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Huntington's disease (HD) is a rare hereditary neurodegenerative disorder characterized in over 90 percent of cases by chorea as the presenting motor symptom. We report a 54-year-old male who presented with Parkinsonism as the initial symptom of the disease. Genetic analysis revealed expansion of 40 CAG repeats, and brain MRI showed both severe caudate nuclei and cortical atrophy. Single-photon emission computed tomography (SPECT) imaging of the dopamine transporter showed nigrostriatal pathway degeneration. Here, we also describe his 2 years of clinical followup after ensuing dopaminergic stimulation.

The deficiency of dystrophin, a sarcolemmal associated protein, is responsible for Duchenne muscular dystrophy (DMD). Gene replacement is attractive as a potential therapy. In this article, we describe a new method for myoblast transplantation and expression of dystrophin in skeletal muscle tissue of dystrophin-deficient mdx mouse through iliac vessels extracorporeal circulation. We evaluated the extracorporeal circulation as an alternative route of delivering myoblasts to the target tissue. Two series of experiments were performed with the extracorporeal circulation. In a first series, L6 rat myoblasts, transfected with LacZ reporter gene, were perfused in limbs of 15 rats. In the second series, the muscle limbs of three 6–8-week-old mdx were perfused with myoblasts of donor C57BL10J mice. Before these perfusions, the right tibialis anterior (TA) muscle of the rats and mdx was injected three times at several sites with bupivacaine (BPVC) and hyaluronidase. The ability of injected cells to migrate in the host tissue was assessed in rats by technetium-99m cell labeling. No radioactivity was detected in the lungs, bowels, and liver of animals treated with extracorporeal circulation. The tissue integration and viability of the myoblasts were ultimately confirmed by genetic and histochemical analysis of LacZ reporter gene. Following a single extracorporeal perfusion of myoblasts from donor C57BL10J, sarcolemmal expression of dystrophin was observed in clusters of myofibers in tibialis anterior muscles previously treated with BPVC and hyaluronidase. Furthermore, large clusters of dystrophin-positive fibers were observed in muscles up to 21 days after repeated treatments. These clusters represented an average of 4.2% of the total muscle fibers. These results demonstrate that the extracorporeal circulation allows selective myoblast-mediated gene transfer to muscles, opening new perspectives in muscular dystrophy gene therapy.

Numerical modelling is a reliable tool for flood simulations, but accurate solutions are computationally expensive. In recent years, researchers have explored data-driven methodologies based on neural networks to overcome this limitation. However, most models are only used for a specific case study and disregard the dynamic evolution of the flood wave. This limits their generalizability to topographies that the model was not trained on and in time-dependent applications. In this paper, we introduce shallow water equation–graph neural network (SWE–GNN), a hydraulics-inspired surrogate model based on GNNs that can be used for rapid spatio-temporal flood modelling. The model exploits the analogy between finite-volume methods used to solve SWEs and GNNs. For a computational mesh, we create a graph by considering finite-volume cells as nodes and adjacent cells as being connected by edges. The inputs are determined by the topographical properties of the domain and the initial hydraulic conditions. The GNN then determines how fluxes are exchanged between cells via a learned local function. We overcome the time-step constraints by stacking multiple GNN layers, which expand the considered space instead of increasing the time resolution. We also propose a multi-step-ahead loss function along with a curriculum learning strategy to improve the stability and performance. We validate this approach using a dataset of two-dimensional dike breach flood simulations in randomly generated digital elevation models generated with a high-fidelity numerical solver. The SWE–GNN model predicts the spatio-temporal evolution of the flood for unseen topographies with mean average errors in time of 0.04 m for water depths and 0.004 m2 s−1 for unit discharges. Moreover, it generalizes well to unseen breach locations, bigger domains, and longer periods of time compared to those of the training set, outperforming other deep-learning models. On top of this, SWE–GNN has a computational speed-up of up to 2 orders of magnitude faster than the numerical solver. Our framework opens the doors to a new approach to replace numerical solvers in time-sensitive applications with spatially dependent uncertainties.

