The role of pro-inflammatory S100A9 in Alzheimer's disease amyloid-neuroinflammatory cascade.

Pro-inflammatory S100A9 protein is increasingly recognized as an important contributor to inflammation-related neurodegeneration. Here, we provide insights into S100A9 specific mechanisms of action in Alzheimer's disease (AD). Due to its inherent amyloidogenicity S100A9 contributes to amyloid plaque formation together with Aß. In traumatic brain injury (TBI) S100A9 itself rapidly forms amyloid plaques, which were reactive with oligomer-specific antibodies, but not with Aß and amyloid fibrillar antibodies. They may serve as precursor-plaques for AD, implicating TBI as an AD risk factor. S100A9 was observed in some hippocampal and cortical neurons in TBI, AD and non-demented aging. In vitro S100A9 forms neurotoxic linear and annular amyloids resembling Aß protofilaments. S100A9 amyloid cytotoxicity and native S100A9 pro-inflammatory signaling can be mitigated by its co-aggregation with Aß, which results in a variety of micron-scale amyloid complexes. NMR and molecular docking demonstrated transient interactions between native S100A9 and Aß. Thus, abundantly present in AD brain pro-inflammatory S100A9, possessing also intrinsic amyloidogenic properties and ability to modulate Aß aggregation, can serve as a link between the AD amyloid and neuroinflammatory cascades and as a prospective therapeutic target.

Evolution of MRI changes in Rasmussen's encephalitis.

PURPOSE: We studied the MRI findings in 16 patients with Rasmussen's encephalitis (RE), further analysed serial MRI changes in 11 of them and correlated it with clinical features. METHODOLOGY: The diagnosis of RE was based on the European consensus statement (Brain, 128, 2005, 454). Details related to demographical, clinical, MRI observations were analysed. RESULTS: Forty MRIs of brain of 16 patients were reviewed. Eleven patients had undergone serial brain MRIs ranging from two to five occasions. All the patients had unihemispheric focal cortical atrophy, predominantly in the perisylvian region (n = 13). Other features were white matter signal changes (n = 14), and ipsilateral caudate (n = 6) and putamen (n = 4) atrophy. Signal alterations in putamen and caudate were noted in four each. In all the 11 patients with serial MRI, there was progression of cerebral atrophy and a trend towards increase in MRI staging. The MRI signal changes remained same in five patients, resolved in three patients, differential change in two patients and increased in one patient. Diffusion-weighted imaging showed facilitated diffusion (n = 5), and MR spectroscopy showed reduced N-acetyl-aspartate and elevated lactate (n = 2). CONCLUSIONS: Pattern recognition of MRI findings and the changes in serial MRI might serve as a surrogate marker of disease viz. unihemispheric progressive focal cortical atrophy and signal changes predominantly in the perisylvian distribution and caudate followed by putamen involvement. This might assist in understanding and monitoring of the disease progression.

Mitochondrial function in human brains is affected by pre- and post mortem factors.

AIM: Mitochondrial function and the ensuing ATP synthesis are central to the functioning of the brain and contribute to neuronal physiology. Most studies on neurodegenerative diseases have highlighted that mitochondrial dysfunction is an important event contributing to pathology. However, studies on the human brain mitochondria in various neurodegenerative disorders heavily rely on post mortem samples. As post mortem tissues are influenced by pre- and post mortem factors, we investigated the effect of these variables on mitochondrial function. METHODS: We examined whether the mitochondrial function (represented by mitochondrial enzymes and antioxidant activities) in post mortem human brains (n=45) was affected by increased storage time (11.8-104.1 months), age of the donor (2 days to 80 years), post mortem interval (2.5-26 h), gender difference and agonal state [based on Glasgow Coma Scale: range=3-15] in the frontal cortex, as a prototype. RESULTS: We observed that the activities of citrate synthase, succinate dehydrogenase and mitochondrial reductase (MTT) were significantly affected only by gender difference (citrate synthase: P=0.005; succinate dehydrogenase: P=0.01; mitochondrial reductase: P=0.006), being higher in females, but not by any other factor. Mitochondrial complex I activity was significantly inhibited by increasing age (r=-0.40; P=0.05). On the other hand, the mitochondrial antioxidant enzyme glutathione reductase decreased with severe agonal state (P=0.003), while the activity of glutathione-S-transferase declined with increased storage time (P=0.005) and severe agonal state (P=0.02). CONCLUSION: Our data highlight the influence of pre- and post mortem factors on preservation of mitochondrial function with implications for studies on brain pathology employing stored human samples.

