopamine transporter (DAT), a reliable marker of degeneration of nigrostriatal dopaminergic innervation, has gained increasing interest in preclinical neurodegenerative research for studying disease mechanisms and testing new therapeutic strategies. We assessed the feasibility and the reliability of in vivo and ex vivo quantification of Methyl (3S,4S,5R)-8-(3-fluoropropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-4-carboxylate ([123I]FP-CIT) binding to striatal DAT sites in mouse brain. METHODS: Dedicated small animal single-photon emission computed tomography (SPECT) images of [123I]FP-CIT binding were obtained in 3 groups of healthy mice: untreated (N.=6), pre-treated with lugol solution (N.=4), and pre-treated with selective dopamine transporter uptake inhibitor GBR12909 (N.=4). Ex-vivo autoradiography studies were performed at the end of SPECT studies with phosphor image system in 4 out of the 6 untreated mice and in all mice pre-treated with lugol. Regions of interest were defined over the striatum. The specific binding (SB) was calculated using the cerebral cortex as reference region. RESULTS: SPECT images in untreated mice showed high [123I]FP-CIT uptake in the striatum and extracerebral regions. Lugol pretreatment improved striatal images quality decreasing salivary and thyroid glands uptake. SB was higher (P<0.0001) in mice pre-treated with lugol (5.97±0.60) than in untreated mice (2.25±0.28). Autoradiography showed similar SB findings in untreated (2.27±0.33) and lugol-treated (4.27±0.57) mice (P<0.0001). In-vivo striatal 123I-FP-CIT SB and ex-vivo striatal 123I-FP-CIT SB were significantly correlated (r=0.87; P<0.0001). SPECT competition studies showed a significant (P<0.0001) reduction of [123I]FP-CIT SB in the striatum after GBR12909. CONCLUSIONS: We demonstrated the feasibility of [123I]FP-CIT imaging of the normal mouse brain using small-animal SPECT without pinhole collimators. The reliability of quantitative measurement of striatal [123I]FP-CIT SB is supported by competition studies showing measurable inhibition of uptake induced by GBR12909 and by the strong correlation between in vivo and ex vivo striatal [123I]FP-CIT SB. Our data also demonstrate that pre-treatment with lugol might improve striatal [123I]FP-CIT SB in mice.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neostriado/diagnóstico por imagem , Neostriado/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tropanos/metabolismo , Animais , Transporte Biológico , Dopamina/metabolismo , Estudos de Viabilidade , Camundongos , Ligação Proteica , Reprodutibilidade dos TestesRESUMO
Mutations in PSEN1 are responsible for familial Alzheimer's disease (FAD) inherited as autosomal dominant trait, but also de novo mutations have been rarely reported in sporadic early-onset dementia cases. Parkinsonism in FAD has been mainly described in advanced disease stages. We characterized a patient presenting with early-onset dystonia-parkinsonism later complicated by dementia and myoclonus. Brain MRI showed signs of iron accumulation in the basal ganglia mimicking neurodegeneration with brain iron accumulation (NBIA) as well as fronto-temporal atrophy. Whole exome sequencing revealed a novel PSEN1 mutation and segregation within the family demonstrated the mutation arose de novo.We suggest considering PSEN1 mutations in cases of dystonia-parkinsonism with positive DAT-Scan, later complicated by progressive cognitive decline and cortical myoclonus even without a dominant family history.
Assuntos
Disfunção Cognitiva/genética , Distonia/genética , Mutação/genética , Transtornos Parkinsonianos/genética , Presenilina-1/genética , Doença de Alzheimer/genética , Encéfalo/metabolismo , Distonia/complicações , Feminino , Humanos , Masculino , Transtornos Parkinsonianos/complicações , FenótipoRESUMO
Neuroinflammation (NI) is an adaptive response to different noxious stimuli, involving microglia, astrocytes and peripheral immune cells. NI is a hallmark of several acute and chronic diseases of central nervous system (CNS) and contributes to both damage and repair of CNS tissue. Interventional or genetically modified rodent models mimicking human neuropathologies may provide valuable insights on basic mechanisms of NI, but also for improving the development of new diagnostic and therapeutic strategies. Preclinical positron emission tomography (PET) allows to investigate noninvasively the inflammatory response in CNS of rodent models at a molecular level, validating innovative probes for early diagnosis, and characterizing the time course of neuroinflammatory changes and their relationship with disease progression, as well as the effects of experimental treatments with high translational potential. In particular, recent efforts of preclinical PET field are intended to develop specific and selective radiotracers that target the activation of innate immune system in CNS. Here, we have reviewed the state of art for PET in relevant rodent models of acute and chronic neuropathologies associated with NI, with particular regard on imaging of activated microglia and astrocytes.
