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One of the major challenges for clinicians who treat patients with Disorders of Consciousness (DoCs) concerns the detection of signs of consciousness that distinguish patients in Vegetative State from those in Minimally Conscious State. Recent studies showed how visual responses to tailored stimuli are one of the first evidence revealing that one patient is changing from one state to another. This study aimed to explore the integrity of the neural structures being part of the visual system in patients with DoCs manifesting a reflexive behavior (visual blink) and in those manifesting a cognitively and cortically mediated behavior (visual pursuit). We collected instrumental data using specialized equipment (EEG following the rules of the International 10-20 system, 3T Magnetic Resonance, and Positron Emission Tomography) in 54 DoC patients. Our results indicated that visual pursuit group showed a better fVEPs response than the visual blink group, because of a greater area under the N2/P2 component of fVEPs (AUC could be seen as an indicator of the residual activity of visual areas). Considering neuroimaging data, the main structural differences between groups were found in the retrochiasmatic areas, specifically in the right optic radiation and visual cortex (V1), areas statistically less impaired in patients able to perform a visual pursuit. FDG-PET analysis confirmed difference between groups at the level of the right calcarine cortex and neighboring right lingual gyrus. In conclusion, although there are methodological and theoretical limitations that should be considered, our study suggests a new perspective to consider for a future diagnostic protocol.
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Estado de Conciencia , Estado Vegetativo Persistente , Humanos , Imagen por Resonancia Magnética , Neuroimagen , Tomografía de Emisión de Positrones , Percepción VisualRESUMEN
PURPOSE: To describe cerebral glucose metabolism pattern as assessed by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in Lafora disease (LD), a rare, lethal form of progressive myoclonus epilepsy caused by biallelic mutations in EPM2A or NHLRC1. METHODS: We retrospectively included patients with genetically confirmed LD who underwent FDG-PET scan referred to three Italian epilepsy centers. FDG-PET images were evaluated both visually and using SPM12 software. Subgroup analysis was performed on the basis of genetic and clinical features employing SPM. Moreover, we performed a systematic literature review of LD cases that underwent FDG-PET assessment. RESULTS: Eight Italian patients (3M/5F, 3 EPM2A/5 NHLRC1) underwent FDG-PET examination after a mean of 6 years from disease onset (range 1-12 years). All patients showed bilateral hypometabolic areas, more diffuse and pronounced in advanced disease stages. Most frequently, the hypometabolic regions were the temporal (8/8), parietal (7/8), and frontal lobes (7/8), as well as the thalamus (6/8). In three cases, the FDG-PET repeated after a mean of 17 months (range 7-36 months) showed a metabolic worsening compared with the baseline examination. The SPM subgroup analysis found no significant differences based on genetics, whereas it showed a more significant temporoparietal hypometabolism in patients with visual symptoms compared with those without. In nine additional cases identified from eight publications, FDG-PET showed heterogeneous findings, ranging from diffusely decreased cerebral glucose metabolism to unremarkable examinations in two cases. CONCLUSIONS: FDG-PET seems highly sensitive to evaluate LD at any stage and may correlate with disease progression. Areas of decreased glucose metabolism in LD are extensive, often involving multiple cortical and subcortical regions, with thalamus, temporal, frontal, and parietal lobes being the most severely affected. Prospective longitudinal collaborative studies are needed to validate our findings.