Deep learning techniques have been increasingly used in flood management to overcome the limitations of accurate, yet slow, numerical models and to improve the results of traditional methods for flood mapping. In this paper, we review 58 recent publications to outline the state of the art of the field, identify knowledge gaps, and propose future research directions. The review focuses on the type of deep learning models used for various flood mapping applications, the flood types considered, the spatial scale of the studied events, and the data used for model development. The results show that models based on convolutional layers are usually more accurate, as they leverage inductive biases to better process the spatial characteristics of the flooding events. Models based on fully connected layers, instead, provide accurate results when coupled with other statistical models. Deep learning models showed increased accuracy when compared to traditional approaches and increased speed when compared to numerical methods. While there exist several applications in flood susceptibility, inundation, and hazard mapping, more work is needed to understand how deep learning can assist in real-time flood warning during an emergency and how it can be employed to estimate flood risk. A major challenge lies in developing deep learning models that can generalize to unseen case studies. Furthermore, all reviewed models and their outputs are deterministic, with limited considerations for uncertainties in outcomes and probabilistic predictions. The authors argue that these identified gaps can be addressed by exploiting recent fundamental advancements in deep learning or by taking inspiration from developments in other applied areas. Models based on graph neural networks and neural operators can work with arbitrarily structured data and thus should be capable of generalizing across different case studies and could account for complex interactions with the natural and built environment. Physics-based deep learning can be used to preserve the underlying physical equations resulting in more reliable speed-up alternatives for numerical models. Similarly, probabilistic models can be built by resorting to deep Gaussian processes or Bayesian neural networks.

Mesenchymal stromal cells (MSCs) are multipotent cells with anti-inflammatory properties. Here we tested the safety of MSCs in patients with progressive supranuclear palsy (PSP; ClinicalTrials.gov: NCT01824121; Eudract No. 2011-004051-39). Seven patients were treated. To improve the safety, protocol adjustments were made during the performance of the study. The objectives of our work were: (1) to assess the safety of MSCs and (2) to identify critical issues in cell therapies for neurodegenerative diseases. Autologous MSCs from the bone marrow of PSP patients were administered through the internal carotid arteries. 1-year survival and number of severe adverse events were considered as safety endpoints. Clinical rating scales, neuropsychological assessments, gait and posture analysis, single-photon emission computed tomography, positron emission tomography, and brain magnetic resonance (BMR) were performed at different follow-up times. Peripheral blood levels of inflammatory cytokines were measured before and after cell infusion. Six of the seven treated patients were living 1 year after cell infusion. Asymptomatic spotty lesions were observed at BMR after 24 h in six of the seven treated patients. The last patient in the preliminary cohort (Case 5) exhibited transiently symptomatic BMR ischemic alterations. No severe adverse events were recorded in the last two treated patients. Interleukin-8 serum concentrations decreased in three patients (Case 2, 3, and 4). An adaptive study design, appropriate and up-to-date efficacy measures, adequate sample size estimation, and, possibly, the use of a cellular and/or allogeneic cell sources may help in performing phase II trials in the field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Giordano, Canesi, Isalberti, Marfia, Campanella, Vincenti, Cereda, Ranghetti, Palmisano, Isaias, Benti, Marotta, Lazzari, Montemurro, Viganò, Budelli, Montelatici, Lavazza, Rivera-Ordaz and Pezzoli.)

The visual fixation represents a doubtful behavioral sign to discriminate Vegetative from Minimally Conscious State (MCS). To disentangle its meaning, we fitted univariate and multivariable logistic regression models matching different neurophysiological and neuroimaging data of 54 patients with Disorders of Consciousness to select the best model predicting which visual performance (visual blink or pursuit) was shown by patients and the best predictors set. The best models found highlighted the importance of the structural MRI and the visual evoked potentials data in predicting visual pursuit. Then, a qualitative pilot test was made on four patients showing visual fixation revealing that the obtained models correctly predict whether the patients' visual performance could support/correlate to a cognitively mediated behavior. The present pilot models could help clinicians to evaluate if the visual fixation response can support the MCS diagnosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

A 69-year-old woman presented with cognitive impairment related to attentive, executive, and mnemonic functions; progressive worsening of walking, speaking, writing, and reading ability; and double sphincter incontinence. Leukoencephalopathy, cystic lesions, and calcifications, suspected for Labrune syndrome, were observed at MRI and CT brain images. Generalized wave abnormalities were also visible at electroencephalogram. Functional brain imaging performed with F-FDG PET/CT demonstrated a decreased glucose metabolism in impaired brain regions, in accordance with MRI findings. Genetic testing confirmed a mutation of SNORD118.

