Pathoarchitectonics of the cerebral cortex in chorea-acanthocytosis and Huntington's disease.

AIMS: Quantitative estimation of cortical neurone loss in cases with chorea-acanthocytosis (ChAc) and its impact on laminar composition. METHODS: We used unbiased stereological tools to estimate the degree of cortical pathology in serial gallocyanin-stained brain sections through the complete hemispheres of three subjects with genetically verified ChAc and a range of disease durations. We compared these results with our previous data of five Huntington's disease (HD) and five control cases. Pathoarchitectonic changes were exemplarily documented in TE1 of a 61-year-old female HD-, a 60-year-old female control case, and ChAc3. RESULTS: Macroscopically, the cortical volume of our ChAc cases (ChAc1-3) remained close to normal. However, the average number of neurones was reduced by 46% in ChAc and by 33% in HD (P = 0.03 for ChAc & HD vs. controls; P = 0.64 for ChAc vs. HD). Terminal HD cases featured selective laminar neurone loss with pallor of layers III, V and VIa, a high density of small, pale, closely packed radial fibres in deep cortical layers VI and V, shrinkage, and chromophilia of subcortical white matter. In ChAc, pronounced diffuse astrogliosis blurred the laminar borders, thus masking the complete and partial loss of pyramidal cells in layer IIIc and of neurones in layers III, V and VI. CONCLUSION: ChAc is a neurodegenerative disease with distinct cortical neurodegeneration. The hypertrophy of the peripheral neuropil space of minicolumns with coarse vertical striation was characteristic of ChAc. The role of astroglia in the pathogenesis of this disorder remains to be elucidated.

[Pathomechanisms and clinical aspects of frontotemporal lobar degeneration]. / Pathomechanismen und klinische Aspekte der frontotemporalen Lobärdegeneration.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) includes a spectrum of heterogeneous clinical and neuropathological diseases. In a strict sense this includes the behavioral variant of frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA) and both variants can be associated with amyotrophic lateral sclerosis (FTD-ALS). In a broader sense FTLD also includes progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). In recent years the strong genetic component of FTLD has become increasingly clear. OBJECTIVE: The association between clinical presentation, neuropathology, genetics and pathophysiological mechanisms of FTLD are presented. RESULTS: The diagnostic criteria and tools for the clinical differential diagnosis of FTLD are presented. At autopsy patients show neuronal and glial inclusions of Tau, TDP-43 or FUS. While Tau pathology is often associated with extrapyramidal symptoms, patients with TDP-43 and FUS inclusions often also show signs of ALS. Pathogenic mutations directly increase the aggregation propensity of these proteins or impair protein degradation through autophagy or the proteasome. Pathogenic mutations in most FTLD genes trigger cytoplasmic missorting and aggregation of the RNA-binding protein TDP-43 and thus lead to a nuclear loss of TDP-43 function. Microgliosis and mutations in GRN and TREM2 suggest an important role of neuroinflammation in FTLD. CONCLUSION: There is still no causal therapy for FTLD but preclinical studies focusing on pathogenic mutations in C9orf72, GRN and Tau may lead to clinical trials soon; therefore, establishing large well characterized patient cohorts is crucial for trial readiness.

Changes in the expression of genes related to neuroinflammation over the course of sporadic Alzheimer's disease progression: CX3CL1, TREM2, and PPARγ.

The role of neuroinflammation in the pathogenesis of neurodegenerative diseases has become more evident in recent years. Research on the etiology and pathogenesis of sporadic Alzheimer's disease (AD) has focused on the role of chemokines such as CX3CL1, on the triggering receptors expressed by myeloid cells (TREMs), especially TREM2, and on the transcription factor/nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARγ). Here we analyzed the expression levels of CX3CL1, TREM2, and PPARγ in tissue homogenates from human brain regions that have different degrees of vulnerability to neuropathological AD-related changes to obtain insights into the pathogenesis and progression of AD. We found that CX3CL1 and TREM2, two genes related to neuroinflammation, are more highly expressed in brain regions with pronounced vulnerability to AD-related changes, such as the hippocampus, and that the expression levels reflect the course of the disease, whereas regions with low vulnerability to AD, seemed generally less affected by neuroinflammation. Furthermore, our results support previous findings of significantly higher CX3CL1 plasma levels in patients with mild to moderate AD than in patients with severe AD. Thus, CX3CL1 should be considered as promising additional marker for the early diagnosis of AD and underlines once more, the involvement of the neuroinflammation in the pathogenesis of this neurodegenerative disease.

[Hereditary diffuse leukencephalopathy with spheroids: a microgliopathy due to CSF1 receptor impairment]. / Hereditäre diffuse Leukenzephalopathie mit Sphäroiden : Eine Mikrogliopathie durch Fehlfunktion des CSF1-Rezeptors.