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Fluorodesoxiglucosa F18 , Enfermedad de Lafora , Encéfalo/diagnóstico por imagen , Humanos , Enfermedad de Lafora/diagnóstico por imagen , Enfermedad de Lafora/genética , Tomografía de Emisión de Positrones , Estudios Prospectivos , Estudios Retrospectivos , Ubiquitina-Proteína LigasasRESUMEN
Reduced bone mass with or without fragility fractures is a common feature of mastocytosis, particularly in adult males. However, bone mineral density does not account for all the fragility fractures, being a part of them attributable to impairment in bone quality. Aim of this study is to assess the usefulness of DXA-derived geometry and structural indexes in the assessment of bone status in mastocytosis. Ninety-six consecutive patients (46 women and 50 men) affected by cutaneous (CM) or systemic (SM) mastocytosis were studied. Mean age (± SD) was 53.3 ± 14.23. Spine lateral X-rays for Genant's scale, DXA for lumbar (L) and femoral (F) bone mineral density (BMD), bone strain index (BSI), lumbar trabecular bone score (TBS), and hip structural analysis (HSA) were performed. Among the laboratory variables, data of serum tryptase were reported. Tryptase was higher in SM (p = 0.035), inversely correlated with LBMD (r = - 0.232; p = 0.022) and TBS (r = - 0.280; p = 0.005), and directly with L-BSI (r = 0.276; p = 0.006). L-BSI remained statistically significant (p = 0.006; adjusted R2 = 0.101) together with mastocytosis (SM or CM: p = 0.034) in the multivariate regression model with tryptase as dependent variable, being LBMD and TBS not statistically significant (p = 0.887, and p = 0.245, respectively). Tryptase increased about 22 units for each unit increase of L-BSI and about 18 units for SM against CM. L-BSI was lower (p = 0.012), while FN-BSI and FT-BSI were higher in women (p < 0.001) than in men. HSA indexes were significantly higher in men, particularly with SM. SM is a risk factor for reduced bone mass, texture and strength. Since mean L-BSI and Z-modulus of all the femoral sites are statistically higher in men than in female, it could be argued that men have a better femoral bone resistance to bending forces than women, but a worse lumbar bone resistance to compressive loads. DXA indexes of bone quality are useful in mastocytosis' bone assessment and its clinical management.
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Densidad Ósea , Hueso Esponjoso/patología , Mastocitosis/complicaciones , Absorciometría de Fotón , Adulto , Femenino , Fémur , Humanos , Vértebras Lumbares , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: The disease course of multiple sclerosis (MS) is unpredictable, and reliable prognostic biomarkers are needed. Positron emission tomography (PET) with ß-amyloid tracers is a promising tool for evaluating white matter (WM) damage and repair. Our aim was to investigate amyloid uptake in damaged (DWM) and normal-appearing WM (NAWM) of MS patients, and to evaluate possible correlations between cerebrospinal fluid (CSF) ß-amyloid1-42 (Aß) levels, amyloid tracer uptake, and brain volumes. METHODS: Twelve MS patients were recruited and divided according to their disease activity into active and non-active groups. All participants underwent neurological examination, neuropsychological testing, lumbar puncture, brain magnetic resonance (MRI) imaging, and 18F-florbetapir PET. Aß levels were determined in CSF samples from all patients. MRI and PET images were co-registered, and mean standardized uptake values (SUV) were calculated for each patient in the NAWM and in the DWM. To calculate brain volumes, brain segmentation was performed using statistical parametric mapping software. Nonparametric statistical analyses for between-group comparisons and regression analyses were conducted. RESULTS: We found a lower SUV in DWM compared to NAWM (p < 0.001) in all patients. Decreased NAWM-SUV was observed in the active compared to non-active group (p < 0.05). Considering only active patients, NAWM volume correlated with NAWM-SUV (p = 0.01). Interestingly, CSF Aß concentration was a predictor of both NAWM-SUV (r = 0.79; p = 0.01) and NAWM volume (r = 0.81, p = 0.01). CONCLUSIONS: The correlation between CSF Aß levels and NAWM-SUV suggests that the predictive role of ß-amyloid may be linked to early myelin damage and may reflect disease activity and clinical progression.
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Péptidos beta-Amiloides/líquido cefalorraquídeo , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Tomografía de Emisión de Positrones , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/metabolismo , Tomografía de Emisión de Positrones/normas , Valores de Referencia , Sustancia Blanca/metabolismo , Adulto JovenRESUMEN
OBJECTIVES: Psychotic symptoms are a common feature in bipolar disorder (BD), especially during manic phases, and are associated with a more severe course of illness. However, not all bipolar subjects experience psychosis during the course of their illness, and this difference often guides assessment and pharmacological treatment. The aim of the present study is to elucidate, for the first time, the FDG uptake dysfunctions associated with psychosis in BD patients with and without a history of past psychotic symptoms, through a positron emission tomography (PET) approach. METHODS: Fifty BD patients with lifetime psychotic symptoms, 40 BD patients without lifetime psychotic symptoms and 27 healthy controls (HC) were recruited and underwent an 18F-FDG-PET session. RESULTS: Compared to HC, BD subjects shared common FDG uptake deficits in several brain areas, including insula, inferior temporal gyrus and middle occipital gyrus. Moreover, we found that BD patients with a history of past psychotic symptoms had a unique FDG uptake alteration in the right fusiform gyrus compared to both BD patients without lifetime psychotic symptoms and HC (all P < 0.01, cFWE corrected). CONCLUSIONS: Overall, our results suggest that FDG uptake alterations in brain regions involved in emotion regulation are a key feature of BD, regardless the presence of past psychosis. Finally, we demonstrated that the FDG uptake reduction in fusiform gyrus is associated with the presence of past psychotic symptoms in BD, ultimately leading towards the idea that the fusiform gyrus might be considered a putative biomarker of psychosis.