In patients with disorder of consciousness (DOC), the corpus callosum (CC) and subcortical white matter (SWM) integrity were shown to discriminate between diagnostic categories. The aims of the study were: (1) to clarify the link between the integrity of CC and of SWM and the clinical status in DOC patients, disentangling the role played by the different brain injuries (traumatic or hemorrhagic brain injury); (2) to investigate the relationship between the CC integrity and the brain metabolism. We assessed the diagnostic accuracy of the CC and SWM integrity, using diffusion tensor imaging (DTI) and structural magnetic resonance imaging (sMRI), in a sample of DOC individuals, well balanced for diagnosis and etiology. The CC DTI-derived measures were correlated with the brain metabolism, computed with fluorodeoxyglucose positron emission tomography. Our results showed that the CC macrostructural DTI-derived measures discriminate between diagnosis and correlate with the clinical status of DOC patients irrespective of the etiology. Moreover, the CC DTI-derived measures strongly correlate with the metabolism of the right hemisphere. No significant diagnostic accuracy emerged for the CC sMRI evaluation and the SWM measures. Our results indicate that: (1) the degree of the interhemispherical anatomical disconnection is a marker of the level of consciousness independent from the type of brain injury; (2) CC alterations might be the consequence of the reduced brain metabolism. Remarkably, our results suggest that the functional interplay between the two hemispheres is linked tightly to the level of consciousness.

Background: The leading cause of early mortality after lung transplantation is Primary graft dysfunction (PGD). We assessed the lung inflammation, inflation status and inhomogeneities after lung transplantation. Our purpose was to investigate the possible differences between patients who did or did not develop PGD., Methods: We designed a prospective observational study enrolling patients who underwent a CT-PET study within 1 week after lung transplantation. Twenty-four patients (10 after double- and 14 after single-lung) were enrolled. Respiratory and hemodynamic data were collected before, during and after lung transplantation. Each patient underwent computed tomography-positron emission tomography (CT-PET) scan early after surgery. Broncho-alveolar lavage (BAL) fluid collection was performed to analyze inflammatory mediators., Results: The grafts showed a [18F]fluoro-2-deoxy-D-glucose ([18F]FDG) uptake rate of 26[18-33]*10-4 mLblood/mLtissue/min (reference values 11[7-15]*10-4). Three double- and six single-lung recipients developed PGD. The grafts of patients who developed PGD had similar [18F]FDG uptake than grafts of patients who did not (28[18-26]*10-4 versus 26[22-31]*10-4, P=0.79). Not-inflated tissue fraction was significantly higher (28[20-38]% versus 14[7-21]%, P=0.01) while well-inflated fraction was significantly lower (29[25-41]% versus 53[39-65]%, P<0.01). Inhomogeneity extent was higher in patients who developed PGD (23[18-26]% versus 14[10-20]%, P=0.01)The lung weight was 650[591-820]g versus 597[480-650]g (P=0.09)). BAL fluid analysis for inflammatory mediators did not detect a difference between the study groups., Conclusions: Compared to healthy lungs, all the grafts showed increased [18F]FDG uptake rate, but there were no differences between patients who developed PGD and patients who did not. Of note, the PGD patients showed a worse inflation status of lungs and a higher inhomogeneity extent.

There is a growing interest in the use of functional imaging to assess brain activity in the absence of behavioural responses in patients with disorders of consciousness (DOC). In the present study, we applied a hierarchical auditory stimulation paradigm to functional magnetic resonance (fMRI) in a group of long-term DOC adult patients. Brain response to pairs of pseudowords, of unrelated words and of semantically related words, i.e. stimuli differing in lexical status (words vs. pseudowords) and semantic relatedness (related vs. unrelated) was assessed. The former contrast was considered to reflect the automatic brain response to the passive presentation of meaningful real words, while the latter aimed to assess the response to meaning relationships. The results of the study indicate that automatic lexical processing can be observed in minimally conscious state (MCS), but also in vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients, as indicated by increase in blood oxygenation level dependent (BOLD) activity in the linguistic networks. DOC patients, for some task conditions, recruited additional areas in comparison to healthy participants. Furthermore this study provides additional evidence of the potential role of fMRI in the assessment of residual cognitive processing in some of these patients, which may not be evident at the clinical level.

