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1.
J Neurochem ; 157(4): 1182-1195, 2021 05.
Article in English | MEDLINE | ID: mdl-33030215

ABSTRACT

The Nucleus Basalis of Meynert (NBM) is the main source of cholinergic neurons in the basal forebrain to be crucially involved in cognitive functions and whose degeneration correlates with cognitive decline in major degenerative pathologies as Alzheimer's and Parkinson's diseases. However, knowledge concerning NBM neurons derived from human brain is very limited to date. We recently characterized a primary culture of proliferating neuroblasts isolated from the human fetal NBM (hfNBM) as immature cholinergic neurons expressing the machinery to synthetize and release acetylcholine. Here we studied in detail electrophysiological features and cholinergic effects in this cell culture by patch-clamp recordings. Our data demonstrate that atropine-blocked muscarinic receptor activation by acetylcholine or carbachol enhanced IK and reduced INa currents by stimulating Gi -coupled M2 or phospholipase C-coupled M3 receptors, respectively. Inhibition of acetylcholine esterase activity by neostigmine unveiled a spontaneous acetylcholine release from hfNBM neuroblasts that might account for an autocrine/paracrine signaling during human brain development. Present data provide the first description of cholinergic effects in human NBM neurons and point to a role of acetylcholine as an autocrine/paracrine modulator of voltage-dependent channels. Our research could be of relevance in understanding the mechanisms of cholinergic system development and functions in the human brain, either in health or disease.


Subject(s)
Acetylcholine/metabolism , Action Potentials/physiology , Basal Forebrain/metabolism , Cholinergic Neurons/metabolism , Neural Stem Cells/metabolism , Basal Nucleus of Meynert/metabolism , Cells, Cultured , Fetus , Humans , Signal Transduction/physiology
2.
Int J Mol Sci ; 21(17)2020 Aug 25.
Article in English | MEDLINE | ID: mdl-32854421

ABSTRACT

TNFα is the main proinflammatory cytokine implicated in the pathogenesis of neurodegenerative disorders, but it also modulates physiological functions in both the developing and adult brain. In this study, we investigated a potential direct role of TNFα in determining phenotypic changes of a recently established cellular model of human basal forebrain cholinergic neuroblasts isolated from the nucleus basalis of Meynert (hfNBMs). Exposing hfNBMs to TNFα reduced the expression of immature markers, such as nestin and ß-tubulin III, and inhibited primary cilium formation. On the contrary, TNFα increased the expression of TNFα receptor TNFR2 and the mature neuron marker MAP2, also promoting neurite elongation. Moreover, TNFα affected nerve growth factor receptor expression. We also found that TNFα induced the expression of DNA-methylation enzymes and, accordingly, downregulated genes involved in neuronal development through epigenetic mechanisms, as demonstrated by methylome analysis. In summary, TNFα showed a dual role on hfNBMs phenotypic plasticity, exerting a negative influence on neurogenesis despite a positive effect on differentiation, through mechanisms that remain to be elucidated. Our results help to clarify the complexity of TNFα effects in human neurons and suggest that manipulation of TNFα signaling could provide a potential therapeutic approach against neurodegenerative disorders.


Subject(s)
Basal Forebrain/cytology , Basal Nucleus of Meynert/cytology , DNA Methylation , Tumor Necrosis Factor-alpha/metabolism , Basal Forebrain/drug effects , Basal Forebrain/metabolism , Basal Nucleus of Meynert/drug effects , Basal Nucleus of Meynert/metabolism , Cell Line , Cholinergic Neurons/cytology , Cholinergic Neurons/metabolism , DNA Methylation/drug effects , Epigenesis, Genetic/drug effects , Humans , Microtubule-Associated Proteins/genetics , Nerve Tissue Proteins/genetics , Neuronal Plasticity/drug effects , Receptors, Nerve Growth Factor/genetics , Receptors, Tumor Necrosis Factor, Type II/genetics , Tumor Necrosis Factor-alpha/pharmacology , Whole Genome Sequencing
4.
Acta Neurochir Suppl ; 125: 235-240, 2019.
Article in English | MEDLINE | ID: mdl-30610327

