Studio del tensore di diffusione per la differenziazione delle strutture renali

La tecnologia della diffusion tensor imaging (DTI) è una tecnica non invasiva, che permette di effettuare una caratterizzazione in vivo di diversi tessuti, è una tecnica consolidata in ambito neurologico e rappresenta una metodica ancora da esplorare ma molto promettente in ambito renale. Questo lavoro di tesi si concentra in primo luogo sulla differenziazione di diverse strutture renali quali, la corteccia e la medulla del rene sano, le cisti del rene affetto dalla malattia policistica autosomica dominante e i carcinomi. La seconda parte del lavoro si concentra sui reni policistici, in quanto è una delle malattie genetiche più comuni e la principale causa di insufficienza renale e non è, ad oggi, stata adeguatamente affrontata in questo genere di studi. Il secondo obiettivo è, quindi, di valutare se la tecnica dell’imaging di diffusione potrebbe essere utile per fornire informazioni sullo stato della malattia e sul grado si avanzamento di essa. Sono stati implementati in Matlab gli algoritmi per la costruzione del tensore di diffusione a partire dalle immagini DWI e per la selezione delle ROI sulle varie regioni di interesse. I risultati ottenuti per l’analisi dei reni policistici dimostrano che per gli intervalli temporali considerati non è possibile correlare il valore di diffusività media del parenchima e lo stadio di avanzamento della malattia, stabilito dai valori di eGFR. Per quanto riguarda i risultati ottenuti dalla differenziazione delle diverse strutture renali la tecnica della diffusion imaging risulta essere potenzialmente in grado di differenziare i diversi tessuti renali e di valutare separatamente la funzionalità dei reni.

Rapid spontaneous malignant progression of supratentorial tanycytic ependymoma with sarcomatous features - "Ependymosarcoma"

By analogy to gliosarcoma, the term "ependymosarcoma" has recently been coined to thematize the rare phenomenon of a malignant mesenchymal component arising within an ependymoma. We report on an example of this paradigm, involving tanycytic ependymoma as the host tumor in a 40-year-old female who underwent two tumor extirpation procedures at one-year interval. She first presented with severe headaches, and was seen by imaging to harbor a moderately enhancing mass 2.5cm in diameter at the rostral septum pellucidum accompanied by occlusive hydrocephalus. Microscopically, the tumor consisted of solid, wavy fascicles of elongated cells that were occasionally interrupted by vague perivascular pseudorosettes. Mitotic activity was absent, and less than 1% of nuclei immunoreacted for MIB-1. A histological diagnosis of tanycytic ependymoma (WHO grade II) was rendered, and no adjuvant therapy given. At recurrence, the lesion was 3.5cm in diameter, intensely enhancing, and had already seeded into the subarachnoid space. Histology showed a biphasic glial-sarcomatous architecture with remnants of the original ependymoma now displaying hypercellularity and atypical - yet not frankly anaplastic - features. The sarcomatous moiety consisted of spindle and epithelioid cells densely interwoven with reticulin fibers. While the ependymal component was GFAP and S100 protein positive, and featured punctate staining for EMA, none of these markers was expressed in the adjacent sarcoma. Instead, the latter reacted for vimentin and smooth muscle actin. To the best of our knowledge, this is the first documentation of tanycytic ependymoma undergoing malignant transformation, one driven by a highly anaplastic mesenchymal component, corresponding to "ependymosarcoma".

Effects of lung recruitment maneuvers on splanchnic organ perfusion during endotoxin-induced pulmonary arterial hypertension