Objective: Over the last decade, the contribution of (18)F-FDG (FDG) PET/CT imaging to the diagnosis of large vessel vasculitis has been widely investigated. The aim of this study was to evaluate a more extensive role for PET/CT in grading vascular inflammation in patients with different clinical stages of disease., Methods: The images of 66 PET/CT studies of 34 patients, performed at diagnosis and/or during follow-up were reviewed. FDG uptake in different regions of aorta and in its major branches was visually (regional Score: rS) and semiquantitatively (regional SUVmean: rSUV) assessed. The global vascular uptake was also evaluated for each study by summing all rSs (summed Score; sS) and averaging rSUVs (averaged SUV; aSUV). FDG uptake in 15 PET/CT studies of control age-matched subjects without signs or symptoms of vasculitis was also analyzed., Results: Higher levels of regional and global FDG uptake were found at diagnosis in comparison with follow-up studies of 12 patients with complete longitudinal observation (p value range 0.0552-0.0026). In the latter group high values were generally observed when disease relapse or incomplete response to therapy (active disease) occurred, whereas lower uptake was found in studies of remitted patients (p = <0.01), whose FDG levels were similar to those of control subjects. At ROC analysis performed on all image dataset, optimal cut-off levels of regional and global FDG vascular uptake provided a good discrimination between 25 patients at diagnosis and 15 control subjects (aSUV greater than 0.697; PPV = 92.3; NPV = 92.9). Major overlap was observed among FDG levels of 21 patients with active disease and in remission (aSUV greater than 0.653; PPV = 58.3; NPV = 94.1). Similar performances of visual and semiquantitative analyses were found when areas under curves (AUCs) were compared., Conclusions: (18)F-FDG PET/CT has a promising role in grading inflammation in patients with large arteries vasculitis. Nevertheless, a cut-off based analysis of FDG vascular uptake is not sufficient to separate patients with active and inactive disease during follow-up.

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.

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., (© 2016 American Neurological Association.)

Systemic sclerosis (SSc) is a rheumatic autoimmune disease of unknown origin causing fibrosis of the skin and the internal organs. The limited cutaneous variant is the most common subtype of SSc, and it is predominantly characterized by skin and soft-tissues involvement. A 72-year-old woman, who had been diagnosed with the limited cutaneous form of SSc 16 years before, underwent fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) examination due to unexplained weight loss and recent onset of fatigue and joint pain. PET/CT images showed widespread soft-tissue calcinosis characterized by elevated glucose uptake.

The aim of the study was to determine the size and location of homogeneous inflamed/noninflamed and inhomogeneous inflamed/noninflamed lung compartments and their association with acute respiratory distress syndrome (ARDS) severity.In total, 20 ARDS patients underwent 5 and 45 cmH2O computed tomography (CT) scans to measure lung recruitability. [(18)F]2-fluoro-2-deoxy-d-glucose ([(18)F]FDG) uptake and lung inhomogeneities were quantified with a positron emission tomography-CT scan at 10 cmH2O. We defined four compartments with normal/abnormal [(18)F]FDG uptake and lung homogeneity.The homogeneous compartment with normal [(18)F]FDG uptake was primarily composed of well-inflated tissue (80±16%), double-sized in nondependent lung (32±27% versus 16±17%, p<0.0001) and decreased in size from mild, moderate to severe ARDS (33±14%, 26±20% and 5±9% of the total lung volume, respectively, p=0.05). The homogeneous compartment with high [(18)F]FDG uptake was similarly distributed between the dependent and nondependent lung. The inhomogeneous compartment with normal [(18)F]FDG uptake represented 4% of the lung volume. The inhomogeneous compartment with high [(18)F]FDG uptake was preferentially located in the dependent lung (21±10% versus 12±10%, p<0.0001), mostly at the open/closed interfaces and related to recruitability (r(2)=0.53, p<0.001).The homogeneous lung compartment with normal inflation and [(18)F]FDG uptake decreases with ARDS severity, while the inhomogeneous poorly/not inflated compartment increases. Most of the lung inhomogeneities are inflamed. A minor fraction of healthy tissue remains in severe ARDS., (Copyright ©ERS 2016.)

Objective: To investigate the cerebral glucose metabolism in subjects with X-linked adrenoleukodystrophy (X-ALD) by using brain [(18)F]-fluorodeoxyglucose PET (FDG-PET)., Methods: Cross-sectional study in which 12 adults with various forms of X-ALD underwent clinical evaluation and brain MRI, followed by brain FDG-PET, neuropsychological assessment, and personality and psychopathology evaluation using the Symptom Checkist-90-Revised (SCL-90-R) and the Millon Clinical Multiaxial Inventory-III (MCMI-III)., Results: When compared to healthy control subjects (n = 27) by using Statistical Parametric Mapping 8 software, the patients with X-ALD-with or without brain MRI changes-showed a pattern of increased glucose metabolism in frontal lobes and reduced glucose metabolism in cerebellum and temporal lobe areas. On single case analysis by Scenium software, we found a similar pattern, with significant (p < 0.02) correlation between the degree of hypermetabolism in the frontal lobes of each patient and the corresponding X-ALD clinical scores. With respect to personality, we found that patients with X-ALD usually present with an obsessive-compulsive personality disorder on the MCMI-III, with significant (p < 0.05) correlation between glucose uptake in ventral striatum and severity of score on the obsessive-compulsive subscale., Conclusions: We examined cerebral glucose metabolism using FDG-PET in a cohort of patients with X-ALD and provided definite evidence that in X-ALD the analysis of brain glucose metabolism reveals abnormalities independent from morphologic and signal changes detected by MRI and related to clinical severity. Brain FDG-PET may be a useful neuroimaging technique for the characterization of X-ALD and possibly other leukodystrophies., (© 2014 American Academy of Neurology.)

