Publications by authors named "Teresa Wierzba-Bobrowicz"

67 Publications

POLG gene mutation. Clinico-neuropathological study.

Folia Neuropathol 2020 ;58(4):386-392

Department of Neuropathology, Institute of Psychiatry and Neurology, Warsaw, Poland.

We present a female patient with a mutation of the POLG gene (POLG DNA polymerase gamma, catalytic subunit; *174763) in which the clinical course suggested a mitochondrial disease, a neuropathological examination identified the syndrome more closely, and a genetic test confirmed the disease. Apart from the morphological lesions typical of Alpers-Huttenlocher syndrome, rarely observed symmetrical degenerative changes in the accessory olivary nuclei were found. It was unusual in the clinical course of the disease that pancreatitis was diagnosed before symptoms of liver failure appeared.
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http://dx.doi.org/10.5114/fn.2020.102441DOI Listing
January 2020

Pretreatment with a glutamine synthetase inhibitor MSO delays the onset of initial seizures induced by pilocarpine in juvenile rats.

Brain Res 2021 Feb 7;1753:147253. Epub 2021 Jan 7.

Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland. Electronic address:

The contribution of glutamatergic transmission to generation of initial convulsive seizures (CS) is debated. We tested whether pretreatment with a glutamine synthetase (GS) inhibitor, methionine sulfoximine (MSO), affects the onset and progression of initial CS by cholinergic stimulus in juvenile rats. Male rats (24 days old, Sprague Dawley) sequentially received i.p. injections of lithium-carbonate, MSO, methyl-scopolamine, and pilocarpine (Pilo). Pilo was given 150 min after MSO. Animals were continuously monitored using the Racine scale, EEG/EMG and intrahippocampal glutamate (Glu) biosensors. GS activity as measured in hippocampal homogenates, was not altered by MSO at 150 min, showed initial, varied inhibition at 165 (15 min post-Pilo), and dropped down to 11% of control at 60 min post-Pilo, whereas GS protein expression remained unaltered throughout. Pilo did neither modulate the effect of MSO on GS activity nor affect GS activity itself, at any time point. MSO reduced from 32% to 4% the number of animals showing CS during the first 12 min post-Pilo, delayed by ~6 min the appearance of electrographic seizures, and tended to decrease EMG power during ~15 min post-Pilo. The results indicate that MSO impairs an aspect of glutamatergic transmission involved in the transition from the first cholinergic stimulus to the onset of seizures. A continuous rise of extracellular Glu lasting 60 min was insignificantly affected by MSO, leaving the nature of the Glu pool(s) involved in altered glutamatergic transmission undefined.
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http://dx.doi.org/10.1016/j.brainres.2020.147253DOI Listing
February 2021

Morphological and ultrastructural changes in Herpes simplex encephalomyelitis: an attempt to determinate the etiological factor.

Folia Neuropathol 2020 ;58(2):143-150

Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland.

Herpes simplex encephalomyelitis (HSE) is a rare disease with a high mortality rate. Correct diagnosis is established on the basis of the combination of the clinical and investigative features. Unfortunately, precise diagnosis remains difficult due to several clinical similarities and false negative or inconclusive results of diagnostic tests. Here, we present two cases of HSE together with the morphological and ultrastructural picture. The first case was a 45-year-old man with acute symptoms of encephalitis, and the other one was a 28-year-old woman presenting subacute encephalomyelitis. Both cases had negative serologic and molecular results for Herpes simplex in the blood and cerebrospinal fluid. Brain and spinal cord samples taken from both cases were stained typically with histological and immunohistochemical methods and small tissue fragments were examined with the transmission electron microscope (TEM). Microscopic examination confirmed viral encephalomyelitis in both cases. An electron micrograph showed typical intranuclear viral particles inside of damaged neurons, which together with topography of brain and spinal cord changes suggest HHV-1/HHV-2 in the first case and/or HHV-3 in the other case. Thus, morphological and ultrastructural examinations may be a useful tool to set up correct diagnosis and help to determine the pathogenic factor in patients suspected of viral encephalomyelitis.
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http://dx.doi.org/10.5114/fn.2020.96985DOI Listing
January 2020

Clinical and ultrastructural findings in an ataxic variant of Kufor-Rakeb syndrome.

Folia Neuropathol 2019 ;57(3):285-294

Chair and Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland.

Introduction: Kufor-Rakeb syndrome (KRS) is a rare autosomal recessive neurodegenerative disorder manifesting as juvenile-onset atypical parkinsonism with pyramidal signs, supranuclear gaze palsy, dementia and characteristic minimyoclonus, with a notable phenotype variability. The responsible gene ATP13A2 was also associated with hereditary spastic paraplegia, uncomplicated early - or late-onset parkinsonism and a form of neuronal ceroid lipofuscinosis. We present clinical and ultrastructural findings in a 28-year-old woman with novel biallelic ATP13A2 mutations.

Material And Methods: An ultrastructural study of the skin and muscle sample was carried out. Sequence analysis of all protein coding exons and exon-intron boundaries of genes was performed on patient's genomic DNA. A proprietary oligonucleotide-selective sequencing method was used for capturing genomic targets and sequencing was performed using Illumina sequencing system.

Results: The patient presented with juvenile-onset progressive parkinsonian syndrome and cognitive deterioration, accompanied by mild spastic paraplegia, supranuclear gaze palsy, cerebellar syndrome, peripheral neuropathy and fine myoclonus. Plentiful and varied osmiophilic deposits were found in skin and muscle biopsy. Sequence analysis identified two novel heterozygous variants in ATP13A2: a nonsense variant c.2209C>T, p.(Gln737*) and a 2-bp deletion c.2366_2367delTC, p.(Leu789Argfs*15) causing a frameshift leading to a premature stop codon. Oral levodopa treatment was initiated resulting in marked improvement of bradykinesia, rigidity, speech and swallowing.

