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Papers by Marco Sparaco

Research paper thumbnail of Primary myxopapillary ependymoma of the cerebellopontine angle: report of a case

Neurosurgical Review, 2008

Myxopapillary ependymoma is a rare variant of ependymoma, almost exclusively occurring in the reg... more Myxopapillary ependymoma is a rare variant of ependymoma, almost exclusively occurring in the region of the cauda equina and filum terminale. We describe a myxopapillary ependymoma located in the left cerebellopontine angle of a young man suffering from peripheral vertigo and left sensorineural hearing loss for years. The patient underwent surgical removal of the tumour. Microscopic examination showed histological and immunohistochemical features consistent with a diagnosis of myxopapillary ependymoma. Imaging studies of the spine yielded normal findings, confirming the lesion's primary nature. To the best of our knowledge, this is the first case of primary intracranial myxopapillary ependymoma described in this location.

Research paper thumbnail of Delayed spongiform leukoencephalopathy after heroin abuse

Acta Neuropathologica, 1997

Here we report the clinical and pathological findings in a 30-year-old drug addict in whom an int... more Here we report the clinical and pathological findings in a 30-year-old drug addict in whom an intravenous injection of heroin led to reversible coma with respiratory depression and heart failure. On regaining consciousness, the patient was found to have rhabdomyolysis with renal failure requiring dialysis and peripheral neuropathy. Three weeks later his neurological condition suddenly deteriorated and delayed encephalopathy developed, leading to death 20 days later. The neuropathological study of the brain disclosed pale, spongy myelin with diffuse reactive astrogliosis and microglial proliferation, without hypoxic necrotic lesions. The cerebral and cerebellar cortices were unchanged. The absence of typical hypoxic lesions and the presence of spongiosis with massive astrocytosis distinguished this case from the previously reported cases of delayed leukoencephalopathy following severe hypoxia. An immunocytochemical study designed to exclude an underlying alteration of the metabolic oxidative pathway detected normal expression of the respiratory chain complexes IV, III and V. Despite the absence of an oxidative chain alteration in our patient, we cannot exclude the possibility that an individual predisposition played a pathogenetic role in this delayed leukoencephalopathy.

Research paper thumbnail of Cerebral Venous Thrombosis and Headache - A Case-Series

Headache, 2015

Headache happens in the majority of patients with Cerebral Venous Thrombosis (CVT) being sometime... more Headache happens in the majority of patients with Cerebral Venous Thrombosis (CVT) being sometimes the sole manifestation of the disease. Herein we report a case-series of CVT, focusing on headache characteristics. Etiological, clinical, and radiological features of 25 consecutive adult patients with CVT were compiled from August 2005 to December 2013. Diagnosis of CVT was confirmed by brain magnetic resonance imaging and magnetic resonance venography. All patients underwent extensive systematic etiological and genetic work-up at admission. A structured questionnaire about the characteristics of headache was responded by all participants. Headache was reported by 23 out of 25 (92%) of participants, being by far the most frequent symptom. It was the sole manifestation in nearly one third of the patients (8/25, 32.0%). Headache was typically severe (19/23, 82.6%) and throbbing (16/23, 69.5%), with sudden onset (13/23, 56.5%) and non-remitting (20/23, 86.9%) characteristics. The sinus ...

Research paper thumbnail of www.mdpi.com/journal/ijms Article Frataxin Silencing Inactivates Mitochondrial Complex I in

Abstract: Friedreich’s ataxia (FRDA) is a hereditary neurodegenerative disease characterized by a... more Abstract: Friedreich’s ataxia (FRDA) is a hereditary neurodegenerative disease characterized by a reduced synthesis of the mitochondrial iron chaperon protein frataxin as a result of a large GAA triplet-repeat expansion within the first intron of the frataxin gene. Despite neurodegeneration being the prominent feature of this pathology involving both the central and the peripheral nervous system, information on the impact of frataxin deficiency in neurons is scant. Here, we describe a neuronal model displaying some major biochemical and morphological features of FRDA. By silencing the mouse NSC34 motor neurons for the frataxin gene with shRNA lentiviral vectors, we generated two cell lines with 40 % and 70 % residual amounts of frataxin, respectively. Frataxin-deficient cells

Research paper thumbnail of Posterior circulation ischaemic stroke—a review part I: anatomy, aetiology and clinical presentations

Research paper thumbnail of Posterior circulation ischemic stroke—a review part II: imaging and acute treatment

Research paper thumbnail of Basilar Artery Occlusion: Clinical Management and Therapy

Clinical Management Issues

Basilar artery occlusion is a potentially life-threatening subset of the larger category of poste... more Basilar artery occlusion is a potentially life-threatening subset of the larger category of posterior circulation strokes, carrying…