ABSTRACT

BACKGROUND: The transoral approach provides the most direct surgical corridor for treatment of congenital bony abnormalities that exert irreducible ventral compression of the cervicomedullary junction. In this paper, based on our experience with the transoral approach over the past three decades, we briefly describe the surgical strategies and the operative nuances that allow effective decompression of the craniovertebral junction (CVJ) while minimizing postoperative morbidity. METHODS: The surgical strategy is dictated by the type and severity of the malformation. Fibre-optic nasotracheal intubation obviates the necessity of preoperative tracheostomy, and avoidance of a soft-palate incision significantly reduces oropharyngeal morbidity. When feasible, the atlas-sparing technique minimizes postoperative instability. The transoral transatlas approach is generally required in patients with severe basilar invagination and allows wider exposure of the anterior CVJ at the price of a higher incidence of postoperative instability. CONCLUSION: The transoral approach is extremely effective in providing excellent decompression of the anterior cervicomedullary junction in patients with fixed malformations. Tailoring the approach to the peculiar anatomy of each malformation reduces iatrogenic instability and minimizes postoperative complications.


Subject(s)
Neuroendoscopy/methods , Cervical Atlas/surgery , Cervical Vertebrae/abnormalities , Cervical Vertebrae/surgery , Decompression, Surgical/adverse effects , Decompression, Surgical/methods , Humans , Joint Instability/etiology , Joint Instability/prevention & control , Mouth/surgery , Neuroendoscopy/adverse effects , Neurosurgical Procedures/adverse effects , Neurosurgical Procedures/methods , Odontoid Process/surgery , Skull/abnormalities , Skull/surgery
5.
Acta Neurochir Suppl ; 125: 273-277, 2019.
Article in English | MEDLINE | ID: mdl-30610333

ABSTRACT

BACKGROUND: Distraction of the C1-C2 joint and maintenance thereof by introduction of spacers into the articular cavity can successfully and durably reduce basilar invagination (BI). Thus, with the adjunct of instrumented fusion and decompression, BI-induced myelopathy can be efficiently treated with a one-stage posterior approach. This intervention is technically challenging, and in this paper we describe a procedural variation to facilitate the approach. METHODS AND RESULTS: Through a description of a case of BI, the main anatomopathological alteration underlying and perpetrating the condition of BI is elucidated. A technique of realignment of BI is then described in which this alteration is specifically targeted and neutralized. The result is a single-stage posterior-only approach with decompression, C1-C2 distraction and introduction of poly(methyl methacrylate) (PMMA) into the joint cavity. Instrumented occipitocervical fusion completes the procedure. CONCLUSION: C1-C2 joint distraction is a technically demanding procedure. By providing a modification of the original technique and a detailed description of the crucial steps necessary to successfully and safely carry it out, we hope to make this excellent procedure more approachable.


Subject(s)
Atlanto-Axial Joint/surgery , Bone Malalignment/surgery , Cervical Vertebrae/surgery , Neurosurgical Procedures/methods , Skull Base/surgery , Spinal Fusion/methods , Axis, Cervical Vertebra/surgery , Cervical Atlas/surgery , Cervical Vertebrae/abnormalities , Decompression, Surgical/methods , Foramen Magnum/abnormalities , Foramen Magnum/surgery , Humans , Odontoid Process/abnormalities , Odontoid Process/surgery , Skull Base/abnormalities
7.
Mol Cell Neurosci ; 75: 50-62, 2016 09.
Article in English | MEDLINE | ID: mdl-27370937

ABSTRACT

Over the past decades, studies in both Huntington's disease animal models and pilot clinical trials have demonstrated that replacement of degenerated striatum and repair of circuitries by grafting fetal striatal primordium is feasible, safe and may counteract disease progression. However, a better comprehension of striatal ontogenesis is required to assess the fetal graft regenerative potential. During neuronal development, neurotrophins exert pleiotropic actions in regulating cell fate and synaptic plasticity. In this regard, brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF2) are crucially implicated in the control of fate choice of striatal progenitor cells. In this study, we intended to refine the functional features of human striatal precursor (HSP) cells isolated from ganglionic eminence of 9-12week old human fetuses, by studying with electrophysiological methods the effect of BDNF and FGF2 on the membrane biophysical properties and the voltage-dependent Ca(2+) currents. These features are particularly relevant to evaluate neuronal cell functioning and can be considered reliable markers of the developmental phenotype of human striatal primordium. Our results have demonstrated that BDNF and FGF2 induced membrane hyperpolarization, increased the membrane capacitance and reduced the resting total and specific conductance values, suggesting a more efficient control of resting ionic fluxes. Moreover, the treatment with both neurotrophins enhanced N-type Ca(2+) current amplitude and reduced L- and T-type ones. Overall, our data indicate that BDNF and FGF2 may help HSP cells to attain a more functionally mature phenotype.