Background: Progressive Supranuclear Palsy (PSP) is a sporadic and progressive neurodegenerative disease which belongs to the family of tauopathies and involves both cortical and subcortical structures. No effective therapy is to date available., Methods/design: Autologous bone marrow (BM) mesenchymal stem cells (MSC) from patients affected by different type of parkinsonisms have shown their ability to improve the dopaminergic function in preclinical and clinical models. It is also possible to isolate and expand MSC from the BM of PSP patients with the same proliferation rate and immuphenotypic profile as MSC from healthy donors. BM MSC can be efficiently delivered to the affected brain regions of PSP patients where they can exert their beneficial effects through different mechanisms including the secretion of neurotrophic factors.Here we propose a randomized, placebo-controlled, double-blind phase I clinical trial in patients affected by PSP with MSC delivered via intra-arterial injection., Discussion: To our knowledge, this is the first clinical trial to be applied in a no-option parkinsonism that aims to test the safety and to exploit the properties of autologous mesenchymal stem cells in reducing disease progression. The study has been designed to test the safety of this "first-in-man" approach and to preliminarily explore its efficacy by excluding the placebo effect., Trial Registration: NCT01824121.

Objective: To investigate dopaminergic function in a large cohort of patients with corticobasal syndrome (CBS) and describe its relationship with clinical features in comparison to Parkinson's disease and healthy control subjects. In addition, we assessed prevalence and features of individuals with CBS and in vivo evidence of preserved nigral neuronal density., Background: Substantia nigra pars compacta (SNc) neuronal degeneration is a mandatory pathological criterion for definite corticobasal degeneration, though sporadic autopsy-proven cases with ante-mortem imaging evidence of preserved nigral terminals have been recently described., Methods: In this multicenter study, we investigated presynaptic nigrostriatal function in 36 outpatients fulfilling clinical criteria for "probable corticobasal degeneration" (age 71±7.3 years; disease duration 3.9±1.6 years), 37 PD and 24 healthy control subjects using FP-CIT single photon emission computed tomography. Clinical, neuropsychological, and magnetic resonance imaging assessment was performed to characterize CBS patients. Linear discriminant analysis was used to categorize normal vs. pathological scans., Results: FP-CIT binding reduction in patients with CBS was characterized by larger variability, more uniform reduction throughout the striatum and greater hemispheric asymmetry compared to PD. Moreover, there was no significant correlation between tracer uptake values and clinical features such as disease duration and severity. Despite all CBS subjects showed obvious bilateral extrapyramidal signs, FP-CIT uptake was found to be normal bilaterally in four CBS patients and only unilaterally in other four cases. Extensive clinical, neuropsychological and imaging assessment did not reveal remarkable differences between CBS subjects with normal vs. pathological FP-CIT uptake., Conclusions: Our findings support the hypothesis that extrapyramidal motor symptoms in CBS are not invariably associated with SNc neuronal degeneration and that supranigral factors may play a major role in several cases. CBS individuals with normal FP-CIT uptake do not show any clinical or cognitive feature suggesting a different pathology than CBD.

To investigate over time changes in striatal dopamine transporter (DAT), we performed two sequential N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl) tropane single photon computed tomography (SPECT) scans in 20 subjects with essential tremor (ET), in 13 with Parkinson disease (PD) and in 23 healthy controls (HC, one scan only). We also performed an [(99m)Tc]ethyl cysteinate dimer bicisate SPECT exam for regional brain network analysis in 9 ET, in a second group of 18 PD (9 with tremor, tPD and 9 akinetic-rigid dominant, arPD) and in 8 HC. PD subjects had a reduced DAT binding in comparison to ET and HC with an annual decline rate of 7.3% in the contralateral putamen. There were no mean uptake differences between ET and HC at baseline and no uptake loss over time in ET. A discriminant analysis grouped 30% (first scan) and 5% (second scan) of ET as PD and a partition analysis showed overlap between ET and PD for caudate nucleus uptake. Spatial covariance analysis revealed that the expression of the PD-related regional pattern separated both tPD and arPD from ET and HC. In conclusion, PD and ET do not share a common pattern of dopaminergic loss over time. However, mild impairment of dopamine transporter in the caudate nucleus may contribute to tremor onset in ET., (2010 Movement Disorder Society)