Research paper thumbnail of Immunohistochemical demonstration of spinal ventral horn cells involvement in a case of myoclonus epilepsy with ragged red fibers (MERRF)

Clinical Neuropathology, 2000

To detect mitochondrial lesions in the spinal cord from an autoptic case of myoclonus epilepsy wi... more To detect mitochondrial lesions in the spinal cord from an autoptic case of myoclonus epilepsy with ragged-red fibers (MERRF) that harbored the A8344G mutation and was deemed to be free of pathological abnormalities in the spinal cord after conventional post-mortem examination. Antibodies against subunits of complex III and IV of the respiratory chain were used to perform immunohistochemical analysis on cervical, thoracic and lumbar sections of the spinal cord from the case of MERRF and from controls. Immunostaining was carried out by the avidin-biotin peroxidase complex (ABC) method. A selective decreased expression of subunit II of cytochrome c oxidase (COX-II) was found in all spinal cord sections from the patient. The immunohistochemical demonstration of mitochondrial lesions in the spinal ventral horn cells from this case with MERRF seems to be consistent with the results of many genetic studies pointing to a high and homogeneous distribution of mutant mtDNA in different neuronal populations of patients with this disease. The use of these immunological probes in the study of mitochondrial encephalomyopathies can increase both the resolution and the specificity of morphological observations in the central nervous system (CNS).

Research paper thumbnail of Cerebral Venous Thrombosis and Headache - A Case-Series

Headache, 2015

Headache happens in the majority of patients with Cerebral Venous Thrombosis (CVT) being sometime... more Headache happens in the majority of patients with Cerebral Venous Thrombosis (CVT) being sometimes the sole manifestation of the disease. Herein we report a case-series of CVT, focusing on headache characteristics. Etiological, clinical, and radiological features of 25 consecutive adult patients with CVT were compiled from August 2005 to December 2013. Diagnosis of CVT was confirmed by brain magnetic resonance imaging and magnetic resonance venography. All patients underwent extensive systematic etiological and genetic work-up at admission. A structured questionnaire about the characteristics of headache was responded by all participants. Headache was reported by 23 out of 25 (92%) of participants, being by far the most frequent symptom. It was the sole manifestation in nearly one third of the patients (8/25, 32.0%). Headache was typically severe (19/23, 82.6%) and throbbing (16/23, 69.5%), with sudden onset (13/23, 56.5%) and non-remitting (20/23, 86.9%) characteristics. The sinus ...

Research paper thumbnail of Frataxin Silencing Inactivates Mitochondrial Complex I in NSC34 Motoneuronal Cells and Alters Glutathione Homeostasis

International Journal of Molecular Sciences, 2014

Friedreich's ataxia (FRDA) is a hereditary neurodegenerative disease characterized by a reduced s... more Friedreich's ataxia (FRDA) is a hereditary neurodegenerative disease characterized by a reduced synthesis of the mitochondrial iron chaperon protein frataxin as a result of a large GAA triplet-repeat expansion within the first intron of the frataxin gene. Despite neurodegeneration being the prominent feature of this pathology involving both the central and the peripheral nervous system, information on the impact of frataxin deficiency in neurons is scant. Here, we describe a neuronal model displaying some major biochemical and morphological features of FRDA. By silencing the mouse NSC34 motor neurons for the frataxin gene with shRNA lentiviral vectors, we generated two cell lines with 40% and 70% residual amounts of frataxin, respectively. Frataxin-deficient cells showed a specific inhibition of mitochondrial Complex I (CI) activity already at 70%

Research paper thumbnail of Primary myxopapillary ependymoma of the cerebellopontine angle: report of a case

Neurosurgical Review, 2009

Myxopapillary ependymoma is a rare variant of ependymoma, almost exclusively occurring in the reg... more Myxopapillary ependymoma is a rare variant of ependymoma, almost exclusively occurring in the region of the cauda equina and filum terminale. We describe a myxopapillary ependymoma located in the left cerebellopontine angle of a young man suffering from peripheral vertigo and left sensorineural hearing loss for years. The patient underwent surgical removal of the tumour. Microscopic examination showed histological and immunohistochemical features consistent with a diagnosis of myxopapillary ependymoma. Imaging studies of the spine yielded normal findings, confirming the lesion's primary nature. To the best of our knowledge, this is the first case of primary intracranial myxopapillary ependymoma described in this location.