Subject(s)
Action Potentials , Brain-Derived Neurotrophic Factor/pharmacology , Calcium Channels/metabolism , Corpus Striatum/physiology , Fibroblast Growth Factor 2/pharmacology , Neural Stem Cells/physiology , Neurogenesis , Cells, Cultured , Corpus Striatum/cytology , Corpus Striatum/embryology , Humans , Neural Stem Cells/drug effects
12.
Br J Neurosurg ; 29(3): 440-2, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25958958

ABSTRACT

We give a case study demonstration, using aqueductal cerebrospinal fluid (CSF) stroke volume quantification with phase-contrast magnetic resonance imaging, of a large opening in the rigid cranium by a decompressive craniectomy and its subsequent closure by bone flap repositioning resulted in the arrest and subsequent restoration of aqueductal CSF flow.


Subject(s)
Cerebral Aqueduct/surgery , Cerebral Ventricles/surgery , Decompressive Craniectomy , Hydrocephalus/surgery , Contrast Media , Decompressive Craniectomy/methods , Humans , Hydrocephalus/diagnosis , Magnetic Resonance Imaging/methods , Male , Young Adult
14.
J Neurol Neurosurg Psychiatry ; 85(9): 974-81, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24347577

ABSTRACT

OBJECTIVE: To assess the clinical effect of caudate-putaminal transplantation of fetal striatal tissue in Huntington's disease (HD). METHODS: We carried out a follow-up study on 10 HD transplanted patients and 16 HD not-transplanted patients. All patients were evaluated with the Unified HD Rating Scale (UHDRS) whose change in motor, cognitive, behavioural and functional capacity total scores were considered as outcome measures. Grafted patients also received morphological and molecular neuroimaging. RESULTS: Patients were followed-up from disease onset for a total of 309.3 person-years (minimum 5.3, median 11.2 years, maximum 21.6 years). UHDRS scores have been available since 2004 (median time of 5.7 years since onset, minimum zero, maximum 17.2 years). Median post-transplantation follow-up was 4.3 years, minimum 2.8, maximum 5.1 years. Adjusted post-transplantation motor score deterioration rate was reduced compared to the pretransplantation period, and to that of not-transplanted patients by 0.9 unit/years (95% CI 0.2 to 1.6). Cognitive score deterioration was reduced of 2.7 unit/years (95% CI 0.1 to 5.3). For grafted patients the 2-year post-transplantation [(18)F]fluorodeoxyglucose positron emission tomography (PET) showed striatal/cortical metabolic increase compared to the presurgical evaluation; 4-year post-transplantation PET values were slightly decreased, but remained higher than preoperatively. [(123)I]iodobenzamide single photon emission CT demonstrated an increase in striatal D2-receptor density during postgrafting follow-up. CONCLUSIONS: Grafted patients experienced a milder clinical course with less pronounced motor/cognitive decline and associated brain metabolism improvement. Life-time follow-up may ultimately clarify whether transplantation permanently modifies the natural course of the disease, allowing longer sojourn time at less severe clinical stage, and improvement of overall survival.


Subject(s)
Brain Tissue Transplantation , Corpus Striatum/surgery , Fetal Tissue Transplantation , Huntington Disease/physiopathology , Huntington Disease/therapy , Adult , Cerebral Cortex/metabolism , Corpus Striatum/metabolism , Female , Fluorodeoxyglucose F18 , Follow-Up Studies , Functional Neuroimaging , Humans , Huntington Disease/metabolism , Huntington Disease/psychology , Iodobenzenes , Male , Middle Aged , Neuropsychological Tests , Positron-Emission Tomography , Receptors, Dopamine D2/metabolism , Treatment Outcome
15.
Stereotact Funct Neurosurg ; 92(4): 211-7, 2014.
Article in English | MEDLINE | ID: mdl-25096235

ABSTRACT

BACKGROUND: Restoration of functions in Huntington's disease (HD) by neurotransplantation stems from the formation of a striatum-like structure capable of establishing host connections as a result of grafted striatal neuroblast maturation. For the first time, we demonstrated some developmental steps accomplished by progenitor cells in the brain of an HD patient and analysed the molecular asset of the human primordium. CASE REPORT: Surgery involved bilateral (two sessions) stereotactic, caudate-putaminal transplantation of whole ganglionic eminence fragments from single legally aborted fetuses. MRI showed that the tissue deposits of the left hemisphere grew and joined to constitute a single tissue mass that remodelled basal ganglia anatomy and remained stable in size over time. No evidence of graft growth was observed contralaterally. PET demonstrated increased striatal and stable cortical metabolism. Unified Huntington's Disease Rating Scale assessments demonstrated improvement of motor performances, which faded over the 36-month follow-up. Cognitive performance tended to decrease at a lower rate than before transplantation. CONCLUSION: The striatal primordium grew into the host brain and this process was associated with metabolic change and some clinical benefit. The study suggests the plasticity and reparative potential of un-manipulated primordium in an era where promising cell-based therapies are still in their infancy.