Background: High-frequency stimulation of the subthalamic nucleus (STN-DBS) improves motor symptoms in advanced Parkinson's disease (PD), but the mechanisms are still unclear. Functional imaging evidenced pathological overactivity in motor cortical areas in advanced PD that can be normalized by effective therapies., Patients and Methods: We studied resting state cerebral blood flow pre-operatively and 12 months after surgery in 40 patients with advanced PD using ECD-SPECT. SPECT scans were also acquired 1 year apart in 21 matched PD controls who did not undergo surgery. Statistical analysis was performed using statistical parametric mapping (SPM2) software. In addition, we correlated brain perfusion changes after surgery with clinical improvement, assessed using the unified PD rating scale motor score (UPDRS-III)., Results: Patients showed marked motor improvement and medication reduction after surgery. Stimulated PD patients revealed bilateral rCBF decrements in motor cortical areas and prefrontal cortex bilaterally compared to pre-surgical condition as well as versus PD controls (p<.01 FDR corrected). Perfusion increases were found in cerebellum, temporal and occipital lobes. Clinical improvement was associated with perfusion decrements in primary motor and premotor cortices., Conclusions: Effective STN-DBS is associated with neuronal activity changes in brain regions implicated in movement programming and performance. We hypothesize that clinical benefit might be associated with stimulation-induced normalization of the abnormal overactivity within the cortico-basal ganglia-thalamo-cortical motor loop in advanced PD.

The overlap among tremor disorders is wide and complex because essential tremor patients may present resting tremor coexisting with postural tremor, while postural may coexist with resting tremor in Parkinson's disease. We investigated dopamine transporter binding in 61 subjects presenting with isolated atypical tremors defined as unilateral either postural, resting, or mixed (i.e. resting and postural) tremor, without rigidity or bradykinesia, by means of 123I-FPCIT SPECT imaging at baseline. Patients were followed-up clinically for 28.4 +/- 7.2 months. Twenty-five patients with baseline normal SPECT continued to present only tremor at follow-up. Among 36 patients with abnormal SPECT, 23 (64%) developed PD, while the remaining 13 continued to present only tremor at follow-up. The value of 123I-FPCIT SPECT in predicting the evolution to PD was very high in a way independent from the first clinical presentation of tremor (Rest tremor, P = 0.015; Mixed tremor, P = 0.015; Postural tremor, P = 0.039; chi-square test). Our data suggest that the clinical presentation of isolated tremors is insufficient to allow a precise early-stage diagnosis, whereas the detection of presynaptic nigrostriatal dopaminergic dysfunction could lead to diagnosis of atypical tremor disorders at a very early stage. We suggest this disorder to be labeled as "isolated tremor with dopaminergic presynaptic dysfunction"., ((c) 2008 Movement Disorder Society.)

Background and Methods: We used (123)I-Ioflupane SPECT to study 32 unrelated patients with essential tremor (16 with positive familial history), 47 sporadic tremor dominant patients with Parkinson's disease and 31 healthy control subjects. Discriminant analysis was used to categorize healthy subjects and patients with Parkinson's disease or essential tremor., Results: Patients with essential tremor had higher uptake values (50% putamen and 21% caudate, P<0.001) compared to those with Parkinson's disease but lower than healthy subjects (15% putamen and 21% caudate, P<0.05). Discriminant analysis classified seven essential tremor patients in the healthy subjects cohort (22%) and two as Parkinson's disease (6%)., Conclusions: Our results show that some essential tremor patients may present mild abnormalities of striatal dopamine transporters and a typical Parkinson's disease-like pattern of uptake loss. These findings suggest a link between the two disorders.