Conclusions: We report two novel ATP13A2 pathogenic mutations, further expanding the phenotype of Kufor-Rakeb syndrome with the unusual features of ataxia and polyneuropathy. We thoroughly describe ultrastructural findings and document a meaningful response to levodopa.
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http://dx.doi.org/10.5114/fn.2019.88459DOI Listing
February 2020

Diagnosing MERRF requires clinical and genetic evidence.

Pol J Pathol 2019;70(2):144-145

Department of Neuropathology, Institute of Psychiatry and Neurology, Warsaw, Poland.

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http://dx.doi.org/10.5114/pjp.2019.87106DOI Listing
November 2019

Concentration of microtubule associated protein tau (MAPT) in urine and saliva as a potential biomarker of traumatic brain injury in relationship with blood-brain barrier disruption in postmortem examination.

Forensic Sci Int 2019 Aug 13;301:28-36. Epub 2019 May 13.

Department of Neuropathology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland. Electronic address:

Traumatic brain injury (TBI) constitutes a frequent finding in medico-legal practice, including forensic autopsy and neuropathological examination. Despite clinico-scientific advances there is a need for identification of novel biomarkers considered for TBI diagnostics in ante- and postmortem cases. The role of MAPT protein as a biomarker in case of TBI was investigated in previous studies by examination of blood and cerebrospinal fluid obtained during forensic autopsies whereas less is known concerning its liberation and occurrence in other biofluids. The aim of this study was to elucidate and identify if elevated MAPT levels in other biofluids, such as urine, saliva, and vitreous body are also seen in TBI cases in population-based autopsy screening. The study was carried out using cases (n = 14) of severe head injury suspected as the cause of death and control cases (n = 13) of sudden death in the mechanism of cardiopulmonary failure. The biofluids, such as urine, saliva, and vitreous body were collected within ∼24 h after death and compared using ELISA test. Tissue specimens including brain and kidney were similarly collected during forensic autopsies. Brain specimens were stained immunohistologically with anti-Vimentin (V9) antibody and histologically using Mallory's trichrome method (to assess structural damage to blood-brain barrier elements) whereas kidney specimens were stained immunohistologically with anti-MAPT antibody (to assess the suitability of such a study in the diagnosis of TBI). In our study, we observed the elevated concentration levels of MAPT in saliva and urine. These changes were accompanied by damage to the structural elements of the blood-brain barrier (damage to the vascular endothelium and vascular basement membrane). According to this elevated cencentration levels of MAPT in this biofluids should be considered as TBI marker in postmortem examination even in cases where the head injury was not supposed to consist the direct cause of death.
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http://dx.doi.org/10.1016/j.forsciint.2019.05.010DOI Listing
August 2019

Immunolocalization of dynein, dynactin, and kinesin in the cerebral tissue as a possible supplemental diagnostic tool for traumatic brain injury in postmortem examination.

Folia Neuropathol 2019 ;57(1):51-62

Traumatic brain injury (TBI) is characterized by various micro- and macrostructural neuropathological changes which can be identified in the light microscope examination. The most common pathophenotype of TBI visualized in postmortem neuropathological assessment includes neuron injury with involvement of all of its structural regions followed by its progressive degeneration defined as traumatic axonal injury (TAI). This is directly related with disruption of the axolemmal cytoskeletal network architecture resulting in breakdown, dissolution and accumulation of a number of neuronal proteins. Regarding the availability and progress in the development of specific antibodies against neuronal proteins, their usage is restricted due to low specificity for injured axons in the pathomechanism of TBI followed by TAI. Taking this into account with relation to expanding the role of axonal cytoskeleton and its based biomarkers we have presented a study documenting neuropathological features concerning the expression of dynein (DNAH9), dynactin (DCTN1) and kinesin (KIF5B) in the brain specimens obtained during forensic autopsies from TBI victims. The study was carried out using cases (n = 21) of severe head injury suspected to be the cause of death and control cases (n = 17) of sudden death in the mechanism of cardiopulmonary failure along with a positive control case which died after suicidal gunshot injury. In our study, we documented that DNAH9, DCTN1, and KIF5B staining should be considered as a supplemental diagnostic tool for TBI in postmortem neuropathological examination and forensic autopsy. This additional motor protein immunohistochemical staining procedure could be useful in the evaluation of lesions that may remain undiagnosed during a routine examination and aid in more accurate identification of TBI followed by TAI.
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http://dx.doi.org/10.5114/fn.2019.83831DOI Listing
August 2019

Pathology of skeletal muscle fibers and small blood vessels in MERRF syndrome: an ultrastructural study.

Pol J Pathol 2018;69(4):422-431

Our studies concerned skeletal muscle biopsy specimens from a patient with clinically suspected MERRF syndrome, confirmed by genetic tests showing the presence of point mutation in the m.8344A> G in the tRNALys gene. Ultrastructurally, extensive damage of mitochondria in skeletal muscle fibres was observed, including the presence of two types of mitochondrial inclusions. Mild damage of mitochondria was revealed in small blood vessels and the presence of calcium deposits in the vascular walls were observed. The differences in mitochondrial damage may be related to different origin and expenditure of biologically useful energy in these cells.
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http://dx.doi.org/10.5114/pjp.2018.80904DOI Listing
May 2019

Neurogenesis in adult human brain after hemorrhage and ischemic stroke.

Folia Neuropathol 2018 ;56(4):293-300

Introduction: Adult neurogenesis includes proliferation and differentiation of progenitor cells as well as their migration and maturation. In the adult human brain, two neurogenic regions, the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) of lateral ventricles, have been identified. In the dentate gyrus, three types of transcriptionally active cells and in the subventricular zone, four types of transcriptionally active cells, including GFAP-positive neural stem cells (NSCs), have been differentiated.