Progressive multifocal leukoencephalopathy (PML) associated with HIV Clade C--is not uncommon.

Progressive multifocal leukoencephalopathy (PML) is a rare, subacute, demyelinating disease of the central nervous system caused by JC virus. Studies of PML from HIV Clade C prevalent countries are scarce. We sought to study the clinical, neuroimaging, and pathological features of PML in HIV Clade C patients from India. This is a prospective cum retrospective study, conducted in a tertiary care Neurological referral center in India from Jan 2001 to May 2012. Diagnosis was considered "definite" (confirmed by histopathology or JCV PCR in CSF) or "probable" (confirmed by MRI brain). Fifty-five patients of PML were diagnosed between January 2001 and May 2012. Complete data was available in 38 patients [mean age 39 ± 8.9 years; duration of illness-82.1 ± 74.7 days). PML was prevalent in 2.8 % of the HIV cohort seen in our Institute. Hemiparesis was the commonest symptom (44.7 %), followed by ataxia (36.8 %). Definitive diagnosis was possible in 20 cases. Eighteen remained "probable" wherein MRI revealed multifocal, symmetric lesions, hypointense on T1, and hyperintense on T2/FLAIR. Stereotactic biopsy (n = 11) revealed demyelination, enlarged oligodendrocytes with intranuclear inclusions and astrocytosis. Immunohistochemistry revelaed the presence of JC viral antigen within oligodendroglial nuclei and astrocytic cytoplasm. No differences in clinical, radiological, or pathological features were evident from PML associated with HIV Clade B. Clinical suspicion of PML was entertained in only half of the patients. Hence, a high index of suspicion is essential for diagnosis. There are no significant differences between clinical, radiological, and pathological picture of PML between Indian and Western countries.

Alteration in glutathione content and associated enzyme activities in the synaptic terminals but not in the non-synaptic mitochondria from the frontal cortex of Parkinson's disease brains.

Altered redox dynamics contribute to physiological aging and Parkinson's disease (PD). This is reflected in the substantia nigra (SN) of PD patients as lowered antioxidant levels and elevated oxidative damage. Contrary to this observation, we previously reported that non-SN regions such as caudate nucleus and frontal cortex (FC) exhibited elevated antioxidants and lowered mitochondrial and oxidative damage indicating constitutive protective mechanisms in PD brains. To investigate whether the sub-cellular distribution of antioxidants could contribute to these protective effects, we examined the distribution of antioxidant/oxidant markers in the neuropil fractions [synaptosomes, non-synaptic mitochondria and cytosol] of FC from PD (n = 9) and controls (n = 8). In the control FC, all the antioxidant activities [Superoxide dismutase (SOD), glutathione (GSH), GSH peroxidase (GPx), GSH-S-transferase (GST)] except glutathione reductase (GR) were the highest in cytosol, but several fold lower in mitochondria and much lower in synaptosomes. However, FC synaptosomes from PD brains had significantly higher levels of GSH (p = 0.01) and related enzymes [GPx (p = 0.02), GR (p = 0.06), GST (p = 0.0001)] compared to controls. Conversely, mitochondria from the FC of PD cases displayed elevated SOD activity (p = 0.02) while the GSH and related enzymes were relatively unaltered. These changes in the neuropil fractions were associated with unchanged or lowered oxidative damage. Further, the mitochondrial content in the synaptosomes of both PD and control brains was ≥five-fold lower compared to the non-synaptic mitochondrial fraction. Altered distribution of oxidant/antioxidant markers in the neuropil fractions of the human brain during aging and PD has implications for (1) degenerative and protective mechanisms (2) distinct antioxidant mechanisms in synaptic terminals compared to other compartments.

Tumefactive demyelination: clinical, imaging and follow-up observations in thirty-nine patients.