Lung recruitment maneuvers (RMs), used to reopen atelectatic lung units and to improve oxygenation during mechanical ventilation, may result in hemodynamic impairment. We hypothesize that pulmonary arterial hypertension aggravates the consequences of RMs in the splanchnic circulation. Twelve anesthetized pigs underwent laparotomy and prolonged postoperative ventilation. Systemic, regional, and organ blood flows were monitored. After 6 h (= baseline), a recruitment maneuver was performed with sustained inflation of the lungs. Thereafter, the pigs were randomly assigned to group C (control, n = 6) or group E with endotoxin-induced pulmonary arterial hypertension (n = 6). Endotoxemia resulted in a normotensive and hyperdynamic state and a deterioration of the oxygenation index by 33%. The RM was then repeated in both groups. Pulmonary artery pressure increased during lipopolysaccharide infusion from 17 ± 2 mmHg (mean ± SD) to 31 ± 10 mmHg and remained unchanged in controls (P < 0.05). During endotoxemia, RM decreased aortic pulse pressure from 37 ± 14 mmHg to 27 ± 13 mmHg (mean ± SD, P = 0.024). The blood flows of the renal artery, hepatic artery, celiac trunk, superior mesenteric artery, and portal vein decreased to 71% ± 21%, 69% ± 20%, 76% ± 16%, 79% ± 18%, and 81% ± 12%, respectively, of baseline flows before RM (P < 0.05 all). Organ perfusion of kidney cortex, kidney medulla, liver, and jejunal mucosa in group E decreased to 65% ± 19%, 77% ± 13%, 66% ± 26%, and 71% ± 12%, respectively, of baseline flows (P < 0.05 all). The corresponding recovery to at least 90% of baseline regional blood flow and organ perfusion lasted 1 to 5 min. Importantly, the decreases in regional blood flows and organ perfusion and the time to recovery of these flows did not differ from the controls. In conclusion, lipopolysaccharide-induced pulmonary arterial hypertension does not aggravate the RM-induced significant but short-lasting decreases in systemic, regional, and organ blood flows.

Pheochromocytoma in rats with multiple endocrine neoplasia (MENX) shares gene expression patterns with human pheochromocytoma

Pheochromocytomas are rare neoplasias of neural crest origin arising from chromaffin cells of the adrenal medulla and sympathetic ganglia (extra-adrenal pheochromocytoma). Pheochromocytoma that develop in rats homozygous for a loss-of-function mutation in p27Kip1 (MENX syndrome) show a clear progression from hyperplasia to tumor, offering the possibility to gain insight into tumor pathobiology. We compared the gene-expression signatures of both adrenomedullary hyperplasia and pheochromocytoma with normal rat adrenal medulla. Hyperplasia and tumor show very similar transcriptome profiles, indicating early determination of the tumorigenic signature. Overrepresentation of developmentally regulated neural genes was a feature of the rat lesions. Quantitative RT-PCR validated the up-regulation of 11 genes, including some involved in neural development: Cdkn2a, Cdkn2c, Neurod1, Gal, Bmp7, and Phox2a. Overexpression of these genes precedes histological changes in affected adrenal glands. Their presence at early stages of tumorigenesis indicates they are not acquired during progression and may be a result of the lack of functional p27Kip1. Adrenal and extra-adrenal pheochromocytoma development clearly follows diverged molecular pathways in MENX rats. To correlate these findings to human pheochromocytoma, we studied nine genes overexpressed in the rat lesions in 46 sporadic and familial human pheochromocytomas. The expression of GAL, DGKH, BMP7, PHOX2A, L1CAM, TCTE1, EBF3, SOX4, and HASH1 was up-regulated, although with different frequencies. Immunohistochemical staining detected high L1CAM expression selectively in 27 human pheochromocytomas but not in 140 nonchromaffin neuroendocrine tumors. These studies reveal clues to the molecular pathways involved in rat and human pheochromocytoma and identify previously unexplored biomarkers for clinical use.

Resting state cerebral blood flow and objective motor activity reveal basal ganglia dysfunction in schizophrenia

Reduced motor activity has been reported in schizophrenia and was associated with subtype, psychopathology and medication. Still, little is known about the neurobiology of motor retardation. To identify neural correlates of motor activity, resting state cerebral blood flow (CBF) was correlated with objective motor activity of the same day. Participants comprised 11 schizophrenia patients and 14 controls who underwent magnetic resonance imaging with arterial spin labeling and wrist actigraphy. Patients had reduced activity levels and reduced perfusion of the left parahippocampal gyrus, left middle temporal gyrus, right thalamus, and right prefrontal cortex. In controls, but not in schizophrenia, CBF was correlated with activity in the right thalamic ventral anterior (VA) nucleus, a key module within basal ganglia-cortical motor circuits. In contrast, only in schizophrenia patients positive correlations of CBF and motor activity were found in bilateral prefrontal areas and in the right rostral cingulate motor area (rCMA). Grey matter volume correlated with motor activity only in the left posterior cingulate cortex of the patients. The findings suggest that basal ganglia motor control is impaired in schizophrenia. In addition, CBF of cortical areas critical for motor control was associated with volitional motor behavior, which may be a compensatory mechanism for basal ganglia dysfunction.

