Proteomics in neurodegeneration – disease driven approaches

Summary. Proteins as a product from genetic information execute and determine how development, growth, aging and disease factors are orchestrated within the lifetime of an organism. Differential protein expression and/or modification are always context dependent i.e. they happen within a specific context of a tissue, organ, environmental situation and individual fate. Consequently, the function/dysfunction (in a certain disease) of a specific gene cannot be predicted comprehensively by its sequence only. Genetic information can only be understood when genes and proteins are analyzed in the context of the biological system and specific networks they are involved in. In regard to neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s disease (PD) many proteins are known for long years to be the cause or the consequence of the pathomechanism of the respective disease. The treatment of these neurodegenerative diseases represents a major challenge for the pharmaceutical industry, whereas the understanding of their pathogenesis is still in its infancy. With the development of several powerful techniques for proteome analysis it is now possible to investigate the expression of thousands of proteins in single cells, tissues or whole organisms at the same time. These developments opened new doors in medical sciences, and identification of cellular alterations associated with e.g. neurodegeneration will result in the identification of novel diagnostic as well as therapeutic targets. In this review, general considerations and strategies of proteomics technologies, the advantages and challenges as well as the special needs for analyzing brain tissue in the context of AD and AD are described and summarized. These authors contribute equally to the review     

Diastematomyelia associated with ectopic dysplastic renal tissue – report of a rare case

BACKGROUND: Presence of heterotopic dysplastic renal tissue in the lumbosacral region is an extremely uncommon condition. CASE REPORT: We report the first case of diastematomyelia associated with ectopic renal tissue. A 10-month-old male child presented with lipomeningomyelocele associated with spina bifida in the lumbosacral region, and the lipoma was excised. Imaging of the spine at 5 years of age showed spina bifida, bony diastematomyelia, lipomeningomyelocele and a small intraspinal cystic lesion. The boy was then operated upon at the age of 5 years, and histopathological examination of the cystic lesion revealed ectopic dysplastic renal tissue.     

Carpal tunnel syndrome? Case report

A patient with an initial misdiagnosis of carpal tunnel syndrome is presented. The clinical manifestations were suggestive of such diagnosis, but there were some anamnesis and exploratory aspects requiring to establish a differential diagnosis. Painful syndrome was caused by a brachial plexus compression at the costoclavicular region due to a subclavicular hematoma in a patient under anticoagulant treatment. Carpal tunnel pathology is a frequent cause of neuropathy, however others diagnosis should be ruled out as shown in the present case.     

Phrenic nerve palsy associated with birth trauma – Case reports and a literature review

Phrenic nerve palsy is a peripheral nerve disorder caused by excessive cervical extension due to birth trauma or cardiac surgery. We describe two new patients with phrenic nerve palsy associated with birth trauma. Both patients exhibited profound dyspnea and general hypotonia immediately after birth. A chest roentgenogram and fluoroscopy revealed elevation of the diaphragm, leading to a diagnosis of phrenic nerve palsy associated with birth trauma. Since they had intermittently exhibited dyspnea and recurrent infection, we performed video-assisted thoracoscopic surgery (VATS) plication in both cases, at an early and a late stage, respectively. Both patients subsequently exhibited a dramatic improvement in dyspnea and recurrent respiratory infection. Interestingly, the late stage operated infant exhibited spontaneous recovery at 7 months with cessation of mechanical ventilation once. However, this recovery was transient and subsequently led to an increased ventilation volume demand, finally resulting in surgical treatment at 15 months. Histological examination of the diaphragm at this time showed grouped muscle atrophy caused by phrenic nerve degeneration. To our knowledge, this is the first pathologically proven report of grouped muscle atrophy of the diaphragm due to phrenic nerve degeneration, suggesting that partial impairment of phrenic nerves resulted in respiratory dysfunction with incomplete recovery. We conclude that recently developed VATS plication is a safe and effective treatment for infants with phrenic nerve palsy, and should be considered as a surgical treatment at an early period.     