Material And Methods: The aim of the study was to identify and compare density of neurogenic cells between two study groups of patients (7 men, 7 women, mean age 70 ± 6.03) with ischemic stroke and with hemorrhage (6 men, 2 women, mean age 64.75 ± 12.23) and the control group of patients (6 men, 2 women, mean age 64 ± 10.95) free of neuropathologic changes who died suddenly within less than 10 min.

Results: In both groups, in the hippocampal dentate gyrus and in the subventricular zone of lateral ventricles, the presence of single GFAP-positive neural stem cells and the transcriptionally active cells labelled with phosphorylated histone H3Ser-10 (p-Histone H3Ser-10)/neural progenitor cells (NPCs), was observed. The quantitative analysis of cells with p-Histone H3Ser-10 expression in the hippocampal DG revealed significant differences between the hemorrhage and control groups (p = 0.001, test t). However, in the SVZ, it showed a statistically significant decrease in the density of transcriptionally active cells in the group of patients with ischemic stroke (p = 0.001, test t). A distinct decrease in the density of transcriptionally active cells, proportional to the length of the patients' hospitalization, was observed.

Conclusions: Hypoxia belongs to pathomechanic factors responsible for ischemic stroke, which can induce neurogenesis. However, hypoxia along with ischemia and other factors implicated in ischemic stroke, such as the patient's age or duration of ischemia can have a decisive influence on the decrease in the density of transcriptionally active cells in this pathologic process.
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http://dx.doi.org/10.5114/fn.2018.80862DOI Listing
May 2019

Brain-originated peptides as possible biochemical markers of traumatic brain injury in cerebrospinal fluid post-mortem examination.

Folia Neuropathol 2018 ;56(2):97-103

The release of brain-originated peptides such as tau protein (MAPT), S-100β, neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP) into the cerebrospinal fluid (CSF) has been positively correlated with head injuries in clinical and basic research. In this study, we wanted to examine if selected CSF biomarkers (GFAP, NFL, and myelin basic protein - MBP) of head injury may be useful in post-mortem examination and diagnosis of forensic cases. The study was carried out using cases of head injury and cases of sudden death (cardiopulmonary failure, no injuries of the head as control group) provided by forensic pathologists at the Department of Forensic Medicine, Medical University of Warsaw. Cerebrospinal fluid was collected within 24 h after death using suboccipital puncture. The concentration of these peptides was compared using an enzyme-linked immunosorbent assay (ELISA). Brain specimens (frontal cortex) were collected during forensic autopsies. Sections were stained immunohistochemically against GFAP, MBP, NF, and amyloid-β precursor protein (APP). As a result we documented that elevated levels of CSF, GFAP, MBP, and NFL should be considered a marker for severe and moderate traumatic brain injury. Elevated levels of those peptides combined with a negative APP staining point to their role as markers of head trauma with a shorter time span than APP (manner of minutes).
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http://dx.doi.org/10.5114/fn.2018.76613DOI Listing
March 2019

Effects of amphetamine administration on neurogenesis in adult rats.

Folia Neuropathol 2017 ;55(4):333-339

In our study expression of phospho-(Ser-10)-histone H3 (pH3S10), a marker for the early stage of neurogenesis, and cellular early response genes were investigated using c-Fos protein as an example of a transcription factor in the neurogenic process in rats. Neurogenesis in the adult brain is regulated by endo- and exogenous factors, which influence the proliferation potential of progenitor cells and accelerate the dendritic development of newborn neurons. D-amphetamine, a psychoactive substance, is one of the exogenous factors able to influence the process of neurogenesis. The rats were injected with D-amphetamine at a dose of 1.5 mg/kg/body weight (b.w.) under one administration scheme. Analysis of the pH3S10 and c-Fos expression levels in the group of D-amphetamine administered rats provided evidence of enhanced expression of these proteins in the regions of neurogenesis occurrence in rats. However, conclusions concerning stimulant effects of amphetamine on neurogenesis should be formulated with great caution, taking into account amphetamine dosage and the administration scheme. It should also be remembered that doses of psychoactive substances used in animal models can be lethal to humans..
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http://dx.doi.org/10.5114/fn.2017.72396DOI Listing
August 2018

Bystin (BYSL) as a possible marker of severe hypoxic-ischemic changes in neuropathological examination of forensic cases.

Forensic Sci Med Pathol 2018 03 18;14(1):26-30. Epub 2018 Jan 18.

Departament of Neuropathology, Institute of Psychiatry and Neurology, 9 Sobieskiego St., 02-957, Warsaw, Poland.

Bystin (BYSL) is a 306-amino acid protein encoded in humans by the BYSL gene located on the 6p21.1 chromosome. It is conserved across a wide range of eukaryotes. BYSL was reported to be a sensitive marker for the reactive astrocytes induced by ischemia/reperfusion and chemical hypoxia in vitro and is considered to be one of the common characteristics of astrogliosis. In our study we examined whether BYSL could be used as a marker for hypoxic-ischemic changes in forensic cases. Groups suspected of acute hypoxic-ischemic changes presented strong BYSL expression in the cytoplasm of neocortical neurons especially in layers 3-5, that seemed to be short-lasting. In the hypoxic-ischemic-reperfusion group we did not find BYSL expression. BYSL expression in the cytoplasm of cortical neurons was minimal in the control group (cardiac arrest). BYSL seems to be a promising early marker of severe hypoxic-ischemic changes in neuropathological examination of forensic cases and certainly requires further studies.
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http://dx.doi.org/10.1007/s12024-017-9942-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830468PMC
March 2018

Pathology of mitochondria in MELAS syndrome: an ultrastructural study.