Extradural motor cortex stimulation (EMCS) has been proposed as alternative to deep brain stimulation (DBS) in the treatment of Parkinson's disease (PD). Its mechanisms of action are still unclear. Neuroimaging evidenced motor cortical dysfunction in PD that can be reversed by therapy. We performed left hemisphere EMCS surgery in six advanced PD patients fulfilling CAPSIT criteria for DBS with the exception of age >70 years. After 6 months, we measured regional cerebral blood flow (rCBF) at rest with SPECT and Tc-99m cysteinate dimer bicisate off-medication with stimulator off and on. Clinical assessment included Unified Parkinson's Disease Rating Scale part II and III, Abnormal Involuntary Movement Scale and mean dopaminergic medication dosage. We used statistical parametric mapping for imaging data analysis. Clinically we observed no mean changes in motor scales, although blinded evaluation revealed some benefit in individual patients. We found significant rCBF decrements in the pre-central gyrus, pre-motor cortex and caudate nucleus bilaterally, left prefrontal areas and right thalamus. Perfusion increments were found in cerebellum bilaterally. EMCS determined significant modulation of neuronal activity within the cortico-basal ganglia-thalamo-cortical motor loop in our cohort of advanced PD patients. However, these effects were paralleled by mild and variable clinical efficacy.

We performed [123I]FP-CIT/SPECT in 20 drug-naive Parkinson's disease (PD) patients, 10 with unilateral akinesia/rigidity at onset (arPD) and 10 with additional tremor-at-rest (tPD), to evaluate whether resting tremor at onset is associated with differences in striatal dopamine transporter binding. Patients of the two cohorts were matched for age, disease duration (<3 years) and severity of non-tremor motor symptoms; 31 healthy participants served as controls. Mean striatal dopamine transporter binding reduction in PD patients vs. controls was 42% for arPD and 50% for tPD; mean ipsilateral striatum and caudate nucleus uptake values were lower by 12 and 24%, respectively, in tPD than arPD. We conclude that widespread degeneration of the nigrostriatal dopaminergic pathway might be necessary for the development of parkinsonian tremor-at-rest.

We describe clinical and imaging features of a patient with sporadic progressive ataxia and palatal tremor (PAPT) of unknown etiology. There was hypertrophy of bilateral inferior olivary nuclei with hyperintense T2-weighted signal and mild cerebellar atrophy at brain magnetic resonance imaging. 18F-fluoro-2-desoxy-d-glucose positron emission tomography scanning (FDG-PET) showed hypometabolism in the red nucleus, external globus pallidus and precuneus while FP-CIT-SPECT imaging revealed mild and progressive loss of striatal dopaminergic terminals. Our findings suggest that in idiopathic PAPT involvement of the dentato-rubro-olivary pathway occurs along with some dopaminergic dysfunction.

We prospectively evaluated 20 patients with Parkinson's disease (PD) preoperatively and 12 months after subthalamic nucleus-deep brain stimulation (STN-DBS). All patients had clinical (UPDRS III) and neuropsychological evaluations as well as brain perfusion SPECT-ECD. Clinical and cognitive data were compared with 12 matched PD patients who had not undergone surgery. STN-DBS patients improved in motor symptoms and reduced medications but selectively declined in category fluency (p<0.01). No clinical and cognitive changes were found in the control group at follow-up. Worsening fluency was associated with perfusion decrements in left dorsolateral prefrontal cortex, anterior cingulate cortex and ventral caudate nucleus (p<.001).

We used 123I-Ioflupane SPECT to study striatal dopamine transporter (DAT) binding in 36 Parkinson's disease (PD) patients with history of severe occupational exposure to hydrocarbons. Data were compared with 38 PD patients without exposure history as well as healthy controls. Both PD cohorts showed significant striatal uptake decrements compared with controls. We found significantly lower values in the whole striatum of exposed compared with non-exposed patients (0.83 +/- 0.25 vs. 1.05 +/- 0.39; P = 0.004), more pronounced in the putamen (0.61 +/- 0.24 vs. 0.85 +/- 0.42; P = 0.004). We conclude that severe occupational exposure to hydrocarbons may modify disease course and ultimately accelerate nigro-striatal denervation.

Autosomal recessive parkinsonism is a genetic condition closely resembling Parkinson disease, the only distinguishing features being an earlier age at onset and a slower disease progression. Three causative genes have been identified so far. While exon rearrangements are frequently encountered in the Parkin gene, most PINK1 mutations are represented by single nucleotide changes. We report a sporadic parkinsonian patient carrying a deletion of the entire PINK1 gene and a splice site mutation (g.15445&#95;15467del23) which produces several aberrant mRNAs. This report expands the genotypic spectrum of PINK1 mutations, with relevant implications for molecular analysis of this gene., ((c) 2006 Wiley-Liss, Inc.)