Subject(s)
Brain Tissue Transplantation , Corpus Striatum/pathology , Fetal Tissue Transplantation , Huntington Disease/surgery , Neuronal Plasticity , Telencephalon/transplantation , Adult , Brain Tissue Transplantation/methods , Central Nervous System Agents/therapeutic use , Cognition Disorders/etiology , Combined Modality Therapy , Corpus Striatum/diagnostic imaging , Fetal Tissue Transplantation/methods , Follow-Up Studies , Gene Expression Profiling , Graft Survival , Humans , Huntington Disease/drug therapy , Huntington Disease/pathology , Huntington Disease/psychology , Italy , Magnetic Resonance Imaging , Male , Neuroimaging , Positron-Emission Tomography , Robotics , Severity of Illness Index , Stereotaxic Techniques , Telencephalon/embryology , Telencephalon/metabolism
16.
Sci Rep ; 14(1): 12966, 2024 06 05.
Article in English | MEDLINE | ID: mdl-38839864

ABSTRACT

The inflow of CSF into perivascular spaces (PVS) in the brain is crucial for clearing waste molecules. Inefficiency in PVS flow leads to neurodegeneration. Failure of PVS flushing is associated with CSF flow impairment in the intracranial hydrodynamic condition of CSF hypo-pulsatility. However, enlarged PVS (ePVS), a finding indicative of PVS flow dysfunction, is also present in patients with derangement of CSF dynamics characterized by CSF hyper-pulsatility, which increases CSF flow. Intriguingly, two opposite intracranial hydrodynamic conditions would lead to the same result of impairing the PVS flushing. To investigate this issue, we assessed the subsistence of a dysfunctional interplay between CSF and PVS flows and, if the case, the mechanisms preventing a hyper-pulsatile brain from providing an effective PVS flushing. We analyzed the association between phase contrast MRI aqueductal CSF stroke volume (aqSV), a proxy of CSF pulsatility, and the burden of ePVS in chronic adult hydrocephalus, a disease involving a broad spectrum of intracranial hydrodynamics disturbances. In the 147 (85 males, 62 females) patients, the age at diagnosis ranged between 28 and 88 years (median 73 years). Ninety-seven patients had tri-ventriculomegaly and 50 tetra-ventriculomegaly. According to the extent of ePVS, 113 patients had a high ePVS burden, while 34 had a low ePVS burden. aqSV, which ranged between 0 and 562 µL (median 86 µL), was increased with respect to healthy subjects. Patients presenting with less ePVS burden had higher aqSV (p < 0.002, corrected for the multiple comparisons) than those with higher ePVS burden. The present study confirmed the association between CSF dynamics and PVS flow disturbances and demonstrated this association in intracranial hyper-pulsatility. Further studies should investigate the association between PVS flow failure and CSF hypo- and hyper-pulsatility as responsible/co-responsible for glymphatic failure in other neurodegenerative diseases, particularly in diseases in which CSF disturbances can be corrected, as in chronic adult hydrocephalus.


Subject(s)
Glymphatic System , Hydrocephalus , Magnetic Resonance Imaging , Humans , Hydrocephalus/cerebrospinal fluid , Hydrocephalus/physiopathology , Hydrocephalus/pathology , Male , Female , Aged , Middle Aged , Adult , Glymphatic System/physiopathology , Glymphatic System/pathology , Aged, 80 and over , Cerebrospinal Fluid , Hydrodynamics , Stroke Volume , Cerebral Aqueduct/pathology , Cerebral Aqueduct/physiopathology , Chronic Disease
17.
Front Neurosci ; 16: 863117, 2022.
Article in English | MEDLINE | ID: mdl-36389221

ABSTRACT

The derangement of CSF circulation impacts the functions of the glymphatic-lymphatic system (G-Ls), which regulates solute trafficking and immune surveillance in the CNS. The G-Ls failure leads to the dysregulation of clearance of waste molecules in the brain and to an altered CNS immune response. The imaging features of dilated perivascular spaces imply the impairment of the G-Ls. We report on the case of a patient with primary progressive multiple sclerosis and dilatation of perivascular spaces, who transiently improved after CSF shunt diversions. The underlying mechanisms remain to be determined and at this stage, it is not possible to link CSF diversion to an effect on MS pathology. However, this observation provides the rationale to incentivize research in the largely unknown area of CSF dynamic disturbances on G-Ls failure and ultimately in neurodegeneration.