Pol J Pathol 2017;68(2):173-181

Ultrastructural changes in skeletal muscle biopsy in a 24-year-old female patient with clinically suspected mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS) syndrome are presented. We observed proliferation and/or pleomorphism of mitochondria in skeletal muscle and smooth muscle cells of arterioles, as well as in pericytes of capillaries. Paracrystalline inclusions were found only in damaged mitochondria of skeletal muscle. Genetic testing revealed a point mutation in A3243G tRNALeu(UUR) typical for MELAS syndrome. We conclude that differentiated pathological changes of mitochondria in the studied types of cells may be associated with the different energy requirements of these cells.
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http://dx.doi.org/10.5114/pjp.2017.65021DOI Listing
December 2017

Intracerebral hemorrhage in the context of cerebral amyloid angiopathy and varied time of onset of cerebral venous thrombosis: a case report.

Folia Neuropathol 2017 ;55(3):242-248

In patients with cerebral venous thrombosis (CVT) the incidence of intracerebral hemorrhage (ICH) is estimated at about 37% and subarachnoid hemorrhage (SAH) at 1% of patients. A case with coincident occurrence of ICH, SAH and CVT in a patient with cerebral amyloid angiopathy (CAA) is reported. A 79-year-old woman was admitted to the Neurological Department after the occurrence of generalized seizures, the first in her life. On admission she was unconscious with right hemiparesis and deviation of eyes to the left. On computed tomography (CT) scan many hemorrhagic infarcts were present in the frontal, parietal, temporal and left occipital lobes. Angio-CT revealed thrombosis in the right transverse sinus, right internal carotid vein and superior sagittal sinus. Her state slowly deteriorated. She died after 6 days. Neuropathologically, many hemorrhagic infarcts were observed in cortical regions in the vicinity of veins with thrombosis and in the white matter. The varied time of onset of thrombosis of the right sigmoid sinus, right superior petrosal sinus, superior sagittal sinus, right transverse sinus and the proximal part of the right internal carotid vein was confirmed. cerebral amyloid angiopathy in brain vessels was diagnosed. Subarachnoid hemorrhage is a very uncommon presentation of CVT and may coexist with CAA. We can only speculate that CAA may have an effect on vein destruction and can promote cerebral vein thrombosis and in consequence also predispose to intracerebral hemorrhage and subarachnoid hemorrhage. The most probable cause of extensive thrombosis was a coagulation disorder.
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http://dx.doi.org/10.5114/fn.2017.70490DOI Listing
September 2018

Tau protein (MAPT) as a possible biochemical marker of traumatic brain injury in postmortem examination.

Forensic Sci Int 2017 Nov 15;280:1-7. Epub 2017 Sep 15.

Department of Neuropathology, Institute of Psychiatry and Neurology, 9 Sobieskiego st., 02-957 Warsaw, Poland.

MAPT is a neuronal protein that plays an important role in axonal stabilization, neuronal development, and neuronal polarity. MAPT release into the CSF and blood has been interpreted as indicative of axonal injury as its elevated levels were observed in olympic boxers even after a mild head trauma suggesting minor CNS injuries. In our study we wanted to check the potential relevance of MAPT examination for forensic purposes. The study was carried out using cases of head injury group and cases of sudden death (cardiopulmonary failure, no injuries of the head - control group) provided by forensic pathologists at the Department of Forensic Medicine, Medical University of Warsaw. CSF and blood were collected within 24h after death using suboccipital puncture and femoral vein puncture. Serum and cerebrospinal fluid Tau protein concentrations were compared using an enzyme-linked immunosorbent assay (elisa). Brain specimens (frontal cortex) were collected during forensic autopsies. Sections were stained histologically (hematoxylin-eosin) and immunohistochemically with anti human Tau antibody, anti glial fibrillary acid protein (GFAP), anti human macrosialin (CD68) or anti human endothelial cells (CD34). In our study we documented that elevated levels of serum and CSF MAPT may also be considered a marker for mild traumatic brain injury and traumatic brain injury (mTBI and TBI). An increase in CSF and serum levels of MAPT in the absence of visible macroscopic traumatic CNS changes indicates that even minor head injuries may result in changes at the neuronal level that could remain undiagnosed during regular forensic autopsy and routine histopathological examination.
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http://dx.doi.org/10.1016/j.forsciint.2017.09.008DOI Listing
November 2017

Autoimmune meningitis and encephalitis in adult-onset still disease - Case report.

Neurol Neurochir Pol 2017 Sep - Oct;51(5):421-426. Epub 2017 Jul 8.

1st Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland. Electronic address:

Introduction: Adult-onset Still disease (AOSD) is a rare systemic inflammatory disease of unknown cause. Its symptoms usually include persistent fever, fugitive salmon-colored rash, arthritis, sore throat (not specific), but it may also lead to internal organs' involvement, which presents with enlargement of the liver and spleen, swollen lymph nodes, carditis or pleuritis - potentially life-threatening complications. In rare cases, AOSD can cause aseptic meningitis or/and encephalitis.

Case Presentation: We report a case of 31-year-old male patient, who was referred to neurological department for extending diagnostics of frontal lobes lesions with involvement of adjacent meninges. Abnormalities have been revealed in brain MRI, which was performed due to persistent headaches, visual disturbances, fever, fatigue and cognitive decline. Wide differential diagnosis was performed including laboratory findings, contrast enhanced MRI, MR spectroscopy, flow cytometry and finally brain biopsy to exclude neoplastic or infectious origin. Final diagnosis of autoimmune meningoencephalitis in adult-onset Still disease has been made.

Conclusion: Adult-onset Still disease is a rare cause of inflammatory changes in central nervous system, which if diagnosed, may be treated successfully with steroids (commonly available agent), intravenous immunoglobulins or more specific immunomodulating regiments.
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http://dx.doi.org/10.1016/j.pjnns.2017.06.006DOI Listing
March 2018

Rats showing low and high sensitization of frequency-modulated 50-kHz vocalization response to amphetamine differ in amphetamine-induced brain Fos expression.