PURPOSE: We describe the clinical, neuroimaging and pathological features and therapeutic outcome in a large cohort of 39 patients with tumefactive demyelination. MATERIALS AND METHODS: A retrospective audit of 39 patients with 'tumefactive demyelination' was performed. The demographic, clinical, MR imaging and pathological details were reviewed. RESULTS: The clinical course was monophasic (n = 22) or relapsing-remitting (n = 17). Common neurological manifestations at presentation included hemiparesis - 27; ataxia - 11; vomiting - 10; headache -9; ophthalmoplegia - 7; seizure - 5; impaired vision - 4; aphasia - 4; visual field defects - 3; papilloedema - 5; extrapyramidal - 5; intellectual decline - 5; behavioural disturbances - 3; altered sensorium - 5. MRI revealed fronto-parietal lesions, which were isolated in 14 (36%) patients. Moderate perilesional oedema and/or mass effect was noted in 12 (30.8%) patients. Post-contrast MR sequences revealed partial ring enhancement in 15, complete ring in seven, patchy enhancement in six, uniform enhancement in two and lack of enhancement in nine cases. Clinical and MR characteristics did not help distinguish between monophasic and relapsing-remitting subgroups. In the monophasic group, 53.8% had complete recovery, while 38.5% had partial improvement (follow-up duration, 8.31 ± 9.3 months). In the relapsing-remitting subgroup, the median time to relapse was 4 months (n = 12, follow-up, 37.8 ± 39.4 months). Patients with monophasic course or single relapse received steroids. Patients with more than one relapse received cyclophosphamide (2), mycophenolate (1), azathioprine (1) or methotrexate (1). CONCLUSIONS: A high proportion of cases of tumefactive demyelination follow a relapsing course, thus necessitating a long-term follow-up. MRI, although helpful in diagnosis, does not predict monophasic or relapsing-remitting course. Guidelines for the management of acute episodes and prevention of relapses are required.

Enterovirus 71 encephalomyelitis and Japanese encephalitis can be distinguished by topographic distribution of inflammation and specific intraneuronal detection of viral antigen and RNA.

AIMS: To investigate if two important epidemic viral encephalitis in children, Enterovirus 71 (EV71) encephalomyelitis and Japanese encephalitis (JE) whose clinical and pathological features may be nonspecific and overlapping, could be distinguished. METHODS: Tissue sections from the central nervous system of infected cases were examined by light microscopy, immunohistochemistry and in situ hybridization. RESULTS: All 13 cases of EV71 encephalomyelitis collected from Asia and France invariably showed stereotyped distribution of inflammation in the spinal cord, brainstem, hypothalamus, cerebellar dentate nucleus and, to a lesser extent, cerebral cortex and meninges. Anterior pons, corpus striatum, thalamus, temporal lobe, hippocampus and cerebellar cortex were always uninflamed. In contrast, the eight JE cases studied showed inflammation involving most neuronal areas of the central nervous system, including the areas that were uninflamed in EV71 encephalomyelitis. Lesions in both infections were nonspecific, consisting of perivascular and parenchymal infiltration by inflammatory cells, oedematous/necrolytic areas, microglial nodules and neuronophagia. Viral inclusions were absent. CONCLUSIONS: Immunohistochemistry and in situ hybridization assays were useful to identify the causative virus, localizing viral antigens and RNA, respectively, almost exclusively to neurones. The stereotyped distribution of inflammatory lesions in EV71 encephalomyelitis appears to be very useful to help distinguish it from JE.

Increased oxidative damage and decreased antioxidant function in aging human substantia nigra compared to striatum: implications for Parkinson's disease.

Parkinson's disease (PD) is characterized by selective degeneration and loss of dopaminergic neurons in the substantia nigra (SN) of the ventral mid brain leading to dopamine depletion in the striatum. Oxidative stress and mitochondrial damage have been implicated in the death of SN neurons during the evolution of PD. In our previous study on human PD brains, we observed that compared to SN, striatum was significantly protected against oxidative damage and mitochondrial dysfunction. To understand whether brain aging contributes to the vulnerability of midbrain to neurodegeneration in PD compared to striatum, we assessed the status of oxidant and antioxidant markers, glutathione metabolic enzymes, glial fibrillary acidic protein (GFAP) expression and mitochondrial complex I(CI) activity in SN (n = 23) and caudate nucleus (n = 24) during physiological aging in human brains. We observed a significant increase in protein oxidation (P < 0.001), loss of CI activity (P = 0.04) and increased astrocytic proliferation indicated by GFAP expression (P < 0.001) in SN compared to CD with increasing age. These changes were attributed to significant decrease in antioxidant function represented by superoxide dismutase (SOD) (P = 0.03), glutathione (GSH) peroxidase (GPx) (P = 0.02) and GSH reductase (GR) (P = 0.03) and a decreasing trend in total GSH and catalase with increasing age. However, these parameters were relatively unaltered in CD. We propose that SN undergoes extensive oxidative damage, loss of antioxidant and mitochondrial function and increased GFAP expression during physiological aging which might make it more vulnerable to neurotoxic insults thus contributing to selective degeneration during evolution of PD.