The ocular motor features of adult-onset alexander disease: a case and review of the literature

A 51-year-old Chinese man presented with gaze-evoked nystagmus, impaired smooth pursuit and vestibular ocular reflex cancellation, and saccadic dysmetria, along with a family history suggestive of late-onset autosomal dominant parkinsonism. MRI revealed abnormalities of the medulla and cervical spinal cord typical of adult-onset Alexander disease, and genetic testing showed homozygosity for the p.D295N polymorphic allele in the gene encoding the glial fibrillary acidic protein. A review of the literature shows that ocular signs are frequent in adult-onset Alexander disease, most commonly gaze-evoked nystagmus, pendular nystagmus, and/or oculopalatal myoclonus, and less commonly ptosis, miosis, and saccadic dysmetria. These signs are consistent with the propensity of adult-onset Alexander disease to cause medullary abnormalities on neuroimaging.

Mental reversal of imagined melodies: A role for the posterior parietal cortex

Two fMRI experiments explored the neural substrates of a musical imagery task that required manipulation of the imagined sounds: temporal reversal of a melody. Musicians were presented with the first few notes of a familiar tune (Experiment 1) or its title (Experiment 2), followed by a string of notes that was either an exact or an inexact reversal. The task was to judge whether the second string was correct or not by mentally reversing all its notes, thus requiring both maintenance and manipulation of the represented string. Both experiments showed considerable activation of the superior parietal lobe (intraparietal sulcus) during the reversal process. Ventrolateral and dorsolateral frontal cortices were also activated, consistent with the memory load required during the task. We also found weaker evidence for some activation of right auditory cortex in both studies, congruent with results from previous simpler music imagery tasks. We interpret these results in the context of other mental transformation tasks, such as mental rotation in the visual domain, which are known to recruit the intraparietal sulcus region, and we propose that this region subserves general computations that require transformations of a sensory input. Mental imagery tasks may thus have both task or modality-specific components as well as components that supersede any specific codes and instead represent amodal mental manipulation.

Brain activation during anticipation of sound sequences

Music consists of sound sequences that require integration over time. As we become familiar with music, associations between notes, melodies, and entire symphonic movements become stronger and more complex. These associations can become so tight that, for example, hearing the end of one album track can elicit a robust image of the upcoming track while anticipating it in total silence. Here, we study this predictive “anticipatory imagery” at various stages throughout learning and investigate activity changes in corresponding neural structures using functional magnetic resonance imaging. Anticipatory imagery (in silence) for highly familiar naturalistic music was accompanied by pronounced activity in rostral prefrontal cortex (PFC) and premotor areas. Examining changes in the neural bases of anticipatory imagery during two stages of learning conditional associations between simple melodies, however, demonstrates the importance of fronto-striatal connections, consistent with a role of the basal ganglia in “training” frontal cortex (Pasupathy and Miller, 2005). Another striking change in neural resources during learning was a shift between caudal PFC earlier to rostral PFC later in learning. Our findings regarding musical anticipation and sound sequence learning are highly compatible with studies of motor sequence learning, suggesting common predictive mechanisms in both domains.

Unique paleopathology in a pre-Columbian mummy remnant from Southern Peru--severe cervical rotation trauma with subluxation of the axis as cause of death

We describe the multidisciplinary findings in a pre-Columbian mummy head from Southern Peru (Cahuachi, Nazca civilisation, radiocarbon dating between 120 and 750 AD) of a mature male individual (40-60 years) with the first two vertebrae attached in pathological position. Accordingly, the atlanto-axial transition (C1/C2) was significantly rotated and dislocated at 38° angle associated with a bulging brownish mass that considerably reduced the spinal canal by circa 60%. Using surface microscopy, endoscopy, high-resolution multi-slice computer tomography, paleohistology and immunohistochemistry, we identified an extensive epidural hematoma of the upper cervical spinal canal-extending into the skull cavity-obviously due to a rupture of the left vertebral artery at its transition between atlas and skull base. There were no signs of fractures of the skull or vertebrae. Histological and immunohistochemical examinations clearly identified dura, brain residues and densely packed corpuscular elements that proved to represent fresh epidural hematoma. Subsequent biochemical analysis provided no evidence for pre-mortal cocaine consumption. Stable isotope analysis, however, revealed significant and repeated changes in the nutrition during his last 9 months, suggesting high mobility. Finally, the significant narrowing of the rotational atlanto-axial dislocation and the epidural hematoma probably caused compression of the spinal cord and the medulla oblongata with subsequent respiratory arrest. In conclusion, we suggest that the man died within a short period of time (probably few minutes) in an upright position with the head rotated rapidly to the right side. In paleopathologic literature, trauma to the upper cervical spine has as yet only very rarely been described, and dislocation of the vertebral bodies has not been presented.