Physical and functional evaluation in Marden–Walker syndrome: Case report – Review of literature

Objective: To review literature concerning Marden–Walker syndrome (MWS) and describe physical–functional characteristics of a child with a suspected diagnosis of MWS.

Methods: Physical examination, laboratory and clinical tests were collected in a two-year-old boy. Bayley Scales of Infant and Toddler Development (BSITD-III) was applied to evaluate motor-cognitive development.

Results: Several facial features (blepharophimosis/micrognathia/cleft palate/pectus deformation/kyphoscoliosis), besides delayed physical growth, anemia, hypoplastic muscles, muscle atrophy and arachnodactyly were found; which are typically described in MWS. BSITD-III scaled scores were 1, 2 and 1, respectively, for gross-motor, fine-motor and cognitive skills; representing delays that were slightly more severe for gross-motor and cognitive skills compared with fine motor. We did not find joint contractures, which are strongly associated with MWS. Instead, we observed moderate muscle shortening.

Conclusions: The results found could be attributed to the early intervention applied to the child since eight months old; findings that highlight the importance of early intervention.     

Monomeric C-reactive protein:a link between chronic inflammation and neurodegeneration?

<正>Pre-diabetic insulin resistance is associated with sub-clinical inflammation and concomitant increase in systemic C-reactive protein(CRP) levels.Type 2 diabetes mellitus(T2DM) patients register even higher chronic levels of inflammation,with excess circulating CRP originating from both typical hepatic synthesis,and also visceral white adipose tissue.     

Acute neurological symptoms of Moschcowitz disease—Case report

Thrombotic thrombocytopenic purpura (TTP, Moschcowitz disease) is characterized by thrombotic microangiopathy leading to microvascular occlusion and ischemic dysfunction of various organs including the brain. In the course of the rare disease most patients develop neurological symptoms of varying severity and characteristics. The case presented is that of a 34-year-old female patient with profound thrombocytopenia, anemia and rapidly progressive neurological deterioration into coma with normal result of brain imaging. TTP was recognized on the basis of hematological analysis. The initiated steroid therapy and plasma exchange failed to prevent the turbulent course of disease in the patient, who died exhibiting symptoms of multiple organ failure caused by thrombotic microangiopathy. TTP remains to be a diagnostic challenge, particularly in the case of atypical symptoms or when neuroimaging and laboratory results are inconclusive. Before using the corticosteroids and plasma exchange, TTP had a case fatality rate of approx. 90% (Podolak-Dawidziak, 2013). Nowadays recovery is possible when vigorous treatment is introduced early in the course of this disease.     

Post-mortem magnetic resonance imaging and its irreplaceable role in determining CNS malformation (hydranencephaly) – Case report

Post-mortem magnetic resonance appears to be a method supplementary to classic pathological–anatomical autopsy in determining foetal abnormalities. Frequently, it plays a key role, primarily where autopsy options are in some way limited (developed autolysis, dilatation of the ventricular system). This case report demonstrates that post-mortem magnetic resonance imaging can precisely determine the type of congenital malformation (hydranencephaly), by contrast to ultrasound, with which alobar holoprosencephaly has been described, often presenting a differential diagnosis problem. Pathological–anatomical autopsy was significantly limited due to this diagnosis and this methodology was incapable of unequivocally determining the type of malformation. We would like to demonstrate by this case report the necessity of performing post-mortem magnetic resonance imaging so that we may precisely determine the diagnosis as requested by the parents and also be able to answer the question posed by risks for future pregnancies.     