Assuntos
Doenças do Sistema Nervoso Central/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Animais , Modelos Animais de Doenças , Humanos , Inflamação/diagnóstico por imagem , Doenças Neurodegenerativas/diagnóstico por imagem , RoedoresRESUMO
BACKGROUND: PARK2 is an autosomal recessive parkinsonism caused by parkin gene mutations. Several Parkinson's Disease (PD) cases harbor single parkin mutations, raising a debate about the pathogenic meaning of heterozygous mutations. Here, we evaluate cardiac autonomic innervation in patients with either two or one parkin mutations compared to patients with idiopathic PD (IPD). PATIENTS AND METHODS: Myocardial 123I-metaiodobenzylguanidine (MIBG) scintigraphy was performed in six PD patients with single parkin mutations (HET), four with two mutations (PARK2), and eight with IPD. RESULTS: In comparison to control group, IPD patients showed lower early and late heart-to-mediastinum (H/M) ratios and higher washout rates, whereas HET patients had only lower early H/M ratio, and PARK2 patients were not different for any parameter. At individual level, MIBG findings were abnormal in 7/8 IPD, in 4/6 HET and in 1/4 PARK2 patients. CONCLUSIONS: Preserved cardiac 123I-MIBG uptake confirms that PARK2 pathogenic mechanism, at least partially, differs from that responsible for IPD. HET subjects show intermediate findings, suggesting possible heterogeneity.
Assuntos
3-Iodobenzilguanidina , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Coração/diagnóstico por imagem , Coração/fisiopatologia , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único/genética , Ubiquitina-Proteína Ligases/genética , Adulto , Idoso , Doenças do Sistema Nervoso Autônomo/diagnóstico por imagem , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Doença de Parkinson/diagnóstico por imagem , Cintilografia/métodos , Compostos RadiofarmacêuticosRESUMO
Rasmussen's encephalitis (RE) is an immune-mediated disease, typically affecting a single cerebral hemisphere. Intractable epilepsy, hemiplegia and cognitive decline represent the clinical features; movement disorders have rarely been described. We report a case of adult-onset RE which developed hemiparkinsonism after an extraordinarily long prodromal period; to date, this is the first description of parkinsonism in RE. The association between cortical symptoms and extrapyramidal features evokes a clinical suspect of corticobasal syndrome (CBS); our patient satisfies the diagnostic criteria for possible CBS. Clinical and neuro-radiological reasons might further explain why RE accompanied by extrapyramidal signs may present as a CBS.
Assuntos
Encéfalo/diagnóstico por imagem , Encefalite/complicações , Transtornos Parkinsonianos/etiologia , Encefalite/diagnóstico por imagem , Fluordesoxiglucose F18/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Tomógrafos Computadorizados , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Recently introduced hybrid PET/MR scanners provide the opportunity to measure simultaneously, and in direct spatial correspondence, both metabolic demand and functional activity of the brain, hence capturing complementary information on the brain's physiological state. Here we exploited PET/MR simultaneous imaging to explore the relationship between the metabolic information provided by resting-state fluorodeoxyglucose-PET (FDG-PET) and fMRI (rs-fMRI) in neurologically healthy subjects. Regional homogeneity (ReHo), fractional amplitude of low frequency fluctuations (fALFF), and degree of centrality (DC) maps were generated from the rs-fMRI data in 23 subjects, and voxel-wise comparison to glucose uptake distribution provided by simultaneously acquired FDG-PET was performed. The mutual relationships among each couple of these four metrics were explored in terms of similarity, both of spatial distribution across the brain and the whole group, and voxel-wise across subjects, taking into account partial volume effects by adjusting for grey matter (GM) volume. Although a significant correlation between the spatial distribution of glucose uptake and rs-fMRI derived metrics was present, only a limited percentage of GM voxels correlated with PET across subjects. Moreover, the correlation between the spatial distributions of PET and rs-fMRI-derived metrics is spatially heterogeneous across both anatomic regions and functional networks, with lowest correlation strength in the limbic network (Spearman rho around -0.11 for DC), and strongest correlation for the default-mode network (up to 0.89 for ReHo and 0.86 for fALFF). Overall, ReHo and fALFF provided significantly higher correlation coefficients with PET (p=10(-8) and 10(-7), respectively) as compared to DC, while no significant differences were present between ReHo and fALFF. Local GM volume variations introduced a limited overestimation of the rs-fMRI to FDG correlation between the modalities under investigation through partial volume effects. These novel results provide the basis for future studies of alterations of the coupling between brain metabolism and functional connectivity in pathologic conditions.