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Trastorno Bipolar/diagnóstico por imagen , Trastorno Bipolar/metabolismo , Trastornos Psicóticos/metabolismo , Adulto , Trastorno Bipolar/psicología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Emociones , Femenino , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones/métodos , Trastornos Psicóticos/diagnóstico por imagen , Trastornos Psicóticos/psicología , RadiofármacosRESUMEN
BACKGROUND: Elderly bipolar disorder (BD) and behavioural variant of frontotemporal dementia (bvFTD) may exhibit similar symptoms and both disorders are characterized by selective abnormalities in cortical and subcortical regions that are associated with cognitive and emotional impairments. We aimed to investigate common and distinct neural substrates of BD and bvFTD by coupling, for the first time, magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques. METHODS: 3-Tesla MRI and 18 fluorodeoxyglucose-PET scans were acquired for 16 elderly BD patients, 23 bvFTD patients with mild cognitive impairments and 68 healthy controls (48 for PET and 20 for MRI analyses). RESULTS: BD and bvFTD patients exhibit a different localization of grey matter reductions in the lateral prefrontal cortex, with the first group showing grey matter decrease in the ventrolateral prefrontal cortex and the latter group showing grey matter reductions in the dorsolateral prefrontal cortex as well as unique grey matter and metabolic alterations within the orbitofrontal cortex. The bvFTD group also displayed unique volumetric shrinkage in regions within the temporo-parietal network together with greater metabolic impairments within the temporal cortex and more extensive volumetric and metabolic abnormalities within the limbic lobe. Finally, while the BD group showed greater grey matter volumes in caudate nucleus, bvFTD subjects displayed lower metabolism. CONCLUSION: This MRI-PET study explored, for the first time to the best of our knowledge, structural and functional abnormalities in bvFTD and elderly BD patients, with the final aim of identifying the specific biological signature of these disorders, which might have important implications not only in prevention but also in differential diagnosis and treatment.
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Envejecimiento , Trastorno Bipolar , Corteza Cerebral , Demencia Frontotemporal , Sustancia Gris , Imagen por Resonancia Magnética , Red Nerviosa , Tomografía de Emisión de Positrones , Anciano , Envejecimiento/metabolismo , Envejecimiento/patología , Trastorno Bipolar/diagnóstico por imagen , Trastorno Bipolar/metabolismo , Trastorno Bipolar/patología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Femenino , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/patología , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/metabolismo , Sustancia Gris/patología , Humanos , Masculino , Imagen Multimodal , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/metabolismo , Red Nerviosa/patologíaRESUMEN
Levodopa-induced dyskinesias are a common and disabling side effect of dopaminergic therapy in Parkinson's disease, but their neural mechanisms in vivo are still poorly understood. Besides striatal pathology, the importance of cortical dysfunction has been increasingly recognized. The supplementary motor area in particular, may have a relevant role in dyskinesias onset given its involvement in endogenously generated actions. The aim of the present study was to investigate the levodopa-related cortical excitability changes along with the emergence of levodopa-induced peak-of-dose dyskinesias in subjects with Parkinson's disease. Thirteen patients without dyskinesias and ten with dyskinesias received 200/50 mg fast-acting oral levodopa/benserazide following overnight withdrawal (12 hr) from their dopaminergic medication. We targeted transcranial magnetic stimulation to the supplementary motor area, ipsilateral to the most dopamine-depleted striatum defined with single-photon emission computed tomography with [123 I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane, and recorded transcranial magnetic stimulation-evoked potentials with high-density electroencephalography before and at 30, 60, and 180 min after levodopa/benserazide intake. Clinical improvement from levodopa/benserazide paralleled the increase in cortical excitability in both groups. Subjects with dyskinesias showed higher fluctuation of cortical excitability in comparison to non-dyskinetic patients, possibly reflecting dyskinetic movements. Together with endogenous brain oscillation, levodopa-related dynamics of brain state could influence the therapeutic response of neuromodulatory interventions.