Brain Res 2016 10 6;1648(Pt A):356-364. Epub 2016 Aug 6.

Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego St., 02-106 Warsaw, Poland.

Individuals predisposed to addiction constitute a minority of drug users, in both humans and animal models of the disorder, but there are no established characteristics that would allow identifying them beforehand. Our studies demonstrate that sensitization of rat 50-kHz ultrasonic vocalization (USV) response to amphetamine shows marked inter-individual diversity but substantial intra-individual stability. Low sensitization of the response shows relevance to the acquisition of self-administration of this drug and hence might be of predictive value regarding the risk of addiction. We compared amphetamine-induced Fos expression in 16 brain regions considered important for the development of addiction between rats preselected for low and high sensitization of the response and next given nine daily amphetamine doses followed by a 2-week withdrawal and final amphetamine challenge. Ventral tegmental area and nucleus accumbens shell Fos-positive nuclei counts correlated positively with 50-kHz USV response to the challenge in high-sensitized rats. Compared to those in amphetamine-untreated controls, Fos-positive nuclei counts were significantly and markedly (2-6 times) higher in 12 regions in high-sensitized rats, whereas in low-sensitized rats they were significantly higher in the cingulate cortex and dorsomedial striatum only. The difference in the counts between the latter two subsets reached statistical significance in dorsomedial and dorsolateral striatum and three out of four cortical regions studied. The fact that the diversification was most distinct in dorsal striatum that plays a critical role in the transition from controlled to compulsive drug intake suggests that the USV-based categorization may be related to divergent vulnerability of rats to AMPH addiction.
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http://dx.doi.org/10.1016/j.brainres.2016.08.008DOI Listing
October 2016

Morphological changes of skeletal muscle in spinal and bulbar muscular atrophy (SBMA), Kennedy's disease: a case report.

Clin Neuropathol 2015 Jul-Aug;34(4):199-206

Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is an X-linked recessive disease affecting lower motor neurons. In the present case report, we describe morphological changes in a muscle biopsy obtained from a 62-year-old patient with gynecomastia and with the following neurological symptoms: dysphagia, dysarthria, wasting and fasciculation of the tongue, proximal weakness, fasciculations in the limb muscles, and an absence of all tendon reflexes. Neurogenic alternations were predominantly observed using light and electron microscopy. The angulated atrophic muscle fibers formed bundles. The numerous nuclei were pyknotic or pale, some of them were also ubiquitin positive; they were grouped inside so-called "nuclear sacks". At the ultrastructural level, atrophic muscle fibers revealed disruption and loss of sarcomeres, duplication of Z-line, and rod-like structures. The nuclei, often with irregular shapes, revealed varying degrees of chromatin condensation, from dispersed to highly condensed, like pyknotic nuclei. Occasionally electron-dense inclusions in the nuclei were found. Some myogenic features like hypertrophic muscle fibers and proliferation of connective tissue were also visible. The neurogenic and myogenic pathological changes suggested SBMA, which was confirmed with genetic analysis (trinucleotide CAG (glutamie)-repeat expansion in the androgen-receptor gene).
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http://dx.doi.org/10.5414/NP300829DOI Listing
August 2015

Neuronal nucleus and cytoplasm volume deficit in children with autism and volume increase in adolescents and adults.

Acta Neuropathol Commun 2015 Jan 17;3. Epub 2015 Jan 17.

Introduction: Characterization of the type and topography of structural changes and their alterations throughout the lifespan of individuals with autism is essential for understanding the mechanisms contributing to the autistic phenotype. The aim of this stereological study of neurons in 16 brain structures of 14 autistic and 14 control subjects from 4 to 64 years of age was to establish the course of neuronal nuclear and cytoplasmic volume changes throughout the lifespan of individuals with autism.

Results: Our data indicate that a deficit of neuronal soma volume in children with autism is associated with deficits in the volume of the neuronal nucleus and cytoplasm. The significant deficits of neuronal nuclear and cytoplasmic volumes in 13 of 16 examined subcortical structures, archicortex, cerebellum, and brainstem in 4- to 8-year-old autistic children suggest a global nature of brain developmental abnormalities, but with region-specific differences in the severity of neuronal pathology. The observed increase in nuclear volumes in 8 of 16 structures in the autistic teenagers/young adults and decrease in nuclear volumes in 14 of 16 regions in the age-matched control subjects reveal opposite trajectories throughout the lifespan. The deficit in neuronal nuclear volumes, ranging from 7% to 42% in the 16 examined regions in children with autism, and in neuronal cytoplasmic volumes from 1% to 31%, as well as the broader range of interindividual differences for the nuclear than the cytoplasmic volume deficits, suggest a partial distinction between nuclear and cytoplasmic pathology.

Conclusions: The most severe deficit of both neuronal nucleus and cytoplasm volume in 4-to 8-year-old autistic children appears to be a reflection of early developmental alterations that may have a major contribution to the autistic phenotype. The broad range of functions of the affected structures implies that their developmental and age-associated abnormalities contribute not only to the diagnostic features of autism but also to the broad spectrum of clinical alterations associated with autism. Lack of clinical improvement in autistic teenagers and adults indicates that the observed increase in neuron nucleus and cytoplasm volume close to control level does not normalize brain function.
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http://dx.doi.org/10.1186/s40478-015-0183-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302585PMC
January 2015

Frontotemporal lobar degeneration with MAPT mutation in an Italian-Polish family. A case report.