Assuntos
Química Encefálica/fisiologia , Glucose/metabolismo , Descanso/fisiologia , Adulto , Feminino , Fluordesoxiglucose F18 , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Imagem Multimodal , Rede Nervosa/fisiologia , Tomografia por Emissão de Pósitrons , Compostos RadiofarmacêuticosRESUMO
SYNJ1 has been recently identified by two independent groups as the gene defective in a novel form of autosomal recessive, early-onset atypical parkinsonism (PARK20). Two consanguineous families were initially reported (one of Sicilian and one of Iranian origins), with the same SYNJ1 homozygous mutation (c.773G > A, p.Arg258Gln) segregating with a similar phenotype of early-onset parkinsonism and additional atypical features. Here, we report the identification of the same SYNJ1 homozygous mutation in two affected siblings of a third pedigree. Both siblings had mild developmental psychomotor delay, followed, during the third decade of life, by progressive parkinsonism, dystonia, and mild cognitive impairment. One sibling suffered one episode of generalized seizures. Neuroimaging studies revealed severe nigrostriatal dopaminergic defects, mild striatal and very mild cortical hypometabolism. Treatment with dopamine agonists and anticholinergics resulted in partial improvements. Genetic analyses revealed in both siblings the SYNJ1 homozygous c.773G > A (p.Arg258Gln) mutation. Haplotype analysis suggests that the mutation has arisen independently in this family and the Sicilian PARK20 family previously described by us, in keeping with the hypothesis of a mutational hot spot. This is the third reported family with autosomal recessive, early-onset parkinsonism associated with the SYNJ1 p.Arg258Gln mutation. This work contributes to the definition of the genetic and clinical aspects of PARK20. This newly recognized form must be considered in the diagnostic work-up of patients with early-onset atypical parkinsonism. The presence of seizures might represent a red flag to suspect PARK20.
Assuntos
Mutação , Transtornos Parkinsonianos/genética , Monoéster Fosfórico Hidrolases/genética , Encéfalo/metabolismo , Saúde da Família , Feminino , Genes Recessivos , Homozigoto , Humanos , Itália , Masculino , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/metabolismo , LinhagemRESUMO
Spinocerebellar ataxia type 2 (SCA2) is an autosomal-dominant degenerative disorder that is neuropathologically characterized primarily by infratentorial damage, although less severe supratentorial involvement may contribute to the clinical manifestation. Diffusion-weighted imaging (DWI)-Magnetic Resonance Imaging (MRI) studies of SCA2 have enabled in vivo quantification of neurodegeneration in infratentorial regions, whereas supratentorial regions have been explored less thoroughly. We measured microstructural changes in both infratentorial and supratentorial regions in 13 SCA2 patients (9 men, 4 women; mean age, 50 ± 12 years) and 15 controls (10 men, 5 women; mean age, 49 ± 14 years) using DWI-MRI and correlated the DWI changes with disease severity and duration. Disease severity was evaluated using the International Cooperative Ataxia Rating Scale and the Inherited Ataxia Clinical Rating Scale. Cerebral diffusion trace ( D¯) values were generated, and regions of interest (ROIs) and voxel-based analysis with Statistical Parametric Mapping (SPM) were used for data analysis. In SCA2 patients, ROI analysis and SPM confirmed significant increases in D¯ values in the pons, cerebellar white matter (CWM) and middle cerebellar peduncles. Moreover, SPM analysis revealed increased D¯ values in the right thalamus, bilateral temporal cortex/white matter, and motor cortex/pyramidal tract regions. Increased diffusivity in the frontal white matter (FWM) and the CWM was significantly correlated with ataxia severity. DWI-MRI revealed that both infratentorial and supratentorial microstructural changes may characterize SCA2 patients in the course of the disease and might contribute to the severity of the symptoms.
Assuntos
Cerebelo/patologia , Córtex Cerebral/patologia , Imagem de Difusão por Ressonância Magnética , Dura-Máter/patologia , Fibras Nervosas Mielinizadas/patologia , Ataxias Espinocerebelares/diagnóstico , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Autosomal-dominant spinocerebellar ataxia (ADCA) due to intronic GAA repeat expansion in FGF14 (SCA27B) is a recent, relatively common form of late-onset ataxia. OBJECTIVE: Here, we aimed to: (1) investigate the relative frequency of SCA27B in different clinically defined disease subgroups with late-onset ataxia collected among 16 tertiary Italian centers; (2) characterize phenotype and diagnostic findings of patients with SCA27B; (3) compare the Italian cohort with other cohorts reported in recent studies. METHODS: We screened 396 clinically diagnosed late-onset cerebellar ataxias of unknown cause, subdivided in sporadic cerebellar ataxia, ADCA, and multisystem atrophy cerebellar type. We identified 72 new genetically defined subjects with SCA27B. Then, we analyzed the clinical, neurophysiological, and imaging features of 64 symptomatic cases. RESULTS: In our cohort, the prevalence of SCA27B was 13.4% (53/396) with as high as 38.5% (22/57) in ADCA. The median age of onset of SCA27B patients was 62 years. All symptomatic individuals showed evidence of impaired balance and gait; cerebellar ocular motor signs were also frequent. Episodic manifestations at onset occurred in 31% of patients. Extrapyramidal features (17%) and cognitive impairment (25%) were also reported. Brain magnetic resonance imaging showed cerebellar atrophy in most cases (78%). Pseudo-longitudinal assessments indicated slow progression of ataxia and minimal functional impairment. CONCLUSION: Patients with SCA27B in Italy present as an adult-onset, slowly progressive cerebellar ataxia with predominant axial involvement and frequent cerebellar ocular motor signs. The high consistency of clinical features in SCA27B cohorts in multiple populations paves the way toward large-scale, multicenter studies.