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Antiparkinsonianos/uso terapéutico , Benserazida/farmacología , Levodopa/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Combinación de Medicamentos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Electroencefalografía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Corteza Motora/fisiopatología , Enfermedad de Parkinson/fisiopatología , Estimulación Magnética Transcraneal/métodosRESUMEN
OBJECTIVE: Understanding residual brain function in disorders of consciousness poses extraordinary challenges, and imaging examinations are needed to complement clinical assessment. The default-mode network (DMN) is known to be dysfunctional, although correlation with level of consciousness remains controversial. We investigated DMN activity with resting-state functional magnetic resonance imaging (rs-fMRI), alongside its structural and metabolic integrity, aiming to elucidate the corresponding associations with clinical assessment. METHODS: We enrolled 119 consecutive patients: 72 in a vegetative state/unresponsive wakefulness state (VS/UWS), 36 in a minimally conscious state (MCS), and 11 with severe disability. All underwent structural MRI and rs-fMRI, and a subset also underwent 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). Data were analyzed with manual and automatic approaches, in relation to diagnosis and clinical score. RESULTS: Excluding the quartile with largest head movement, DMN activity was decreased in VS/UWS compared to MCS, and correlated with clinical score. Independent-component and seed-based analyses provided similar results, although the latter and their combination were most informative. Structural MRI and FDG-PET were less sensitive to head movement and had better diagnostic accuracy than rs-fMRI only when all cases were included. rs-fMRI indicated relatively preserved DMN activity in a small subset of VS/UWS patients, 2 of whom evolved to MCS. The integrity of the left hemisphere appears to be predictive of a better clinical status. INTERPRETATION: rs-fMRI of the DMN is sensitive to clinical severity. The effect is consistent across data analysis approaches, but heavily dependent on head movement. rs-fMRI could be informative in detecting residual DMN activity for those patients who remain relatively still during scanning and whose diagnosis is uncertain. Ann Neurol 2016;79:841-853.
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OBJECTIVE: The objective of this work was to investigate survival, dementia, and genotype-phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene (GBA). METHODS: We included 2,764 unrelated consecutive PD patients: 123 GBA carriers (67 mild-p.N370S and 56 severe mainly p.L444P) and 2,641 noncarriers. Brain perfusion and dopamine transporter imaging was analyzed, including dementia with Lewy Bodies (DLB) as an additional control group. RESULTS: Multivariable analysis adjusted by sex, age at onset, and disease duration attributed to GBA carriers a greater risk for dementia (hazard ratio [HR] = 3.16; p < 0.001) and death (HR = 1.85; p = 0.002) than noncarriers. When dementia was introduced in the model as a time-dependent covariate, the mortality risk remained greater in carriers (HR = 1.65; p = 0.016), suggesting that other clinical features are likely to contribute to reduced survival. At last examination, GBA carriers had worse motor symptoms, particularly nondopaminergic features. Carriers of severe mutations had greater risk for dementia compared to mild mutations (p < 0.001), but similar mortality risk. Consistent with clinical data, GBA carriers showed reduced posterior parietal and occipital cortical synaptic activity and nigrostriatal function than PD noncarriers. Neuroimaging features of carriers of mild mutations overlapped with PD noncarriers, whereas carriers of severe mutations were closer to DLB. INTERPRETATION: Survival is reduced in GBA carriers compared to noncarriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by type of mutation. In the clinical continuum between PD and DLB, patients with GBA mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. Ann Neurol 2016;80:662-673.