Folia Neuropathol 2014 ;52(4):457-66

Prof. Teresa Wierzba-Bobrowicz, Department of Neuropathology, Institute of Psychiatry and Neurology, 9 Sobieskiego St., 02-957 Warsaw, Poland, e-mail:

Frontotemporal lobar degeneration (FTLD) with mutations in the MAPT (microtubule-associated protein tau) gene (FTLD with MAPT mutation) is a neurodegenerative disease with various clinical phenotypes. We present an Italian- Polish family with a IVS10+3G>A mutation in the MAPT gene, linked with haplotype H1s in a male proband (Fig. 2, II.2, H1s/H1b diplotype) and his sister (Fig. 2, II.1, the H1s/H1j diplotype). This report presents clinical, neuropathological and genetic testing of the proband and his affected sister, two members of an Italian-Polish family consisting of 25 family members. Their clinical history includes dementia as well as movement and cardiovascular disorders. Magnetic resonance imaging showed frontal and temporal cerebral atrophy. Neuropathological studies of the brain samples showed loss of neurons, gliosis, and the occurrence of neurofibrillary tangles, numerous neuropil threads, coiled bodies and abundant deposits of tau protein, including 3- and 4-repeated isoforms in neurons and glial cells. Only in the male proband brain, there were Pick body-like deposits in granule neurons of the hippocampus. Pathology of vascular walls was found in both cases. Ultrastructurally, the male proband showed clusters of collagen fibers mainly in a pericyte position. Beside the typical neurofibrillary pathology, aggregated gliofilaments and lipofuscin deposits in astroglia are described. Our report suggests that FTLD with IVS10+3G>A MAPT mutation causes damage mainly to the central nervous system and induces neuropathological changes, depending on the haplotypes of MAPT. In the clinical course of this disease, damage of the cardiovascular system may also be observed.
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http://dx.doi.org/10.5114/fn.2014.47848DOI Listing
December 2015

CADASIL patient with extracellular calcium deposits.

Folia Neuropathol 2013 ;51(4):302-11

Teresa Wierzba-Bobrowicz, Department of Neuropathology, Institute of Psychiatry and Neurology, 9 Sobieskiego Str., 02-957 Warsaw, Poland, phone/fax: +48 22 458 25 24, e-mail:

We report the case of a 57-year-old male patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) diagnosed on the basis of ultrastructural and genetic examinations. Ultrastructurally, granular osmiophilic material (GOM) deposits, degeneration and loss of vascular smooth muscle cells (VSMC) and pericytes in small arterial and capillary vessels from skin-muscle biopsy typical of CADASIL were visible. Degeneration of pericytes and endothelial cells were often pronounced, which resulted in a complete disappearance of mural cells and extremely severe thickening of the basement membrane. Degenerative changes in blood vessels, especially evident in skeletal muscle arterioles, also included significant vacuolization of VSMC, misshapen nuclei both in vessel wall cells and skeletal muscle fibres, and deposits of a hyaline material and calcium in the vessel wall. Abundant calcium deposits were located in the vascular basement membrane and exhibited laminar morphology with abnormally arranged light and dark bands. In the basement membrane of the most severely affected microvessels, only clusters of calcium deposits and remnants of the mural cells were observed. Laminar calcifications were also observed within the basement membrane surrounding skeletal muscle fibres. Such abundant calcium deposits in CADASIL have not as yet been described. Morphological findings, described in this report, expand the spectrum of histopathological changes in this genetically determined angiopathy.
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July 2014

The association between cerebral amyloid angiopathy and atherosclerosis in patients with intracerebral hemorrhages.

Folia Neuropathol 2013 ;51(3):243-9

Tomasz Stępień, Department of Neuropathology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland, e-mail:

Unlabelled: aim of the study: To analyze the incidence and grade of cerebral amyloid angiopathy (CAA) and atherosclerosis (AS) in cerebral vessels in patients who died from spontaneous intracerebral hemorrhage.

Material And Methods: The clinical diagnosis, based on CT scans of the brain, was made and immunohistochemic neuropathological examinations were performed in patients with intracerebral hemorrhages due to CAA. Cerebral amyloid angiopathy was diagnosed according to the Boston criteria. The Vonsattel and Mountoy scales were used to assess the grade and score of CAA. Atherosclerosis was assessed according to a four-grade scale presented in the Coding Guide from Collaborative Study of Epidemiological Factors in Cerebral Vascular Disease.

Results: Of the 189 patients who died due to intracerebral hemorrhages 42 (22%) presented CAA. According to the Vonsattel scale this group comprised 32 (76%) patients who showed severe, 6 (14%) moderate and 4 (10%) mild CAA. Atherosclerosis was diagnosed in the CAA group of patients as follows: 6 (14%) with grade 1; 20 (49%) with grade 2; 9 (20%) with grade 3; and 7 (17%) patients with grade 4.

Conclusions: There was no correlation between CAA and AS. The CAA was probably the direct cause of death in part of cases with advanced CAA. The different mechanisms presumably can cause CAA and AS.
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http://dx.doi.org/10.5114/fn.2013.37709DOI Listing
March 2014

β-amyloid deposits in veins in patients with cerebral amyloid angiopathy and intracerebral haemorrhage.

Folia Neuropathol 2013 ;51(2):120-6

2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.

Aim Of The Study: To review the incidence and grade of cerebral amyloid angiopathy (CAA) in veins in patients who died due to spontaneous intracerebral haemorrhage (ICH).

Material And Methods: Neuropathological examinations were performed in the study group of 189 patients. Cerebral amyloid angiopathy was diagnosed according to the Boston criteria and confirmed during an autopsy. The Vonsattel and Mountjoy scales were used to assess the grade and scores of CAA.

Results: In the study group composed of 189 ICH patients, 42 presented CAA. In the microscopic examination, of the 42 patients 33 (78%) showed β-amyloid deposits in veins, which makes 17% of the total group of patients with ICH. In this group, the age ranged from 54 to 97 (mean age 80.18 ± 8.15 years). A group of 33 (27 women and 6 men) patients comprised 15 (45%) patients with severe CAA, 13 (40%) with moderate and 5 (15%) with mild CAA classified according to the Vonsattel scale. According to the Mountjoy scale 28 (85%) patients had a score of 4, which indicated the total involvement of the vessel.