Assuntos
Progressão da Doença , Humanos , Pessoa de Meia-Idade , Itália/epidemiologia , Masculino , Feminino , Idoso , Estudos de Coortes , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/epidemiologia , Adulto , Ataxia Cerebelar/genética , Ataxia Cerebelar/epidemiologia , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/fisiopatologia , Idade de Início , Fatores de Crescimento de Fibroblastos , Degenerações EspinocerebelaresRESUMO
Autosomal recessive, early-onset Parkinsonism is clinically and genetically heterogeneous. Here, we report the identification, by homozygosity mapping and exome sequencing, of a SYNJ1 homozygous mutation (p.Arg258Gln) segregating with disease in an Italian consanguineous family with Parkinsonism, dystonia, and cognitive deterioration. Response to levodopa was poor, and limited by side effects. Neuroimaging revealed brain atrophy, nigrostriatal dopaminergic defects, and cerebral hypometabolism. SYNJ1 encodes synaptojanin 1, a phosphoinositide phosphatase protein with essential roles in the postendocytic recycling of synaptic vesicles. The mutation is absent in variation databases and in ethnically matched controls, is damaging according to all prediction programs, and replaces an amino acid that is extremely conserved in the synaptojanin 1 homologues and in SAC1-like domains of other proteins. Sequencing the SYNJ1 ORF in unrelated patients revealed another heterozygous mutation (p.Ser1422Arg), predicted as damaging, in a patient who also carries a heterozygous PINK1 truncating mutation. The SYNJ1 gene is a compelling candidate for Parkinsonism; mutations in the functionally linked protein auxilin cause a similar early-onset phenotype, and other findings implicate endosomal dysfunctions in the pathogenesis. Our data delineate a novel form of human Mendelian Parkinsonism, and provide further evidence for abnormal synaptic vesicle recycling as a central theme in the pathogenesis.
Assuntos
Transtornos Parkinsonianos/genética , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Adolescente , Adulto , Idade de Início , Auxilinas/metabolismo , Criança , Transtornos Cognitivos , Consanguinidade , Distonia , Exoma , Feminino , Genes Recessivos , Variação Genética , Homozigoto , Humanos , Itália , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/tratamento farmacológico , Linhagem , Radiografia , Análise de Sequência de DNA , Adulto JovemRESUMO
PURPOSE: Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia, supranuclear ophthalmoplegia, and peripheral neuropathy. Autonomic nervous system dysfunction is often present. This study evaluated the cardiac sympathetic function in patients with SCA2 using (123)I-metaiodobenzylguanidine (MIBG) in comparison with patients with Parkinson's disease (PD) and control subjects. METHODS: Nine patients with SCA2, nine patients with PD, and nine control subjects underwent (123)I-MIBG imaging studies from which early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates were calculated. RESULTS: Early (F = 12.3, p < 0.0001) and late (F = 16.8, p < 0.0001) H/M ratios were significantly different among groups. In controls, early and late H/M ratios (2.2 ± 0.12 and 2.1 ± 0.20) were significantly higher than in patients with SCA2 (1.9 ± 0.23 and 1.8 ± 0.20, both p < 0.05) and with patients with PD (1.7 ± 0.29 and 1.4 ± 0.35, both p < 0.001). There was also a significant difference in washout rates among groups (F = 11.7, p < 0.0001). In controls the washout rate (19.9 ± 9.6%) was significantly lower (p < 0.005) than in patients with PD (51.0 ± 23.7%), but not different from that in SCA2 patients (19.5 ± 9.4%). In SCA2 patients, in a multivariable linear regression analysis only the Scale for the Assessment and Rating of Ataxia score was independently associated with early H/M ratio (ß = -0.12, p < 0.05). CONCLUSION: (123)I-MIBG myocardial scintigraphy demonstrated an impairment of cardiac sympathetic function in patients with SCA2, which was less marked than in PD patients. These results suggest that (123)I-MIBG cardiac imaging could become a useful tool for analysing the pathophysiology of SCA2.