The distribution of E-cadherin expression in listeric rhombencephalitis of ruminants indicates its involvement in Listeria monocytogenes neuroinvasion

AIM: To investigate the expression of E-cadherin, a major host cell receptor for Listeria monocytogenes (LM) internalin A, in the ruminant nervous system and its putative role in brainstem invasion and intracerebral spread of LM in the natural disease. METHODS: Immunohistochemistry and double immunofluorescence was performed on brains, cranial nerves and ganglia of ruminants with and without natural LM rhombencephalitis using antibodies against E-cadherin, protein gene product 9.5, myelin-associated glycoprotein and LM. RESULTS: In the ruminant brain, E-cadherin is expressed in choroid plexus epithelium, meningothelium and restricted neuropil areas of the medulla, but not in the endothelium. In cranial nerves and ganglia, E-cadherin is expressed in satellite cells and myelinating Schwann cells. Expression does not differ between ruminants with or without listeriosis and does not overlap with the presence of microabscesses in the medulla. LM is observed in phagocytes, axons, Schwann cells, satellite cells and ganglionic neurones. CONCLUSION: Our results support the view that the specific ligand-receptor interaction between LM and host E-cadherin is involved in the neuropathogenesis of ruminant listeriosis. They suggest that oral epithelium and Schwann cells expressing E-cadherin provide a port of entry for free bacteria offering a site of primary intracellular replication, from where the bacterium may invade the axonal compartment by cell-to-cell spread. As E-cadherin expression in the ruminant central nervous system is weak, only very locally restricted and not related to the presence of microabscesses, it is likely that further intracerebral spread is independent of E-cadherin and relies primarily on axonal spread.

Neuropathogenesis of naturally occurring encephalitis caused by Listeria monocytogenes in ruminants

Listeriosis is a serious food-borne disease with increasing frequency in humans and ruminants. Despite the facts that in both hosts, listeriosis can occur as rhombencephalitis and ruminants are a reservoir of Listeria monocytogenes (LM) strains pathogenic for humans, little work has been done on the pathogenesis in ruminants. This study investigates the neuropathogenesis of listeric encephalitis in over 200 natural cases in cattle, sheep and goats by analyzing anatomical distribution, severity, bacterial load and temporal evolution of the lesions. Our results suggest that LM gains access to the brainstem of all three species via axonal migration not only along the trigeminal nerve, but also along other nerves. The ensuing encephalitis does not remain restricted to the brainstem. Rather, LM spreads further from the brainstem into rostral brain regions likely by intracerebral axonal migration. Significant differences in severity of the lesions and bacterial load were found between cattle and small ruminants, which may be caused by species-specific properties of antibacterial immune responses. As histopathological lesions of human rhombencephalitis caused by LM strongly resemble those of ruminants, the disease likely has a similar pathogenesis in both hosts.

Suspected paradoxical nerve root signature in a dog with right-sided intervertebral lumbar disk extrusion: a case report

A 7 year old male mongrel dog was presented with a 3 weeks history of gait disturbance in the pelvic limbs more pronounced on the left side associated with pain in the lumbar spine. At presentation neurologic deficits consisted of mild bilateral proprioceptive deficits and nerve root signature in the left pelvic limb. A large intervertebral disc herniation L3-L4 located in a right ventrolateral area of the spinal canal was diagnosed by magnetic resonance imaging. The herniated disc was removed through right hemilaminectomy and fenestration. The dog recovered quickly and returned to the owners 4 days after surgery with a slight lameness in the left pelvic limb. On the follow-up examination 2 months later the dog showed normal gait and normal neurological examination. Nerve root signature is not always indicative for the side of the lesion in case of lateralized intervertebral disc herniation

Cortico-cortical white matter motor pathway microstructure is related to psychomotor retardation in major depressive disorder