Research paper thumbnail of Immunolocalization of heat shock proteins in ragged-red fibers of patients with mitochondrial encephalomyopathies

Neuromuscular Disorders, 1993

A~traet--Monoclonal antibodies against the 60 kDa heat shock protein (HSP-60) and against ubiquit... more A~traet--Monoclonal antibodies against the 60 kDa heat shock protein (HSP-60) and against ubiquitin (UB) were used to study the expression of these proteins in muscle samples from patients with qualitative and quantitative alterations of mitochondrial DNA (mtDNA). We found an enhanced expression of HSP-60 and UB that was preferentially localized in ragged-red fibers (RRFs). HSP-60 may act as a protein repair enzyme catalyzing the refolding of misfolded proteins in the matrix of mitochondria of RRFs. On the other hand, UB could promote the elimination of abnormal proteins by its covalent interaction to substrates.

Research paper thumbnail of The THRombolysis and STatins (THRaST) study

Neurology, 2013

To assess the impact on stroke outcome of statin use in the acute phase after IV thrombolysis. Mu... more To assess the impact on stroke outcome of statin use in the acute phase after IV thrombolysis. Multicenter study on prospectively collected data of 2,072 stroke patients treated with IV thrombolysis. Outcome measures of efficacy were neurologic improvement (NIH Stroke Scale [NIHSS] ≤ 4 points from baseline or NIHSS = 0) and major neurologic improvement (NIHSS ≤ 8 points from baseline or NIHSS = 0) at 7 days and favorable (modified Rankin Scale [mRS] ≤ 2) and excellent functional outcome (mRS ≤ 1) at 3 months. Outcome measures of safety were 7-day neurologic deterioration (NIHSS ≥ 4 points from baseline or death), symptomatic intracerebral hemorrhage type 2 with NIHSS ≥ 4 points from baseline or death within 36 hours, and 3-month death. Adjusted multivariate analysis showed that statin use in the acute phase was associated with neurologic improvement (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.26-2.25; p < 0.001), major neurologic improvement (OR 1.43, 95% CI 1.11-1.85; p = 0.006), favorable functional outcome (OR 1.63, 95% CI 1.18-2.26; p = 0.003), and a reduced risk of neurologic deterioration (OR: 0.31, 95% CI 0.19-0.53; p < 0.001) and death (OR 0.48, 95% CI 0.28-0.82; p = 0.007). Statin use in the acute phase of stroke after IV thrombolysis may positively influence short- and long-term outcome.

Research paper thumbnail of Neuropathology of Mitochondrial Encephalomyopathies Due to Mitochondrial DNA Defects

Journal of Neuropathology and Experimental Neurology, 1993

From the Department of Neurology, College of Physicians and Surgeons of Columbia University, New ... more From the Department of Neurology, College of Physicians and Surgeons of Columbia University, New York, New York (MS, EB, SDM), and the Neuropathology Unit, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester ...

Research paper thumbnail of New Morphological Approaches to the Study of Mitochondrial Encephalomyopathies

Brain Pathology, 1992

Molecular genetics, biochemistry, immunology and morphology, are being applied in a coordinated f... more Molecular genetics, biochemistry, immunology and morphology, are being applied in a coordinated fashion to unveil the molecular basis of the mitochondrial encephalomyopathies. Mutations of mitochondrial DNA (mtDNA) have been found in well characterized clinical groups of these disorders. New and old morphologic methods have been applied to investigate muscle biopsies from patients with mtDNA mutations. Important observations have been made on the cellular localization of normal and mutated mtDNA and on the expression of mtDNA-encoded polypeptides. These observations have provided insight into the pathogenesis of respiratory chain enzyme deficiency at the level of individual muscle fibers. Application of immunocytochemical and in situ hybridization techniques at the electron microscopic level will extend these studies to the level of individual mitochondria.

Research paper thumbnail of Cytochrome C Oxidase Deficiency and Neuronal Involvement in Menkes' Kinky Hair Disease: Immunohistochemical Study

Brain Pathology, 1993

Antibodies against subunits II and IV of cytochrome c oxidase (COX) and against complex III of th... more Antibodies against subunits II and IV of cytochrome c oxidase (COX) and against complex III of the respiratory chain were used to study the expression of these proteins in the cerebellum, spinal cord, and other regions of the central nervous system in an autoptic case of Menkes' kinky hair disease (MKHD). We found a reduced expression of COX subunits in all examined areas whereas staining for complex III appeared normal. Immunostaining was altered in morphologically well-preserved neurons, suggesting that COX deficiency may have a pathogenetic role in the neuronal degeneration of MKHD.