Elevated oxidative stress and decreased antioxidant function in the human hippocampus and frontal cortex with increasing age: implications for neurodegeneration in Alzheimer's disease.

Oxidative stress and mitochondrial damage are implicated in the evolution of neurodegenerative diseases. Increased oxidative damage in specific brain regions during aging might render the brain susceptible to degeneration. Previously, we demonstrated increased oxidative damage and lowered antioxidant function in substantia nigra during aging making it vulnerable to degeneration associated with Parkinson's disease. To understand whether aging contributes to the vulnerability of brain regions in Alzheimer's disease, we assessed the oxidant and antioxidant markers, glutathione (GSH) metabolic enzymes, glial fibrillary acidic protein (GFAP) expression and mitochondrial complex I (CI) activity in hippocampus (HC) and frontal cortex (FC) compared with cerebellum (CB) in human brains with increasing age (0.01-80 years). We observed significant increase in protein oxidation (HC: p = 0.01; FC: p = 0.0002) and protein nitration (HC: p = 0.001; FC: p = 0.02) and increased GFAP expression (HC: p = 0.03; FC: p = 0.001) with a decreasing trend in CI activity in HC and FC compared to CB with increasing age. These changes were associated with a decrease in antioxidant enzyme activities, such as superoxide dismutase (HC: p = 0.005), catalase (HC: p = 0.02), thioredoxin reductase (FC: p = 0.04), GSH reductase (GR) (HC: p = 0.005), glutathione-s-transferase (HC: p = 0.0001; FC: p = 0.03) and GSH (HC: p = 0.01) with age. However, these parameters were relatively unaltered in CB. We suggest that the regions HC and FC are subjected to widespread oxidative stress, loss of antioxidant function and enhanced GFAP expression during aging which might make them more susceptible to deranged physiology and selective neuronal degeneration.

Dengue-associated transient muscle dysfunction: clinical, electromyography and histopathological changes.

BACKGROUND: Dengue is commonly associated with myalgia, but there is paucity of studies on the frequency, severity, and basis of muscle involvement. The aim of this study was to document the clinical, electromyographic, and histological changes in dengue-associated muscle dysfunction. MATERIALS AND METHODS: Seropositive dengue patients admitted to the neurology ward during 2010 were enrolled in this study. Detailed medical history, including bleeding diathesis and organomegaly, were noted. Muscle power on a 0-5 scale, muscle tone, reflex, sensations and coordination were tested. Blood counts, hemoglobin, and serum chemistry, including creatine kinase (CK) evaluations, were carried out. Concentric needle electromyography (EMG) and muscle biopsy were performed when clinical conditions were suitable. RESULTS: The study cohort comprised 39 patients with dengue, with a median age of 28 years. Of these, 31 patients showed evidence of muscle involvement-16 with clinical and 15 with subclinical muscle involvement. Eight of these patients had severe weakness and five had hyporeflexia. Thrombocytopenia was present in 26 patients, elevated serum creatinine in three patients and liver dysfunction in 31 patients. The median CK level was 837 (range 194-3,832) U/L. The EMG revealed polyphasic normal to short duration motor unit potentials, but spontaneous activity was absent. Muscle biopsy in three patients revealed interstitial hemorrhage with occasional necrosis and myophagocytosis. There was no vasculitis, but subtle inflammatory changes were present in one patient. The severity of muscle weakness correlated with the platelet count and CK level. All patients improved by 15 days of treatment initiation. CONCLUSION: Dengue commonly results in benign and self-limiting transient muscle dysfunction.