Conclusions: β-amyloid deposits in veins were found in 78% of patients with CAA and ICH, which makes 17% of the total group of patients with ICH. Interestingly, β-amyloid deposits in veins are not so rare in patients with CAA who died due to intracerebral haemorrhage. Cerebral amyloid angiopathy localization in the veins of the brain was observed more frequently than previously suspected. Veins may play a role in the elimination of β-amyloid from the brain.
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http://dx.doi.org/10.5114/fn.2013.35954DOI Listing
July 2014

Alcohol-induced changes in the developing cerebellum. Ultrastructural and quantitative analysis of neurons in the cerebellar cortex.

Folia Neuropathol 2012 ;50(4):397-406

Department of Neuropathology, Institute of Psychiatry and Neurology, Warsaw, Poland.

Maternal ethanol consumption during pregnancy may cause foetal alcohol syndrome (FAS). Our experiments of ethanol-treated female rats were based on the FAS model in humans; therefore, the results obtained may help explain the clinical mechanism of the disease development. The ultrastructural examination of the cerebellar cortex of ten-day-old rat pups of ethanol-treated dams during pregnancy (group IA), pregnancy and lactation (group IIA), and lactation (group IIIA) revealed that alcohol administration leads to a delayed maturation of Purkinje cells. This was most strongly manifested in the pups of dams treated with ethanol during pregnancy and lactation. Moreover, this study showed degenerative changes in Purkinje cells as well as in granular layer cells in all experimental groups. There was a difference in the ultrastructural picture of both types of dying cells, which might result from different time frame of their sensitivity to ethanol administration. The quantitative analysis showed the most pronounced decrease in the density of Purkinje cells in the posterior superior fissure of cerebellar cortex in the pups of dams treated with ethanol during pregnancy.
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http://dx.doi.org/10.5114/fn.2012.32374DOI Listing
November 2013

Morphological and quantitative analysis of cerebellar cortical cells in Alzheimer's disease.

Folia Neuropathol 2012 ;50(3):250-60

Department of Neuropathology, Institute of Psychiatry and Neurology, Warsaw, Poland.

Alzheimer's disease (AD) is a neurodegenerative amyloid disease, although a great deal of research has been done, its aetiology is still unknown. In Khachaturian's hypothesis on the involvement of calcium in the aetiology of Alzheimer's disease, particular attention is paid to the disorder of calcium metabolism. Ludo van Bogaert, describing AD, has drawn attention to the presence of a multi-system damage to the brain and described four forms of the disease, including two cerebellar types: cerebellar-pyramidal and cerebellar. The aim of our study was to analyze the expression of calcium-binding proteins (calbindin, calretinin, parvalbumin) in cortical neurons of the cerebellum in patients diagnosed with Alzheimer's disease (experimental group) and in a control group (patients without Alzheimer's disease). We performed the quantitative analysis of the density of Purkinje cells and Bergmann glial cells in the cerebellar cortex. We observed weak immunoreaction with a calretinin antibody in Lugaro cells, and with parvalbumin in Purkinje cells in the experimental group. A weaker expression of calcium-binding proteins in the experimental group may indicate the disturbance of the transport and buffering of intracellular Ca(2+) levels. The quantitative analysis showed that the density of Bergmann glial cells was higher in the experimental group. Our study suggests the disturbance of calcium metabolism in Alzheimer's disease.
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April 2014

Cerebral amyloid angiopathy manifested as a brain tumour. Clinical and neuropathological characteristics of two cases.

Folia Neuropathol 2012 ;50(2):194-200

Department of Neuropathology, Institute of Psychiatry and Neurology, Warszawa, Poland.

We present two cases (female and male patients, aged 64 and 38, respectively) of focal mass lesions mimicking a brain tumour: one with cognitive function deficit, memory troubles, behavioral changes and left hemiparesis, the other with difficulty in orientation and right hemiparesis. General physical and neurological examinations, laboratory tests and neuroimaging were used to diagnose the cases. Both of them showed nonspecific changes in the brain tissue and the brain tumour was suspected. In the first case MRI scan revealed two pathological masses in the right frontal region and hemorrhagical focus with destructions inside lesions. Second patient's MRI scan revealed a pathological mass at the interface of the left temporal and occipital regions. The neurosurgical procedure was performed. The final diagnosis was established on the basis of neuropathological examination of postoperative material. On light microscopy examination a severe cerebral amyloid angiopathy (CAA) was revealed. Amyloidoma was excluded due to the absence of amorphous material and eosynophylic masses. Tumefactive CAA is a rare condition. These two cases of focal, tumefactive, masslike lesions of diffuse cerebral amyloid angiopathy are reported because of diagnostic dilemmas. In patients with history of memory disfunction, neurological deterioration and different multiple changes observed in CT and MRI scans, such as hemorrhagic infarcts and ischemic cerebral lesions, CAA should be suspected. The imaging findings make a distinction between tumefactive CAA and brain tumours like gliomas difficult. A differential diagnosis of CAA and amyloidoma plays a significant role in a neuropathological examination.
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November 2012

Differences between the pattern of developmental abnormalities in autism associated with duplications 15q11.2-q13 and idiopathic autism.

J Neuropathol Exp Neurol 2012 May;71(5):382-97

Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA.