18.
Sci Rep ; 11(1): 7095, 2021 03 29.
Article in English | MEDLINE | ID: mdl-33782441

ABSTRACT

CSF shunting with adjustable valve is the treatment of idiopathic normal pressure hydrocephalus. The opening pressure valve setting is left to the neurosurgeon's experience. Aqueductal CSF stroke volume by phase-contrast magnetic resonance measures the CSF passing through the Sylvian aqueduct and it changes with intracranial hydrodynamics. We sought to identify a window of stroke volume differences associated with the best clinical outcome and lowest rate of complications. The records of 69 patients were reviewed. At every clinical check, stroke volume, opening pressure valve, clinical outcome, and CSF overdrainage were analyzed. The correlation between stroke volume differences and negative outcome was also analyzed. The median follow-up was 2.3 years (range 0.3-10.4 years). The odds of negative outcome between two consecutive checks significantly increased by 16% (95%CI 4-28%, p = 0.006). Taking the lowest risk group as reference, the odds ratio of negative outcome was 1.16 (95%CI 0.51-2.63, p = 0.726) for SV differences less than - 37.6 µL, while it was 1.96 (95%CI 0.97-3.98, p = 0.062) for stroke volume changes above + 23.1 µL. Maintaining stroke volume values within a definite range might help maximize clinical benefit and avoid the risk of CSF overdrainage.


Subject(s)
Cerebral Aqueduct/physiopathology , Hydrocephalus, Normal Pressure/physiopathology , Hydrocephalus, Normal Pressure/therapy , Stroke Volume , Adult , Female , Humans , Male , Middle Aged
19.
J Neurol Surg A Cent Eur Neurosurg ; 82(2): 166-168, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33260246

ABSTRACT

Ventriculoperitoneal shunt (VPS) is a well-known procedure in the neurosurgical field. However, it has high complication and reoperation rates. Abdominal pseudocyst (APC) formation is a rare complication of VPS with reports in the literature varying from 4 to 10%. In this article, we report a simple and effective technique, with no additional cost, to avoid APC formation by making small multiple slits along the length of the peritoneal catheter.


Subject(s)
Catheters/adverse effects , Cysts/prevention & control , Peritoneal Cavity/surgery , Ventriculoperitoneal Shunt/adverse effects , Cysts/etiology , Cysts/surgery , Humans , Reoperation
20.
Neurol Sci ; 31(3): 283-91, 2010 Jun.
Article in English | MEDLINE | ID: mdl-19936883

ABSTRACT

The aim of our pilot study was to investigate, by a proteomic approach, the expressed differences in cerebrospinal fluid (CSF) protein patterns in order to aid in the diagnosis and treatment of normal pressure hydrocephalus (NPH). Seventeen patients with NPH, selected by Intracranial-Pressure monitoring (ICPmo), underwent implantation of a shunt and after 6 months were clinically re-evaluated. Thirteen patients improved, whereas four did not. During ICPmo CSF was collected and its proteoma was analyzed by 2D gel electrophoresis and mass spectrometry. The over-expression of alpha2HS glycoprotein, alpha1 antichimotrypsin and alpha1beta glycoprotein and the under-expression of glial fibrillary acidic protein, apolipoproteins (AIV, J and E), complement C3c, anti-thrombin, alpha2 antiplasmin and albumin seem to be associated with a positive response to surgery. Most of these proteins have been reported to be altered in Alzheimer disease, supporting the hypothesis of a possible link between these two nosological entities.


Subject(s)
Cerebrospinal Fluid Shunts , Hydrocephalus, Normal Pressure/cerebrospinal fluid , Hydrocephalus, Normal Pressure/surgery , Aged , Biomarkers/cerebrospinal fluid , Electrophoresis, Gel, Two-Dimensional , Female , Follow-Up Studies , Humans , Hydrocephalus, Normal Pressure/diagnosis , Intracranial Pressure , Male , Patient Selection , Peptide Mapping , Pilot Projects , Proteome , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Time Factors , Treatment Outcome
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