Research paper thumbnail of Myoclonic Epilepsy with Ragged-red Fibers (MERRF): An Immunohistochemical Study of the Brain

Brain Pathology, 1995

Myoclonic epilepsy with ragged-red fibers (MERRFI is a maternally inherited disorder of oxidative... more Myoclonic epilepsy with ragged-red fibers (MERRFI is a maternally inherited disorder of oxidative phosphorylation due to specific point mutations within the mitochondrial tRNALvs gene. Mitochondria1 dysfunction in the central nervous system (CNS) of patients with MERRF accounts for the neurological manifestations of the disease. Antibodies against subunits of complex I, 111, IV and V of the respiratory chain were used to study the expression of these proteins in the frontal cortex, cerebellum and medulla from an autoptic case of MERRF. We found a selective decreased expression of subunit II of cytochrome c oxidase (COX-II) in these regions. lmmunohistochemical abnormalities were more widespread than the lesions described by traditional histopathological techniques and made possible an attempt of explanation for the neurological symptoms of the patient.

Research paper thumbnail of MELAS: clinical phenotype and morphological brain abnormalities

Acta Neuropathologica, 2003

We describe the clinical and neuropathological findings of three unrelated autopsy cases of MELAS... more We describe the clinical and neuropathological findings of three unrelated autopsy cases of MELAS harboring the A3243G transition in the mitochondrial DNA (mtDNA). Using immunohistochemical techniques, we studied the expression of several subunits of the respiratory chain in various brain regions from the same cases. In all three cases there was a reduced immunocytochemical staining for mtDNA-encoded subunits of the respiratory chain, confirming the presence of a defective mitochondrial protein synthesis in this disease. Mitochondrial abnormalities were mostly confined to multiple areas of different size and shape, in agreement with the focal character of the brain pathology in MELAS, and were most prominent in the cerebral cortex, providing a morphological contribution to the explanation of the cognitive regression of the patients. Immunoreactivity for mtDNA-encoded subunits was reduced in the walls of many pial and intracerebral arterioles of different brain regions but there was no clear correlation between territories of affected vessels and distribution of the histological and immunohistochemical lesions. Cerebral focal lesions in MELAS might have a metabolic nature and several pathogenetic mechanisms might be involved in the genesis of stroke-like episodes when there is a local increased ATP demand.

Research paper thumbnail of Effect of protein glutathionylation on neuronal cytoskeleton: a potential link to neurodegeneration

Neuroscience, 2011

Neurons are highly susceptible to oxidative stress and oxidation of cytoskeletal proteins is cons... more Neurons are highly susceptible to oxidative stress and oxidation of cytoskeletal proteins is considered one of the first steps of neurodegeneration. Protein glutathionylation is a key event in the redox regulation of protein function and constitutes a sensor of tissue oxidative stress in pathophysiological conditions. In this study, we analyzed for the first time tubulin glutathionylation and its relation to neurites degeneration. For this purpose, we exposed motoneuronal cells to the physiological oxidant glutathione disulfide (GSSG) and we analyzed the extent and morphology of axonal changes caused by protein glutathionylation in these cells. Then we studied the effect of glutathionylation on the distribution of stable and dynamic microtubules in the same cells. Our results indicate that oxidative stress conditions determined by an increased intracellular level of oxidized glutathione may cause an alteration of the cytoskeleton organization and function leading to axon degeneration. These findings might contribute to understand the sequence of pathogenic events involved in the axonal degeneration that characterizes many diseases of the nervous system associated with oxidative stress.

Research paper thumbnail of Friedreich's ataxia: Oxidative stress and cytoskeletal abnormalities

Journal of the Neurological Sciences, 2009

Friedreich's ataxia (FRDA) is an autosomal recessive disorder caused by mutations in the gene enc... more Friedreich's ataxia (FRDA) is an autosomal recessive disorder caused by mutations in the gene encoding frataxin, a mitochondrial protein implicated in iron metabolism. Current evidence suggests that loss of frataxin causes iron overload in tissues, and increase in free-radical production leading to oxidation and inactivation of mitochondrial respiratory chain enzymes, particularly Complexes I, II, III and aconitase. Glutathione plays an important role in the detoxification of ROS in the Central Nervous System (CNS), where it also provides regulation of protein function by glutathionylation. The cytoskeletal proteins are particularly susceptible to oxidation and appear constitutively glutathionylated in the human CNS. Previously, we showed loss of cytoskeletal organization in fibroblasts of patients with FRDA found to be associated with increased levels of glutathione bound to cytoskeletal proteins. In this study, we analysed the glutathionylation of proteins in the spinal cord of patients with FRDA and the distribution of tubulin and neurofilaments in the same area. We found, for the first time, a significant rise of the dynamic pool of tubulin as well as abnormal distribution of the phosphorylated forms of human neurofilaments in FRDA motor neurons. In the same cells, the cytoskeletal abnormalities co-localized with an increase in protein glutathionylation and the mitochondrial proteins were normally expressed by immunocytochemistry. Our results suggest that in FRDA oxidative stress causes abnormally increased protein glutathionylation leading to prominent abnormalities of the neuronal cytoskeleton.