Alterations of brain structure and function have been associated with psychomotor retardation in major depressive disorder (MDD). However, the association of motor behaviour and white matter integrity of motor pathways in MDD is unclear. The aim of the present study was to first investigate structural connectivity of white matter motor pathways in MDD. Second, we explore the relation of objectively measured motor activity and white matter integrity of motor pathways in MDD. Therefore, 21 patients with MDD and 21 healthy controls matched for age, gender, education and body mass index underwent diffusion tensor imaging and 24 hour actigraphy (measure of the activity level) the same day. Applying a probabilistic fibre tracking approach we extracted connection pathways between the dorsolateral prefrontal cortex (dlPFC), the rostral anterior cingulate cortex (rACC), the pre-supplementary motor area (pre-SMA), the SMA-proper, the primary motor cortex (M1), the caudate nucleus, the putamen, the pallidum and the thalamus. Patients had lower activity levels and demonstrated increased mean diffusivity (MD) in pathways linking left pre-SMA and SMA-proper, and right SMA-proper and M1. Exploratory analyses point to a positive association of activity level and mean-fractional anisotropy in the right rACC-pre-SMA connection in MDD. Only MDD patients with low activity levels had a negative linear association of activity level and mean-MD in the left dlPFC-pre-SMA connection. Our results point to structural alterations of cortico-cortical white matter motor pathways in MDD. Altered white matter organisation of rACC-pre-SMA and dlPFC-pre-SMA pathways may contribute to movement initiation in MDD.

Altered cortico-basal ganglia motor pathways reflect reduced volitional motor activity in schizophrenia

Little is known about the neurobiology of hypokinesia in schizophrenia. Therefore, the aim of this study was to investigate alterations of white matter motor pathways in schizophrenia and to relate our findings to objectively measured motor activity. We examined 21 schizophrenia patients and 21 healthy controls using diffusion tensor imaging and actigraphy. We applied a probabilistic fibre tracking approach to investigate pathways connecting the dorsolateral prefrontal cortex (dlPFC), the rostral anterior cingulate cortex (rACC), the pre-supplementary motor area (pre-SMA), the supplementary motor area proper (SMA-proper), the primary motor cortex (M1), the caudate nucleus, the striatum, the pallidum and the thalamus. Schizophrenia patients had lower activity levels than controls. In schizophrenia we found higher probability indices forming part of a bundle of interest (PIBI) in pathways connecting rACC, pre-SMA and SMA-proper as well as in pathways connecting M1 and pre-SMA with caudate nucleus, putamen, pallidum and thalamus and a reduced spatial extension of motor pathways in schizophrenia. There was a positive correlation between PIBI and activity level in the right pre-SMA-pallidum and the left M1-thalamus connection in healthy controls, and in the left pre-SMA-SMA-proper pathway in schizophrenia. Our results point to reduced volitional motor activity and altered motor pathway organisation in schizophrenia. The identified associations between the amount of movement and structural connectivity of motor pathways suggest dysfunction of cortico-basal ganglia pathways in the pathophysiology of hypokinesia in schizophrenia. Schizophrenia patients may use cortical pathways involving the supplementary motor area to compensate for basal ganglia dysfunction.

Subcortical electrostimulation to identify network subserving motor control

Objectives: Recent anatomical-functional studies have transformed our understanding of cerebral motor control away from a hierarchical structure and toward parallel and interconnected specialized circuits. Subcortical electrical stimulation during awake surgery provides a unique opportunity to identify white matter tracts involved in motor control. For the first time, this study reports the findings on motor modulatory responses evoked by subcortical stimulation and investigates the cortico-subcortical connectivity of cerebral motor control. Experimental design: Twenty-one selected patients were operated while awake for frontal, insular, and parietal diffuse low-grade gliomas. Subcortical electrostimulation mapping was used to search for interference with voluntary movements. The corresponding stimulation sites were localized on brain schemas using the anterior and posterior commissures method. Principal observations: Subcortical negative motor responses were evoked in 20/21 patients, whereas acceleration of voluntary movements and positive motor responses were observed in three and five patients, respectively. The majority of the stimulation sites were detected rostral of the corticospinal tract near the vertical anterior-commissural line, and additional sites were seen in the frontal and parietal white matter. Conclusions: The diverse interferences with motor function resulting in inhibition and acceleration imply a modulatory influence of the detected fiber network. The subcortical stimulation sites were distributed veil-like, anterior to the primary motor fibers, suggesting descending pathways originating from premotor areas known for negative motor response characteristics. Further stimulation sites in the parietal white matter as well as in the anterior arm of the internal capsule indicate a large-scale fronto-parietal motor control network. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.