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Demencia , Glucosilceramidasa/genética , Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Tomografía Computarizada de Emisión de Fotón Único/métodos , Edad de Inicio , Anciano , Anciano de 80 o más Años , Estudios Transversales , Demencia/diagnóstico por imagen , Demencia/genética , Demencia/fisiopatología , Femenino , Heterocigoto , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Enfermedad por Cuerpos de Lewy/genética , Enfermedad por Cuerpos de Lewy/fisiopatología , Masculino , Persona de Mediana Edad , Mutación , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/fisiopatologíaRESUMEN
Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple 18 F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar syndrome caused by a maladaptive response to neurostimulation of the (sub)thalamic area. The metabolic signature of progressive gait ataxia is an activation of the cerebellar nodule, which may be caused by inadvertent current spread and antidromic stimulation of a cerebellar outflow pathway originating in the vermis. An anatomical candidate could be the ascending limb of the uncinate tract in the subthalamic area. Adjustments in programming and precise placement of the electrode may prevent this adverse effect and help fine-tuning deep brain stimulation to ameliorate tremor without negative cerebellar signs.
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Estimulación Encefálica Profunda/efectos adversos , Ataxia de la Marcha/etiología , Tálamo/fisiología , Anciano , Anciano de 80 o más Años , Biofisica , Temblor Esencial/diagnóstico por imagen , Temblor Esencial/terapia , Femenino , Fluorodesoxiglucosa F18/metabolismo , Ataxia de la Marcha/diagnóstico por imagen , Humanos , Imagenología Tridimensional , Imagen por Resonancia Magnética , Masculino , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: The trophic, anti-apoptotic and regenerative effects of bone marrow mesenchymal stromal cells (MSC) may reduce neuronal cell loss in neurodegenerative disorders. METHODS: We used MSC as a novel candidate therapeutic tool in a pilot phase-I study for patients affected by progressive supranuclear palsy (PSP), a rare, severe and no-option form of Parkinsonism. Five patients received the cells by infusion into the cerebral arteries. Effects were assessed using the best available motor function rating scales (UPDRS, Hoehn and Yahr, PSP rating scale), as well as neuropsychological assessments, gait analysis and brain imaging before and after cell administration. RESULTS: One year after cell infusion, all treated patients were alive, except one, who died 9 months after the infusion for reasons not related to cell administration or to disease progression (accidental fall). In all treated patients motor function rating scales remained stable for at least six-months during the one-year follow-up. CONCLUSIONS: We have demonstrated for the first time that MSC administration is feasible in subjects with PSP. In these patients, in whom deterioration of motor function is invariably rapid, we recorded clinical stabilization for at least 6 months. These encouraging results pave the way to the next randomized, placebo-controlled phase-II study that will definitively provide information on the efficacy of this innovative approach. Trial registration ClinicalTrials.gov NCT01824121.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Trastornos Parkinsonianos/terapia , Parálisis Supranuclear Progresiva/terapia , Anciano , Fenómenos Biomecánicos , Médula Ósea/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/diagnóstico por imagen , Tomografía de Emisión de Positrones , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Parálisis Supranuclear Progresiva/fisiopatología , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.
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GTP Ciclohidrolasa/genética , Heterocigoto , Mutación/genética , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Bases de Datos Genéticas , Europa (Continente)/epidemiología , Femenino , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Linaje , Riesgo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
INTRODUCTION: The relation between schizophrenia and cannabis abuse has been widely discussed from etiopathogenetic, psychopathological and neurometabolic points of view. Relatively little has been written about the differences between schizophrenia with co-occurrent cannabis abuse and substance-induced psychotic disorder (SIPD). Given these premises, our study aims to investigate the psychopathological and neurometabolic features of these clinical entities. METHODS: We enrolled patients experiencing an acute psychotic episode, affected either by schizophrenia with or without cannabis abuse (SCZ +/- CA; n = 5 and n = 5, respectively) with recent onset (<5 years of illness) or by SIPD (n = 6), as diagnosed by the Structured Clinical Interview for DSM-IV Axis I. Patients affected by SIPD were all cannabis abusers. All patients were assessed with the PANSS (Positive and Negative Scale for Schizophrenia), urinary toxicological tests and brain 18-FDG-PET scanning in resting condition. Statistical analysis (ANOVA) was performed with Statistical Parametric Mapping SPM8 and Scenium software. RESULTS: Bilateral hypermetabolism in the posterior cingulum and the precuneus (p < 0.001) was observed in SIPD patients compared to patients with schizophrenia, with or without cannabis abuse. CONCLUSIONS: Our preliminary PET findings suggest that substance abuse may cause increased brain metabolism in patients with induced psychosis but not in those with schizophrenia. These differences in brain metabolism were found in the posterior cingulum and precuneus, which are two core regions of the default mode network in humans.