The purposes of this study were to identify differences in patterns of developmental abnormalities between the brains of individuals with autism of unknown etiology and those of individuals with duplications of chromosome 15q11.2-q13 (dup[15]) and autism and to identify alterations that may contribute to seizures and sudden death in the latter. Brains of 9 subjects with dup(15), 10 with idiopathic autism, and 7 controls were examined. In the dup(15) cohort, 7 subjects (78%) had autism, 7 (78%) had seizures, and 6 (67%) had experienced sudden unexplained death. Subjects with dup(15) autism were microcephalic, with mean brain weights 300 g less (1,177 g) than those of subjects with idiopathic autism (1,477 g; p<0.001). Heterotopias in the alveus, CA4, and dentate gyrus and dysplasia in the dentate gyrus were detected in 89% of dup(15) autism cases but in only 10% of idiopathic autism cases (p < 0.001). By contrast, cerebral cortex dysplasia was detected in 50% of subjects with idiopathic autism and in no dup(15) autism cases (p<0.04). The different spectrum and higher prevalence of developmental neuropathologic findings in the dup(15) cohort than in cases with idiopathic autism may contribute to the high risk of early onset of seizures and sudden death.
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http://dx.doi.org/10.1097/NEN.0b013e318251f537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612833PMC
May 2012

Astroglia disturbances during development of the central nervous system in fetuses with Down's syndrome.

Folia Neuropathol 2011 ;49(2):109-14

Department of Neuropathology, Institute of Psychiatry and Neurology, Warsaw, Poland.

Down's syndrome (DS), caused by aneuploidy of chromosome 21, is the most common chromosomal disorder. The most significant symptom of this disorder is mental retardation. Neuropathological changes found in the DS central nervous system (CNS), such as reduced number of neurons, alteration of synapses and synaptic spines or delayed myelination have been widely described. But there are only a few studies of DS-related glia disturbances. A growing number of astroglia new functions have recently been described. In our study we compared the number of astrocytes and radial glial cells in the frontal lobe of DS fetuses at 18-20 weeks of gestation with that observed in age-matched controls. We found a substantially increased number of glial fibrillary acid protein (GFAP) positive cells in all age range samples of DS brains. We also noticed that in our study astrocytes in DS brains seem to be morphologically more mature than in controls of corresponding age. The same observation was made for radial glia. Taking into consideration the role played by astroglia during CNS development we believe that any change in their number, reduced or increased, can affect CNS development and lead to disturbances of both neurogenesis and synaptogenesis. A possible correlation between the increased number of astroglia and disturbances in CNS development is discussed.
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December 2011

Differential expression of calbindin D28k, calretinin and parvalbumin in the cerebellum of pups of ethanol-treated female rats.

Folia Neuropathol 2011 ;49(1):47-55

Department of Neuropathology, Institute of Psychiatry and Neurology, Warsaw, Poland.

Three calcium-binding proteins (CaBPs), calbindin D28k, calretinin and parvalbumin, were immunohistochemically examined in the cerebellum of ten-day-old rat pups of ethanol-treated dams. Dams were treated with ethanol during pregnancy and/or lactation. In the cerebellar cortex of the pups from control groups, Purkinje cells with their processes and Golgi cells were positive for calbindin D28k, whereas interneurons (Lugaro, Golgi and unipolar brush cells) and sometimes Purkinje cells were positive for calretinin. Parvalbumin immunoreactivity was observed in Golgi and basket cells, stellate cells and in some Purkinje cells. The number of positive cells and staining intensity for calbindin D28k and parvalbumin decreased in all experimental groups, whereas the immunoreaction for calretinin was visible only in interneurons and was more intense in experimental than in control groups. Calbindin D28k immunoreactivity in experimental groups was detected in some Purkinje cells and rarely in Golgi cells. The localization of very intense calretinin expression was visible mainly in unipolar brush cells. A parvalbumin-positive reaction was detected in single Purkinje cells and sometimes in basket cells. The results of the present study showed that immunoreactivity of the three calcium-binding proteins was found in the cells of the cerebellum of the ten-day-old pups from the control groups. In experimental groups of females treated with ethanol during pregnancy and/or lactation, we observed the most significant decrease in both the intensity and the number of immunoreactions of calbindin D28k and parvalbumin, but the intensity of the immunoreaction for calretinin was increased for interneurons. Ischaemic damage to Purkinje cells and loss of interneurons and Purkinje cells were also noted in these groups. A possible correlation between the duration of ethanol intoxication, expression of calcium-binding proteins and pathological changes of cells in the cerebellar cortex of the pups of ethanol-treated dams is discussed.
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July 2011

Case report. Cervical spinal tuberculosis.

Folia Neuropathol 2010 ;48(4):300-4

Department of Neuropathology, Institute of Psychiatry and Neurology, Sobieskiego 9, Warsaw, Poland.

Cervical spinal tuberculosis is a rare variant of extra-pulmonary tuberculosis. We present the case of Vietnamese woman, aged 48, who was admitted to the Department of Neurosurgery because of a cervical spine (C7) compression fracture. Several months earlier, the patient complained of neck pain and numbness of the hands. On physical examination, the woman was subfebrile and complained of pain over the cervical spinal area. Neurological examination revealed no focal motor weakness. The roentgenograms of chest, pelvis and cranium were without pathological changes. Abdominal ultrasonography was normal. Radioisotope bone-scanning showed abnormal accumulation of isotope in the lower cervical region, thoracic vertebra, as well as in the articulations of knees and shoulders and in the left tibial bone. An MRI scan revealed compression fracture of the C7 vertebral body with infiltration of paraspinal tissues at the vertebral column with indentation of osseous masses into the spinal canal. The lesion resembled neoplasm metastasis. The neoplasm infiltrating vertebral body C7, two discs, C6-C7 and C7-Th1, and ligament were removed surgically. Neuropathological examination of the removed material showed typical granulomatous inflammation with characteristic infiltrate of lymphocytes, epithelioid macrophages and Langhans-type multi-nucleated giant cells. The spoligotyping method confirmed the presence of Mycobacterium tuberculosis complex in the specimens.
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May 2011