CSF neurofilament protein (NFL) — a marker of active HIV-related neurodegeneration

Abstract Background and methods The light subunit of the neurofilament protein (NFL), a major structural component of myelinated axons, is a sensitive indicator of axonal injury in the central nervous system (CNS) in a variety of neurodegenerative disorders. Cerebrospinal fluid (CSF) NFL concentrations were measured by ELISA (normal < 250 ng/l) in archived samples from 210 HIV-infected patients not taking antiretroviral treatment: 55 with AIDS dementia complex (ADC), 44 with various CNS opportunistic infections/tumours (CNS OIs), 95 without neurological symptoms or signs, and 16 with primary HIV infection (PHI). The effect of highly active antiretroviral treatment (HAART) was studied by repeated CSF sampling in four of the ADC patients initiating treatment. Results CSF NFL concentrations were significantly higher in patients with ADC (median 2590 ng/l, IQR 780–7360) and CNS OIs (2315 ng/l, 985–7390 ng/l) than in neuroasymptomatic patients (<250 ng/l, <250–300) or PHI (<250 ng/l, <250–280), p < 0.001. Among patients with ADC, those with more severe disease (stage 2–4) had higher levels than those with milder disease (stage 0.5–1), p < 0.01. CSF NFL declined during HAART to the limit of detection in parallel with virological response and neurological improvement in ADC.CSF NFL concentrations were higher in neuroasymptomatic patients with lower CD4-cell strata than higher, p < 0.001. This increase was less marked than in the ADC patients and noted in 26/58 neuroasymptomatic patients with CD4 counts <200/μl compared to 1/37 with CD4-cells ≥200/μl. Conclusions The findings of this study support the value of CSF NFL as a useful marker of ongoing CNS damage in HIV infection. Markedly elevated CSF NFL concentrations in patients without CNS OIs are associated with ADC, follow the grade of severity, and decrease after initiation of effective antiretroviral treatment. Nearly all previously suggested CSF markers of ADC relate to immune activation or HIV viral load that do not directly indicate brain injury. By contrast NFL is a sensitive marker of such injury, and should prove useful in evaluating the presence and activity of ongoing CNS injury in HIV infection. Drs. Abdulle and Mellgren contributed equally to this work.     

Mitochondrial DNA depletion syndromes – Many genes,common mechanisms

Mitochondrial DNA depletion syndrome has become an important cause of inherited metabolic disorders, especially in children, but also in adults. The manifestations vary from tissue-specific mtDNA depletion to wide-spread multisystemic disorders. Nine genes are known to underlie this group of disorders, and many disease genes are still unidentified. However, the disease mechanisms seem to be intimately associated with mtDNA replication and nucleotide pool regulation. We review here the current knowledge on the clinical and molecular genetic features of mitochondrial DNA depletion syndrome.     

Vasculitis-related stroke in young as a presenting feature of novel coronavirus disease (COVID19) – Case report

COVID-19 is the disease caused by Novel Coronavirus (SARS-CoV-2) infection and world current main public health problem, due to its easy transmissibility and multiple clinical presentations. The main symptoms reported worldwide are dry cough, dyspnea, and fever, as well as anosmia and ageusia. COVID-19 diagnosis is made with RT-PCR, but many other complementary exams may be used to guide clinical practice, such as Chest Computerized Tomography (CT), showing ground glass opacities; increase in inflammatory markers, as C-Reactive Protein and Erythrocyte Sedimentation Rate; hemogram might show hypoalbuminemia, thrombocytopenia. Severe cases may evolve to thromboembolic and atheroembolic events, leading to stroke, myocardial infarction, pulmonary thromboembolism. Male, 28 years old, went for neurological appointment after presenting episode of intense headache, dysarthria, deviation of lip rhyme on appointment’s eve. Previously healthy, no comorbidities or risk factors. Underwent brain MRI and serum serological analysis. SARS-CoV-2 capacity of affecting brain homeostasis by breaking blood–brain barrier, makes it easier to develop ischemic or inflammatory damage, and invading central nervous system. Neurological symptoms and syndromes are the main consequences of COVID-19 pandemic and must be prevented through adequate clinical management.     

Mitochondrial diabetes complicated by or associated with "MELAS" syndrome?