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Encéfalo/metabolismo , Abuso de Marihuana/metabolismo , Psicosis Inducidas por Sustancias/metabolismo , Esquizofrenia/metabolismo , Adolescente , Adulto , Femenino , Giro del Cíngulo/metabolismo , Humanos , Masculino , Lóbulo Parietal/metabolismo , Tomografía de Emisión de Positrones , Adulto JovenRESUMEN
BACKGROUND: Leukodystrophy with vanishing white matter (LVWM) is an autosomal recessive disease with typical pediatric-onset caused by mutations in one of the five EIF2B genes. Adult-onset (AO) cases are rare. METHODS: In this observational study, we reviewed clinical and laboratory information of the patients with AO-LVWM assessed at two referral centers in Italy and Portugal from Jan-2007 to Dec-2019. RESULTS: We identified 18 patients (13 females) with AO-LVWM caused by EIF2B5 or EIF2B3 mutations. Age of neurological onset ranged from 16 to 60 years, with follow-ups occurring from 2 to 37 years. Crucial symptoms were cognitive and motor decline. In three patients, stroke-like events were the first manifestation; in another, bladder dysfunction remained the main complaint across decades. Brain MRI showed white matter (WM) rarefaction in all cases, except two. Diffusion-weighted imaging documented focal hyperintensity in the acute stage of stroke-like events. 1H-spectroscopy primarily showed N-acetyl-aspartate reduction; 18fluorodeoxyglucose-PET revealed predominant frontoparietal hypometabolism; evoked potential studies demonstrated normal-to-reduced amplitudes; neuro-ophthalmological assessment showed neuroretinal thinning, and b-wave reduction on full-field electroretinogram. Interestingly, we found an additional patient with LVWM-compatible phenotype and monoallelic variants in two distinct eIF2B genes, EIF2B1 and EIF2B2. CONCLUSIONS: AO-LVWM presents varying clinical manifestations at onset, including stroke-like events. WM rarefaction is the most consistent diagnostic clue even in the latest onset cases. Spectroscopy and electrophysiological features are compatible with axon, rather than myelin, damage. Cerebral glucose metabolic abnormalities and retinal alterations can be present. LVWM might also be caused by a digenic inheritance affecting the eIF2B complex.
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Enfermedades Desmielinizantes , Leucoencefalopatías , Enfermedades por Almacenamiento Lisosomal , Enfermedades Neurodegenerativas , Accidente Cerebrovascular , Sustancia Blanca , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Factor 2B Eucariótico de Iniciación/genética , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/genética , Imagen por Resonancia Magnética , Mutación/genética , Estudios Observacionales como Asunto , Sustancia Blanca/diagnóstico por imagenRESUMEN
We investigated whether dopamine influences the rate of adaptation to a visuomotor distortion and the transfer of this learning from the right to the left limb in human subjects. We thus studied patients with Parkinson disease as a putative in vivo model of dopaminergic denervation. Despite normal adaptation rates, patients showed a reduced transfer compared with age-matched healthy controls. The magnitude of the transfer, but not of the adaptation rate, was positively predicted by the values of dopamine-transporter binding of the right caudate and putamen. We conclude that striatal dopaminergic activity plays an important role in the transfer of visuomotor skills.