We measured striatal dopamine transporter binding using [(123)I]ioflupane and SPECT in patients with Parkinson's disease associated with the LRRK2 (PARK8) Gly2019Ser gene mutation (LRRK2-PD) and in gene-negative patients with idiopathic Parkinson's disease (IPD) of comparable disease duration and severity. The LRRK2-PD group consisted of a total of 10 patients (3 sporadic) with mean age 62 +/- 14 years, disease duration 9 +/- 3 years, and UPDRS III motor score 21.60 +/- 6.65. The control IPD group consisted of 15 patients with mean age 59 +/- 9 years, disease duration 9 +/- 5 years, and UPDRS III motor score 23.80 +/- 8.69. [(123)I]ioflupane-specific uptake ratios were calculated for caudate nucleus and putamen using the occipital cortex as reference region. We found no differences between the LRRK2-PD group and IPD in all items studied. In particular, putamen and caudate uptake values as well as side asymmetry indexes and putamen/caudate ratios all revealed comparable between-group values. We conclude that in these patients carrying the LRRK2 Gly2019Ser mutation, the neurodegenerative process results in a pattern of nigrostriatal dopaminergic dysfunction similar to that observed in IPD., ((c) 2006 Movement Disorder Society)

We report on a patient with late-onset, pantothenate kinase-associated neurodegeneration (PKAN) who revealed two new heterozygous mutations at gene testing and showed asymmetric moderately reduced striatal dopamine transporter binding with single photon emission computed tomography, possibly due to prolonged neuroleptic treatment. These findings expand the genetic and imaging spectrum of this rare disorder., ((c) 2005 Movement Disorder Society.)

Clinical diagnosis of multiple system atrophy (MSA) relays on signs and symptoms that are often difficult to identify particularly at early stage. Indeed neuropathological studies have demonstrated that MSA is the first cause of misdiagnosis in a cohort of patients presenting with parkinsonian features. Dopamine transporter imaging (DAT) shows striatal decrements in both MSA and Parkinson's disease (PD) making it not sensitive for differential diagnosis. Studies of dopamine D2 receptors with IBZM may help revealing striatal degeneration but a large overlap exist particularly if PD patients with advanced disease are included. We have measured brain flow with technetium-99m ethyl cysteinate dimer (ECD-SPECT) in 36 MSA patients and compared it with 43 PD and 39 age-matched controls. Using Statistical Parametric Mapping (SPM99) we found areas of significant reduced perfusion in the striatum, brain stem and cerebellum in MSA compared to the other groups. We believe that ECD-SPECT imaging may offer significant advantages compared to other imaging techniques in the assessment of neuronal degeneration in MSA and may help the clinician in the diagnostic characterization of patients presenting with atypical parkinsonism.

We used SPECT and the tracer (123)I-Ioflupane to measure dopamine transporter (DAT) binding in the caudate nucleus and the putamen of 70 patients with Parkinson's disease (PD), 10 with multiple system atrophy (MSA-P type), and 10 with progressive supranuclear palsy (PSP). Data were compared with 12 age-matched control subjects. We found significant reductions in mean striatal values in all three forms of parkinsonism. However, decrements were significantly greater in PSP (0.51+/-0.39, p<0.01) compared with MSA-P (0.70+/-0.33) and PD (0.95+/-0.38). No differences were found between MSA and PD. Putamen/caudate ratios were greater in PSP (0.83+/-0.12, p<0.01) than in PD (0.51+/-0.11), suggesting a more-uniform involvement of dopamine nerve terminals in both caudate nucleus and putamen. Our results confirm that DAT binding can provide an accurate and highly sensitive measure of dopamine degeneration. PSP patients may show a different pattern of neuronal loss compared with MSA and PD.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) markedly improves motor symptoms and reduces medication needs in Parkinson's disease (PD) patients. However, its effect on brain function has remained unclear. We used SPECT and the tracer ECD to measure regional cerebral blood flow before and 6 months after DBS of the STN in 22 PD patients and 13 healthy controls. PD patients were divided into good and poor responders to DBS, if changes in "off" UPDRS motor scores after surgery were >60% or <40%, respectively. Statistical analysis was performed using the SPM99 software. At baseline, all PD patients showed significant perfusion reductions in cortical areas (premotor frontal, parietal, and occipital). After DBS, changes were normalized only in the good responders, while cortical defects in the poor responders were unchanged. No flow decrements were detected in basal ganglia and thalamus in both groups, suggesting that DBS does not have a "lesion-like" effect. We conclude that good surgery outcome is associated with normalization of cortical flow abnormalities in PD.