Septo-optic dysplasia: an autopsy study of a 23-week fetus.

Septo-optic dysplasia is a rare congenital anomaly with an incidence of 1 in 10,000 live births. Recognizing this anomaly early can help parents take an informed decision. There are very few reports of pathological descriptions of this anomaly. We present neuropathological findings at autopsy following medical termination of pregnancy of a 23-week fetus with septo-optic dysplasia (SOD), optic nerve hypoplasia, absent septum pellucidum with aplastic posterior pituitary.

Brain banking in India: Relevance in current day practice.

Biobanks are set to become the norm. The explosion of new and powerful technologies like genomics and other multiomics has catapulted research from individual laboratories to multi-institutional and international partners. Today, with increasing life span, and the rising incidence of brain diseases, Brain Banks have become an invaluable source for unravelling the pathogenesis of several brain disorders, and develop effective therapies. The article briefly reviews the evolution of brain banking, rise of global networks, with a brief overview of steps involved from donor recruitment, protocols of processing, storage, annotation, and tissue distribution. The ethics of biobanking is one of the most controversial issues in bioethics, the key issues being consent, confidentiality, and commercialisation. Regulatory authorities in different countries and in India, the Indian Council of Medical Research has taken a lead to formulate new ethical guidelines for research involving human participants protecting rights, and well-being of research participants. Although brain banks have been established in the 1960s, in India, the first Brain Bank was established in 1995 at the National Institute of Mental Health and Neurosciences, Bengaluru. Now a network with two more Brain banks is being established in the country. The challenges and benefits of establishing the first Brain Bank as a National Research Facility in India is shared. For optimising available resources and promote brain banking, it is essential for medical professionals, and the public to perceive the crucial advantage in conversion of biological waste into invaluable resources for neuroscience. This will be the greatest "gift of hope" that we can offer for the future generations to overcome hitherto untreatable disorders such as dementias.

Evaluation of markers of oxidative stress, antioxidant function and astrocytic proliferation in the striatum and frontal cortex of Parkinson's disease brains.

Dopaminergic neurons die in Parkinson's disease (PD) due to oxidative stress and mitochondrial dysfunction in the substantia nigra (SN). We evaluated if oxidative stress occurs in other brain regions like the caudate nucleus (CD), putamen (Put) and frontal cortex (FC) in human postmortem PD brains (n = 6). While protein oxidation was elevated only in CD (P < 0.05), lipid peroxidation was increased only in FC (P < 0.05) and protein nitration was unchanged in PD compared to controls. Interestingly, mitochondrial complex I (CI) activity was unaffected in PD compared to controls. There was a 3-5 fold increase in the total glutathione (GSH) levels in the three regions (P < 0.01 in FC and CD; P < 0.05 in Put) but activities of antioxidant enzymes catalase, superoxide dismutase, glutathione reductase and glutathione-s-tranferase were not increased. Total GSH levels were elevated in these areas because of decreased activity of gamma glutamyl transpeptidase (γ-GT) (P < 0.05) activity suggesting a decreased breakdown of GSH. There was an increase in expression of glial fibrillary acidic protein (GFAP) (P < 0.001 in FC; P < 0.05 in CD) and glutathione peroxidase (P < 0.05 in CD and Put) activity due to proliferation of astrocytes. We suggest that increased GSH and astrocytic proliferation protects non-SN brain regions from oxidative and mitochondrial damage in PD.

Supratentorial and cerebellar liponeurocytomas: report of four cases with review of literature.

Liponeurocytoma is not exclusive to the cerebellar or fourth ventricular location. Since its inclusion in the central nervous system tumor classification in 2000, six cases with similar radiological, histomorphological and immunohistochemical features have also been described in the lateral ventricles. In the present study, we report clinical, radiological and pathological findings of three supratentorial and one cerebellar liponeurocytoma from our records, evaluated with an extensive panel of immunohistochemistry, and review published cases in the literature. The immunohistochemical pattern of supratentorial and infratentorial liponeurocytomas are almost identical, which indicates that these tumors are homologous.

Molecular characterization of Indian rabies virus isolates by partial sequencing of nucleoprotein (N) and phosphoprotein (P) genes.