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Adaptación Fisiológica/fisiología , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Extremidades/fisiopatología , Destreza Motora/fisiología , Transferencia de Experiencia en Psicología/fisiología , Adulto , Anciano , Mapeo Encefálico , Cuerpo Estriado/diagnóstico por imagen , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Estimulación Luminosa/métodos , Factores de Tiempo , Tomografía Computarizada de Emisión de Fotón Único/métodos , Tropanos/metabolismoRESUMEN
BACKGROUND: Association between cerebrospinal fluid (CSF)-amyloid-ß (Aß)42 and amyloid-PET measures is inconstant across the Alzheimer's disease (AD) spectrum. However, they are considered interchangeable, along with Aß42/40 ratio, for defining 'Alzheimer's Disease pathologic change' (A+). OBJECTIVE: Herein, we further characterized the association between amyloid-PET and CSF biomarkers and tested their agreement in a cohort of AD spectrum patients. METHODS: We included 23 patients who underwent amyloid-PET, MRI, and CSF analysis showing reduced levels of Aß42 within a 365-days interval. Thresholds used for dichotomization were: Aß42â<â640âpg/mL (Aß42+); pTauâ>â61âpg/mL (pTau+); and Aß42/40â<â0.069 (ADratio+). Amyloid-PET scans were visually assessed and processed by four pipelines (SPMCL, SPMAAL, FSGM, FSWC). RESULTS: Different pipelines gave highly inter-correlated standardized uptake value ratios (SUVRs) (rhoâ=â0.93-0.99). The most significant findings were: pTau positive correlation with SPMCL SUVR (rhoâ=â0.56, pâ=â0.0063) and Aß42/40 negative correlation with SPMCL and SPMAAL SUVRs (rhoâ=â-0.56, pâ=â0.0058; rhoâ=â-0.52, pâ=â0.0117 respectively). No correlations between CSF-Aß42 and global SUVRs were observed. In subregion analysis, both pTau and Aß42/40 values significantly correlated with cingulate SUVRs from any pipeline (R2â=â0.55-0.59, pâ<â0.0083), with the strongest associations observed for the posterior/isthmus cingulate areas. However, only associations observed for Aß42/40 ratio were still significant in linear regression models. Moreover, combining pTau with Aß42 or using Aß42/40, instead of Aß42 alone, increased concordance with amyloid-PET status from 74% to 91% based on visual reads and from 78% to 96% based on Centiloids. CONCLUSION: We confirmed that, in the AD spectrum, amyloid-PET measures show a stronger association and a better agreement with CSF-Aß42/40 and secondarily pTau rather than Aß42 levels.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides , Amiloide , Biomarcadores/líquido cefalorraquídeo , Fragmentos de Péptidos , Anciano , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Tomografía de Emisión de Positrones , Estudios Retrospectivos , Proteínas tau/líquido cefalorraquídeoRESUMEN
Resting-state fMRI (rs-fMRI) is a widely used technique to investigate the residual brain functions of patients with Disorders of Consciousness (DoC). Nonetheless, it is unclear how the networks that are more associated with primary functions, such as the sensory-motor, medial/lateral visual and auditory networks, contribute to clinical assessment. In this study, we examined the rs-fMRI lower-order networks alongside their structural MRI data to clarify the corresponding association with clinical assessment. We studied 109 chronic patients with DoC and emerged from DoC with structural MRI and rs-fMRI: 65 in vegetative state/unresponsive wakefulness state (VS/UWS), 34 in minimally conscious state (MCS) and 10 with severe disability. rs-fMRI data were analyzed with independent component analyses and seed-based analyses, in relation to structural MRI and clinical data. The results showed that VS/UWS had fewer networks than MCS patients and the rs-fMRI activity in each network was decreased. Visual networks were correlated to the clinical status, and in cases where no clinical response occurred, rs-fMRI indicated distinctive networks conveying information in a similar way to other techniques. The information provided by single networks was limited, whereas the four networks together yielded better classification results, particularly when the model included rs-fMRI and structural MRI data (AUC = 0.80). Both quantitative and qualitative rs-fMRI analyses yielded converging results; vascular etiology might confound the results, and disease duration generally reduced the number of networks observed. The lower-order rs-fMRI networks could be used clinically to support and corroborate visual function assessments in DoC.
RESUMEN
PURPOSE: Positron emission tomography (PET) with amyloid tracers (amy-PET) allows the quantification of pathological amyloid deposition in the brain tissues, including the white matter (WM). Here, we evaluate amy-PET uptake in WM lesions (WML) and in the normal-appearing WM (NAWM) of patients with Alzheimer's disease (AD) and non-AD type of dementia. METHODS: Thirty-three cognitively impaired subjects underwent brain magnetic resonance imaging (MRI), Aß1-42 (Aß) determination in the cerebrospinal fluid (CSF) and amy-PET. Twenty-three patients exhibiting concordant results in both CSF analysis and amy-PET for cortical amyloid deposition were recruited and divided into two groups, amyloid positive (A+) and negative (A-). WML quantification and brain volumes' segmentation were performed. Standardized uptake values ratios (SUVR) were calculated in the grey matter (GM), NAWM and WML on amy-PET coregistered to MRI images. RESULTS: A+ compared to A- showed a higher WML load (p = 0.049) alongside higher SUVR in all brain tissues (p < 0.01). No correlations between CSF Aß levels and WML and NAWM SUVR were found in A+, while, in A-, CSF Aß levels were directly correlated to NAWM SUVR (p = 0.04). CSF Aß concentration was the only predictor of NAWM SUVR (adj R2 = 0.91; p = 0.04) in A-. In A+ but not in A- direct correlations were identified between WM and GM SUVR (p < 0.01). CONCLUSIONS: Our data provide evidence on the role of amy-PET in the assessment of microstructural WM injury in non-AD dementia, whereas amy-PET seems less suitable to assess WM damage in AD patients due to a plausible amyloid accrual therein.