We report the case of fifty-two year-old mentally deficient female who presented with diabetes mellitus, deafness, stroke-like episodes, cardiomyopathy, and macular pattern dystrophy of the retina. Her brain exhibited calcification within basal ganglia, lactacidaemia was not increased. Although her skeletal muscles had never been clinically impaired, a quadriceps biopsy led to the diagnosis of mitochondrial disease because it exhibited ragged red fibers and heteroplasmic point-mutation at position 3243 of the mitochondrial DNA, although not any detectable respiratory chain complex deficiency was found. The mutant percentage in muscle was 70 p.100 and 5 to 10 p.100 in leukocytes. The question of whether a diabetic microangiopathy may be responsible stroke-like episodes is discussed. We suggest it was rather a complicated form of diabetes-deafness than a incomplete MELAS syndrome associated with mitochondrial diabetes.     

Amyloid-β protein precursor regulates phosphorylation and cellular compartmentalization of microtubule associated protein tau

Tau is a multifunctional protein detected in different cellular compartments in neuronal and non-neuronal cells. When hyperphosphorylated and aggregated in atrophic neurons, tau is considered the culprit for neuronal death in familial and sporadic tauopathies. With regards to Alzheimer's disease (AD) pathogenesis, it is not yet established whether entangled tau represents a cause or a consequence of neurodegeneration. In fact, it is unquestionably accepted that amyloid-β protein precursor (AβPP) plays a pivotal role in the genesis of the disease, and it is postulated that the formation of toxic amyloid-β peptides from AβPP is the primary event that subsequently induces abnormal tau phosphorylation. In this work, we show that in the brain of AD patients there is an imbalance between the nuclear and the cytoskeletal pools of phospho-tau. We observed that in non-AD subjects, there is a stable pool of phospho-tau which remains strictly confined to neuronal nuclei, while nuclear localization of phospho-tau is significantly underrepresented in neurons of AD patients bearing neurofibrillary tangles. A specific phosphorylation of tau is required during mitosis in vitro and in vivo, likely via a Grb2-ERK1/2 signaling cascade. In differentiated neuronal A1 cells, the overexpression of AβPP modulates tau phosphorylation, altering the ratio between cytoskeletal and nuclear pools, and correlates with cell death. Altogether our data provide evidence that AβPP, in addition to amyloid formation, modulates the phosphorylation of tau and its subcellular compartmentalization, an event that may lead to the formation of neurofibrillary tangles and to neurodegeneration when occurring in postmitotic neurons.     

Meningoencephalitis caused by Lactobacillus plantarum – case report

Specific strains of Lactobacillus spp. are widely used as probiotic agents but it has been repeatedly reported that may have a pathogenic potential. We present the report on a case of meningoencephalitis caused by Lactobacillus plantarum in a 63-year-old man with newly diagnosed metastatic planoepitheliale lung cancer. The patient was hospitalised due to newly diagnosed cancer and during the course of hospitalisation developed symptoms of neuroinfection. On the basis of the symptoms and results of the conducted tests the patient was diagnosed with bacterial meningoencephalitis. In microbiological tests of the blood and cerebrospinal fluid L. plantarum was cultured. During the course of antibiotic therapy the patient’s condition improved. Lactobacilli are now recognised as a causative agent of infection, most notably bacteraemia. To our knowledge, this is the fourth documented case of Lactobacillus-associated neuroinfection, and only the second in an adult. Lactobacilli cause mostly opportunistic infections in immunocompromised individuals.     

Mitochondrial dysfunction – a pathogenetic factor in Parkinson’s disease

The cause of Parkinson’s disease is still unknown. Nonetheless, there are some generally accepted hypotheses with respect to the cascade of dopaminergic cell degeneration. One of the factors is a decrease in respiratory chain complex I activity. This enzyme abnormality is only found in substantia nigra pars compacta. It is not currently known whether this is due to a genetic abnormality of the nuclear or mitochondrial genome or to an exo- or endotoxin. To date, no specific abnormality of the mitochondrial genome has been detected, although ageing leads to deletions in up to 5% of all mitochondrial genome molecules in the brain. There is controversy whether this complex I defect is also detectable in muscle or blood cells. It is our conviction that the considerable overlap between blood cells from normal controls and patients with Parkinson’s disease means that such measurements are not distinctive for the two conditions. A decrease in complex I activity in post-mitotic cells may be one of the crucial factors for cell death.