Research paper thumbnail of Primary myxopapillary ependymoma of the cerebellopontine angle: report of a case

Neurosurgical Review, 2008

Myxopapillary ependymoma is a rare variant of ependymoma, almost exclusively occurring in the reg... more Myxopapillary ependymoma is a rare variant of ependymoma, almost exclusively occurring in the region of the cauda equina and filum terminale. We describe a myxopapillary ependymoma located in the left cerebellopontine angle of a young man suffering from peripheral vertigo and left sensorineural hearing loss for years. The patient underwent surgical removal of the tumour. Microscopic examination showed histological and immunohistochemical features consistent with a diagnosis of myxopapillary ependymoma. Imaging studies of the spine yielded normal findings, confirming the lesion's primary nature. To the best of our knowledge, this is the first case of primary intracranial myxopapillary ependymoma described in this location.

Research paper thumbnail of Delayed spongiform leukoencephalopathy after heroin abuse

Acta Neuropathologica, 1997

Here we report the clinical and pathological findings in a 30-year-old drug addict in whom an int... more Here we report the clinical and pathological findings in a 30-year-old drug addict in whom an intravenous injection of heroin led to reversible coma with respiratory depression and heart failure. On regaining consciousness, the patient was found to have rhabdomyolysis with renal failure requiring dialysis and peripheral neuropathy. Three weeks later his neurological condition suddenly deteriorated and delayed encephalopathy developed, leading to death 20 days later. The neuropathological study of the brain disclosed pale, spongy myelin with diffuse reactive astrogliosis and microglial proliferation, without hypoxic necrotic lesions. The cerebral and cerebellar cortices were unchanged. The absence of typical hypoxic lesions and the presence of spongiosis with massive astrocytosis distinguished this case from the previously reported cases of delayed leukoencephalopathy following severe hypoxia. An immunocytochemical study designed to exclude an underlying alteration of the metabolic oxidative pathway detected normal expression of the respiratory chain complexes IV, III and V. Despite the absence of an oxidative chain alteration in our patient, we cannot exclude the possibility that an individual predisposition played a pathogenetic role in this delayed leukoencephalopathy.

Research paper thumbnail of Cerebral Venous Thrombosis and Headache - A Case-Series

Headache, 2015

Headache happens in the majority of patients with Cerebral Venous Thrombosis (CVT) being sometime... more Headache happens in the majority of patients with Cerebral Venous Thrombosis (CVT) being sometimes the sole manifestation of the disease. Herein we report a case-series of CVT, focusing on headache characteristics. Etiological, clinical, and radiological features of 25 consecutive adult patients with CVT were compiled from August 2005 to December 2013. Diagnosis of CVT was confirmed by brain magnetic resonance imaging and magnetic resonance venography. All patients underwent extensive systematic etiological and genetic work-up at admission. A structured questionnaire about the characteristics of headache was responded by all participants. Headache was reported by 23 out of 25 (92%) of participants, being by far the most frequent symptom. It was the sole manifestation in nearly one third of the patients (8/25, 32.0%). Headache was typically severe (19/23, 82.6%) and throbbing (16/23, 69.5%), with sudden onset (13/23, 56.5%) and non-remitting (20/23, 86.9%) characteristics. The sinus ...

Research paper thumbnail of www.mdpi.com/journal/ijms Article Frataxin Silencing Inactivates Mitochondrial Complex I in

Abstract: Friedreich’s ataxia (FRDA) is a hereditary neurodegenerative disease characterized by a... more Abstract: Friedreich’s ataxia (FRDA) is a hereditary neurodegenerative disease characterized by a reduced synthesis of the mitochondrial iron chaperon protein frataxin as a result of a large GAA triplet-repeat expansion within the first intron of the frataxin gene. Despite neurodegeneration being the prominent feature of this pathology involving both the central and the peripheral nervous system, information on the impact of frataxin deficiency in neurons is scant. Here, we describe a neuronal model displaying some major biochemical and morphological features of FRDA. By silencing the mouse NSC34 motor neurons for the frataxin gene with shRNA lentiviral vectors, we generated two cell lines with 40 % and 70 % residual amounts of frataxin, respectively. Frataxin-deficient cells

Research paper thumbnail of Posterior circulation ischaemic stroke—a review part I: anatomy, aetiology and clinical presentations

Research paper thumbnail of Posterior circulation ischemic stroke—a review part II: imaging and acute treatment

Research paper thumbnail of Basilar Artery Occlusion: Clinical Management and Therapy

Clinical Management Issues

Basilar artery occlusion is a potentially life-threatening subset of the larger category of poste... more Basilar artery occlusion is a potentially life-threatening subset of the larger category of posterior circulation strokes, carrying…