Rabies is endemic and an important zoonosis in India. There are very few reports available on molecular epidemiology of rabies virus of Indian origin. In this study to know the dynamics of rabies virus, a total of 41 rabies positive brain samples from dogs, cats, domestic animals, wildlife, and humans from 11 states were subjected to RT-PCR amplification of N gene between nucleotide N521-N1262 (742 bp) and P gene between nucleotide P239-P750 (512 bp). The N gene could be amplified from 30, while P gene from 41 samples, using specific sets of primers. The N gene-based phylogenetic analysis indicated that all Indian virus isolates are genetically closely related with a single cluster under arctic/arctic-like viruses. However, two distinct clusters were realized in P gene-based phylogeny viz., Rabies virus isolates of Punjab and Rabies virus isolates of remaining parts of India (other than Punjab). All the Indian rabies virus isolates were closely related to geography (>95% homology), but not to host species.

Cerebral coenurosis mimicking hydatid disease - report of two cases from South India.

Coenurosis, a rare zoonotic disease caused by the larval form of Taenia multiceps (bladderworm) is common in sheep rearing countries, but human infections are rare. Central nervous system involvement produces large giant sized cysts that radiologically closely mimic hydatid cysts. Most human infections resulting in cerebral coenuri have been reported from Europe and Africa. We report two cases of cerebral coenurosis from India, the first in a 55-year-old male presenting with a large cystic lesion in the right parietooccipital region and the second occurring in a 36-year-old male involving the left temporal trigonal region, that radiologically closely mimicked hydatid cyst. Histopathologic examination revealed characteristic features of coenuri with multiple protoscolices invaginating into a large cyst lined by outer cuticular layer. Awareness of this rare parasitic infestation is important to discriminate from the more common hydatid and giant cysticercal cysts.

Calcium alginate entrapped preparation of α-galactosidase: its stability and application in hydrolysis of soymilk galactooligosaccharides.

Thermostable α-galactosidase from Aspergillus terreus (GR) was insolubilized using concanavalin A obtained from jack bean extract and in order to maintain the integrity of complex in the presence of its substrate or products, this complex was crosslinked with glutaraldehyde. Soluble α-galactosidase entrapped in calcium alginate retained 82% of enzyme activity whereas, Con A-α-galactosidase complex entrapped in calcium alginate and crosslinked Con A-α-galactosidase complex entrapped calcium alginate retained 74 and 61% activity, respectively. A fluidized bed reactor was constructed for continuous hydrolysis of galactooligosaccharides in soymilk using crosslinked Con A-α-galactosidase complex entrapped calcium alginate. Optimum conditions such as pH (5.0) and temperature (65°C) were the same for all immobilized enzyme preparations and soluble enzyme. Crosslinked Con A-α-galactosidase entrapped complex exhibited enhanced thermostability and showed 62% of activity (38%) after 360 min at 65°C. Entrapped crosslinked Con A-α-galactosidase complex preparation was superior in the continuous hydrolysis of oligosaccharides in soymilk by batch processes compared to the other entrapped preparations. The entrapped crosslinked concanavalin A-α-galactosidase complex retained 95% activity after eight cycles of use.

Rosai-Dorfman disease presenting as cervical extradural lesion: a case report with review of literature.

Sinus histiocytosis with massive lymphadenopathy or Rosai-Dorfman disease is a rare, but well documented entity. We report a lady who presented with progressive quadriparesis, with cervical extradural lesion on magnetic resonance imaging. She underwent decompression of the lesion and histological diagnosis of the lesion was Rosai-Dorfman disease. On one-year follow-up, she had complete improvement of the deficits with no further progression of the lesion. The presentation of this disease as an isolated spinal extradural mass lesion is quite rare, with only six cases reported in literature.

Glycogen storage disease type V (Mc Ardle's disease): a report on three cases.

McArdle's disease (myophosphorylase deficiency), an uncommon autosomal recessive metabolic disorder, is characterized clinically by exercise intolerance beginning in childhood, myalgia, cramps, exercise-induced rhabdomyolysis, "second wind" phenomenon, elevated Creatine Kinase (CK) levels at rest, and previous episodes of raised CK levels following exercise. Several mutations in the PYGM gene and geographic variations have been described. We report three biopsy confirmed cases of McArdle's disease.