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Enfermedad de Alzheimer , Sustancia Blanca , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Amiloide/metabolismo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Humanos , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones/métodos , Sustancia Blanca/diagnóstico por imagenRESUMEN
BACKGROUND: Pathological gambling may occur in Parkinson's disease (PD) as a complication of dopaminergic therapy. Neuroimaging studies have suggested an abnormal dopamine transmission within the reward system, but the changes in the neural network characterizing PD patients with pathological gambling have never been investigated. METHODS: Thirty PD patients (15 with active gambling and 15 matched controls, on-medication) and 15 healthy subjects underwent brain perfusion single photon emission tomography at rest. The severity of gambling was assessed using the South Oaks Gambling Scale. Covariance analysis was applied to identify brain regions whose activity was associated with gambling severity. These regions were used as volume-of-interest to identify functionally interconnected areas using voxel-wise covariance analysis. A path model was defined by means of effective connectivity analysis within the Structural Equation Modeling framework. RESULTS: Gambling severity in PD was associated with a dysfunction of the brain network implicated in decision making, risk processing, and response inhibition, including the ventrolateral prefrontal cortex, anterior (ACC) and posterior cingulate cortex, medial prefrontal cortex, insula and striatum. PD gamblers showed a disconnection between the ACC and the striatum, while this interaction was very robust in both control groups. DISCUSSION: ACC-striatal disconnection may underlie a specific impairment of shifting behaviors after negative outcomes, possibly explaining why PD gamblers use to perseverate into risktaking behaviors despite self-destructive consequences.
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Cuerpo Estriado/fisiopatología , Juego de Azar/fisiopatología , Enfermedad de Parkinson/fisiopatología , Corteza Prefrontal/fisiopatología , Anciano , Análisis de Varianza , Mapeo Encefálico , Cuerpo Estriado/diagnóstico por imagen , Femenino , Juego de Azar/complicaciones , Juego de Azar/diagnóstico por imagen , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiopatología , Pruebas Neuropsicológicas , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagen , Corteza Prefrontal/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
BACKGROUND: Studies in animals suggest that the noradrenergic system arising from the locus coeruleus (LC) and dopaminergic pathways mutually influence each other. Little is known however, about the functional state of the LC in patients with Parkinson disease (PD). METHODS: We retrospectively reviewed clinical and imaging data of 94 subjects with PD at an early clinical stage (Hoehn and Yahr stage 1-2) who underwent single photon computed tomography imaging with FP-CIT ([¹²³I] N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl) tropane). FP-CIT binding values from the patients were compared with 15 healthy subjects: using both a voxel-based whole brain analysis and a volume of interest analysis of a priori defined brain regions. RESULTS: Average FP-CIT binding in the putamen and caudate nucleus was significantly reduced in PD subjects (43% and 57% on average, respectively; p < 0.001). In contrast, subjects with PD showed an increased binding in the LC (166% on average; p < 0.001) in both analyses. LC-binding correlated negatively with striatal FP-CIT binding values (caudate: contralateral, ρ = -0.28, p < 0.01 and ipsilateral ρ = -0.26, p < 0.01; putamen: contralateral, ρ = -0.29, p < 0.01 and ipsilateral ρ = -0.29, p < 0.01). CONCLUSIONS: These findings are consistent with an up-regulation of noradrenaline reuptake in the LC area of patients with early stage PD, compatible with enhanced noradrenaline release, and a compensating activity for degeneration of dopaminergic nigrostriatal projections.