Research paper thumbnail of Immunohistochemical demonstration of spinal ventral horn cells involvement in a case of myoclonus epilepsy with ragged red fibers (MERRF)

Clinical Neuropathology, 2000

To detect mitochondrial lesions in the spinal cord from an autoptic case of myoclonus epilepsy wi... more To detect mitochondrial lesions in the spinal cord from an autoptic case of myoclonus epilepsy with ragged-red fibers (MERRF) that harbored the A8344G mutation and was deemed to be free of pathological abnormalities in the spinal cord after conventional post-mortem examination. Antibodies against subunits of complex III and IV of the respiratory chain were used to perform immunohistochemical analysis on cervical, thoracic and lumbar sections of the spinal cord from the case of MERRF and from controls. Immunostaining was carried out by the avidin-biotin peroxidase complex (ABC) method. A selective decreased expression of subunit II of cytochrome c oxidase (COX-II) was found in all spinal cord sections from the patient. The immunohistochemical demonstration of mitochondrial lesions in the spinal ventral horn cells from this case with MERRF seems to be consistent with the results of many genetic studies pointing to a high and homogeneous distribution of mutant mtDNA in different neuronal populations of patients with this disease. The use of these immunological probes in the study of mitochondrial encephalomyopathies can increase both the resolution and the specificity of morphological observations in the central nervous system (CNS).

Research paper thumbnail of Cerebral Venous Thrombosis and Headache - A Case-Series

Headache, 2015

Headache happens in the majority of patients with Cerebral Venous Thrombosis (CVT) being sometime... more Headache happens in the majority of patients with Cerebral Venous Thrombosis (CVT) being sometimes the sole manifestation of the disease. Herein we report a case-series of CVT, focusing on headache characteristics. Etiological, clinical, and radiological features of 25 consecutive adult patients with CVT were compiled from August 2005 to December 2013. Diagnosis of CVT was confirmed by brain magnetic resonance imaging and magnetic resonance venography. All patients underwent extensive systematic etiological and genetic work-up at admission. A structured questionnaire about the characteristics of headache was responded by all participants. Headache was reported by 23 out of 25 (92%) of participants, being by far the most frequent symptom. It was the sole manifestation in nearly one third of the patients (8/25, 32.0%). Headache was typically severe (19/23, 82.6%) and throbbing (16/23, 69.5%), with sudden onset (13/23, 56.5%) and non-remitting (20/23, 86.9%) characteristics. The sinus ...

Research paper thumbnail of Frataxin Silencing Inactivates Mitochondrial Complex I in NSC34 Motoneuronal Cells and Alters Glutathione Homeostasis

International Journal of Molecular Sciences, 2014

Friedreich's ataxia (FRDA) is a hereditary neurodegenerative disease characterized by a reduced s... more Friedreich's ataxia (FRDA) is a hereditary neurodegenerative disease characterized by a reduced synthesis of the mitochondrial iron chaperon protein frataxin as a result of a large GAA triplet-repeat expansion within the first intron of the frataxin gene. Despite neurodegeneration being the prominent feature of this pathology involving both the central and the peripheral nervous system, information on the impact of frataxin deficiency in neurons is scant. Here, we describe a neuronal model displaying some major biochemical and morphological features of FRDA. By silencing the mouse NSC34 motor neurons for the frataxin gene with shRNA lentiviral vectors, we generated two cell lines with 40% and 70% residual amounts of frataxin, respectively. Frataxin-deficient cells showed a specific inhibition of mitochondrial Complex I (CI) activity already at 70%

Research paper thumbnail of Primary myxopapillary ependymoma of the cerebellopontine angle: report of a case

Neurosurgical Review, 2009

Myxopapillary ependymoma is a rare variant of ependymoma, almost exclusively occurring in the reg... more Myxopapillary ependymoma is a rare variant of ependymoma, almost exclusively occurring in the region of the cauda equina and filum terminale. We describe a myxopapillary ependymoma located in the left cerebellopontine angle of a young man suffering from peripheral vertigo and left sensorineural hearing loss for years. The patient underwent surgical removal of the tumour. Microscopic examination showed histological and immunohistochemical features consistent with a diagnosis of myxopapillary ependymoma. Imaging studies of the spine yielded normal findings, confirming the lesion's primary nature. To the best of our knowledge, this is the first case of primary intracranial myxopapillary ependymoma described in this location.

Research paper thumbnail of Immunolocalization of heat shock proteins in ragged-red fibers of patients with mitochondrial encephalomyopathies

Neuromuscular Disorders, 1993

A~traet--Monoclonal antibodies against the 60 kDa heat shock protein (HSP-60) and against ubiquit... more A~traet--Monoclonal antibodies against the 60 kDa heat shock protein (HSP-60) and against ubiquitin (UB) were used to study the expression of these proteins in muscle samples from patients with qualitative and quantitative alterations of mitochondrial DNA (mtDNA). We found an enhanced expression of HSP-60 and UB that was preferentially localized in ragged-red fibers (RRFs). HSP-60 may act as a protein repair enzyme catalyzing the refolding of misfolded proteins in the matrix of mitochondria of RRFs. On the other hand, UB could promote the elimination of abnormal proteins by its covalent interaction to substrates.

Research paper thumbnail of The THRombolysis and STatins (THRaST) study

Neurology, 2013

To assess the impact on stroke outcome of statin use in the acute phase after IV thrombolysis. Mu... more To assess the impact on stroke outcome of statin use in the acute phase after IV thrombolysis. Multicenter study on prospectively collected data of 2,072 stroke patients treated with IV thrombolysis. Outcome measures of efficacy were neurologic improvement (NIH Stroke Scale [NIHSS] ≤ 4 points from baseline or NIHSS = 0) and major neurologic improvement (NIHSS ≤ 8 points from baseline or NIHSS = 0) at 7 days and favorable (modified Rankin Scale [mRS] ≤ 2) and excellent functional outcome (mRS ≤ 1) at 3 months. Outcome measures of safety were 7-day neurologic deterioration (NIHSS ≥ 4 points from baseline or death), symptomatic intracerebral hemorrhage type 2 with NIHSS ≥ 4 points from baseline or death within 36 hours, and 3-month death. Adjusted multivariate analysis showed that statin use in the acute phase was associated with neurologic improvement (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.26-2.25; p < 0.001), major neurologic improvement (OR 1.43, 95% CI 1.11-1.85; p = 0.006), favorable functional outcome (OR 1.63, 95% CI 1.18-2.26; p = 0.003), and a reduced risk of neurologic deterioration (OR: 0.31, 95% CI 0.19-0.53; p < 0.001) and death (OR 0.48, 95% CI 0.28-0.82; p = 0.007). Statin use in the acute phase of stroke after IV thrombolysis may positively influence short- and long-term outcome.

Research paper thumbnail of Neuropathology of Mitochondrial Encephalomyopathies Due to Mitochondrial DNA Defects

Journal of Neuropathology and Experimental Neurology, 1993

From the Department of Neurology, College of Physicians and Surgeons of Columbia University, New ... more From the Department of Neurology, College of Physicians and Surgeons of Columbia University, New York, New York (MS, EB, SDM), and the Neuropathology Unit, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester ...

Research paper thumbnail of New Morphological Approaches to the Study of Mitochondrial Encephalomyopathies

Brain Pathology, 1992

Molecular genetics, biochemistry, immunology and morphology, are being applied in a coordinated f... more Molecular genetics, biochemistry, immunology and morphology, are being applied in a coordinated fashion to unveil the molecular basis of the mitochondrial encephalomyopathies. Mutations of mitochondrial DNA (mtDNA) have been found in well characterized clinical groups of these disorders. New and old morphologic methods have been applied to investigate muscle biopsies from patients with mtDNA mutations. Important observations have been made on the cellular localization of normal and mutated mtDNA and on the expression of mtDNA-encoded polypeptides. These observations have provided insight into the pathogenesis of respiratory chain enzyme deficiency at the level of individual muscle fibers. Application of immunocytochemical and in situ hybridization techniques at the electron microscopic level will extend these studies to the level of individual mitochondria.

Research paper thumbnail of Cytochrome C Oxidase Deficiency and Neuronal Involvement in Menkes' Kinky Hair Disease: Immunohistochemical Study

Brain Pathology, 1993

Antibodies against subunits II and IV of cytochrome c oxidase (COX) and against complex III of th... more Antibodies against subunits II and IV of cytochrome c oxidase (COX) and against complex III of the respiratory chain were used to study the expression of these proteins in the cerebellum, spinal cord, and other regions of the central nervous system in an autoptic case of Menkes' kinky hair disease (MKHD). We found a reduced expression of COX subunits in all examined areas whereas staining for complex III appeared normal. Immunostaining was altered in morphologically well-preserved neurons, suggesting that COX deficiency may have a pathogenetic role in the neuronal degeneration of MKHD.

Research paper thumbnail of Myoclonic Epilepsy with Ragged-red Fibers (MERRF): An Immunohistochemical Study of the Brain

Brain Pathology, 1995

Myoclonic epilepsy with ragged-red fibers (MERRFI is a maternally inherited disorder of oxidative... more Myoclonic epilepsy with ragged-red fibers (MERRFI is a maternally inherited disorder of oxidative phosphorylation due to specific point mutations within the mitochondrial tRNALvs gene. Mitochondria1 dysfunction in the central nervous system (CNS) of patients with MERRF accounts for the neurological manifestations of the disease. Antibodies against subunits of complex I, 111, IV and V of the respiratory chain were used to study the expression of these proteins in the frontal cortex, cerebellum and medulla from an autoptic case of MERRF. We found a selective decreased expression of subunit II of cytochrome c oxidase (COX-II) in these regions. lmmunohistochemical abnormalities were more widespread than the lesions described by traditional histopathological techniques and made possible an attempt of explanation for the neurological symptoms of the patient.

Research paper thumbnail of MELAS: clinical phenotype and morphological brain abnormalities

Acta Neuropathologica, 2003

We describe the clinical and neuropathological findings of three unrelated autopsy cases of MELAS... more We describe the clinical and neuropathological findings of three unrelated autopsy cases of MELAS harboring the A3243G transition in the mitochondrial DNA (mtDNA). Using immunohistochemical techniques, we studied the expression of several subunits of the respiratory chain in various brain regions from the same cases. In all three cases there was a reduced immunocytochemical staining for mtDNA-encoded subunits of the respiratory chain, confirming the presence of a defective mitochondrial protein synthesis in this disease. Mitochondrial abnormalities were mostly confined to multiple areas of different size and shape, in agreement with the focal character of the brain pathology in MELAS, and were most prominent in the cerebral cortex, providing a morphological contribution to the explanation of the cognitive regression of the patients. Immunoreactivity for mtDNA-encoded subunits was reduced in the walls of many pial and intracerebral arterioles of different brain regions but there was no clear correlation between territories of affected vessels and distribution of the histological and immunohistochemical lesions. Cerebral focal lesions in MELAS might have a metabolic nature and several pathogenetic mechanisms might be involved in the genesis of stroke-like episodes when there is a local increased ATP demand.

Research paper thumbnail of Effect of protein glutathionylation on neuronal cytoskeleton: a potential link to neurodegeneration

Neuroscience, 2011

Neurons are highly susceptible to oxidative stress and oxidation of cytoskeletal proteins is cons... more Neurons are highly susceptible to oxidative stress and oxidation of cytoskeletal proteins is considered one of the first steps of neurodegeneration. Protein glutathionylation is a key event in the redox regulation of protein function and constitutes a sensor of tissue oxidative stress in pathophysiological conditions. In this study, we analyzed for the first time tubulin glutathionylation and its relation to neurites degeneration. For this purpose, we exposed motoneuronal cells to the physiological oxidant glutathione disulfide (GSSG) and we analyzed the extent and morphology of axonal changes caused by protein glutathionylation in these cells. Then we studied the effect of glutathionylation on the distribution of stable and dynamic microtubules in the same cells. Our results indicate that oxidative stress conditions determined by an increased intracellular level of oxidized glutathione may cause an alteration of the cytoskeleton organization and function leading to axon degeneration. These findings might contribute to understand the sequence of pathogenic events involved in the axonal degeneration that characterizes many diseases of the nervous system associated with oxidative stress.

Research paper thumbnail of Friedreich's ataxia: Oxidative stress and cytoskeletal abnormalities

Journal of the Neurological Sciences, 2009

Friedreich's ataxia (FRDA) is an autosomal recessive disorder caused by mutations in the gene enc... more Friedreich's ataxia (FRDA) is an autosomal recessive disorder caused by mutations in the gene encoding frataxin, a mitochondrial protein implicated in iron metabolism. Current evidence suggests that loss of frataxin causes iron overload in tissues, and increase in free-radical production leading to oxidation and inactivation of mitochondrial respiratory chain enzymes, particularly Complexes I, II, III and aconitase. Glutathione plays an important role in the detoxification of ROS in the Central Nervous System (CNS), where it also provides regulation of protein function by glutathionylation. The cytoskeletal proteins are particularly susceptible to oxidation and appear constitutively glutathionylated in the human CNS. Previously, we showed loss of cytoskeletal organization in fibroblasts of patients with FRDA found to be associated with increased levels of glutathione bound to cytoskeletal proteins. In this study, we analysed the glutathionylation of proteins in the spinal cord of patients with FRDA and the distribution of tubulin and neurofilaments in the same area. We found, for the first time, a significant rise of the dynamic pool of tubulin as well as abnormal distribution of the phosphorylated forms of human neurofilaments in FRDA motor neurons. In the same cells, the cytoskeletal abnormalities co-localized with an increase in protein glutathionylation and the mitochondrial proteins were normally expressed by immunocytochemistry. Our results suggest that in FRDA oxidative stress causes abnormally increased protein glutathionylation leading to prominent abnormalities of the neuronal cytoskeleton.