Hereditary diffuse leukencephalopathy with spheroids (HDLS) is a rare progressive form of leukodystrophy with variable clinical presentation and little known pathophysiology. Characteristic pathological features at brain biopsy or postmortem can support the diagnosis. The genetic basis of HDLS was elusive until 2011 when mutations in the colony-stimulating factor 1 receptor (CSF1R) gene were identified as the cause. Mutations in the CSF1R gene had previously been associated with tumor development, including hematological malignancies. We report three patients with HDLS who carried missense mutations in the CSF1R gene, two of them novel (p.L582P and p.V383L). Particularly in younger patients with rapid cognitive decline and/or leukencephalopathy of unknown origin, HDLS appears to be more common than previously thought. Various compounds acting on the CSF1 receptor are available from the treatment of hemato-oncological malignancies, so novel therapeutic approaches could be developed for this devastating condition.

Gene expression in superior temporal cortex of schizophrenia patients.

We investigated gene expression pattern obtained from microarray data of 10 schizophrenia patients and 10 control subjects. Brain tissue samples were obtained postmortem; thus, the different ages of the patients at death also allowed a study of the dynamic behavior of the expression patterns over a time frame of many years. We used statistical tests and dimensionality reduction methods to characterize the subset of genes differentially expressed in the two groups. A set of 10 genes were significantly downregulated, and a larger set of 40 genes were upregulated in the schizophrenia patients. Interestingly, the set of upregulated genes includes a large number of genes associated with gene transcription (zinc finger proteins and histone methylation) and apoptosis. We furthermore identified genes with a significant trend correlating with age in the control (MLL3) or the schizophrenia group (SOX5, CTRL). Assessments of correlations of other genes with the disorder (RRM1) or with the duration of medication could not be resolved, because all patients were medicated. This hypothesis-free approach uncovered a series of genes differentially expressed in schizophrenia that belong to a number of distinct cell functions, such as apoptosis, transcriptional regulation, cell motility, energy metabolism and hypoxia.

Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: a study of the BrainNet Europe Consortium.

AIMS: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurones. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. METHODS: We evaluated immunoreactivity (IR) for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. RESULTS: Mean age at death was 68.2 years (range 49-96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of frontotemporal dementia, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein IR was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurones. Aß IR was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. CONCLUSIONS: (i) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; (ii) even minor deviation from these morphological criteria suggests a different disorder; and (iii) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification.

Microglia activation is related to substantia nigra echogenicity.

Hyperechogenicity of the substantia nigra (SN) is a sensitive marker for Parkinson's disease (PD). Previously, a relation between SN echogenicity and iron as well as neuromelanin content could be described in 60 human brains. In the present study on a subset of 33 brains, SN echogenicity was found to be correlated with microglia activation (ρ = 0.46, p = 0.008) after correction for iron and neuromelanin content. These findings strengthen the hypothesis of a close pathophysiological connection between SN hyperechogenicity and PD pathology.

Combined surgical and radiosurgical treatment of symptomatic aggressive vertebral osteomyelitis.

INTRODUCTION: The surgical treatment of vertebral osteomyelitis can be complicated by severe additional diseases or the need for extensive debridement with concomitant risks. We report a case of combined surgical and radiosurgical treatment of idiopathic vertebral osteomyelitis of L4. CASE REPORT: The patient presented with progressive enlargement of the right side of the vertebral body L4 due to chronic fibrous osteomyelitis without evidence of infection, leading to compression of nerve roots L4, L5 and the dural sac with resulting radicular paresis. During decompression of the nerve roots via a dorsal approach, massive bleeding from the inflammatory vertebral body occurred, making abortion of surgery necessary. Remnant inflammatory masses of vertebral body L4 were treated by spinal robotic radiosurgery with a high tumoricidal dose of 20 Gy without clinical and radiological signs of relapse of disease in the following three years. CONCLUSION: We describe a case of the combined surgical and radiosurgical treatment of lumbar osteomyelitis with symptomatic nerve root compression. Dorsal decompression followed by spinal radiosurgery for the anterior vertebral parts with avoidance of potentially dangerous anterior spondylectomy led to a rapid improvement of paresis and pain with persistent control of vertebral inflammation and enlargement. The described case of close cooperation of surgeons and radiosurgeons offered an effective and functionality preserving treatment in this challenging case.

[Fatal familial insomnia--a rare differential diagnosis in dementia]. / Letale familiäre Insomnie--Eine seltene Differenzialdiagnose in der Demenzabklärung.

Fatal familial insomnia (FFI)--first reported in 1986--is a hereditary prion disease with autosomal-dominant inheritance, caused by a missense-mutation at codon 178 of the prion-protein gene (PRNP) on chromosome 20. A methionine-valine polymorphism at codon 129 of PRNP expresses different phenotypes. The clinical features of FFI are characterized by a disrupted sleep-wake cycle with resulting fluctuations of vigilance, autonomic hyperactivation, myoclonus, motor abnormalities and by cognitive disturbances. The age of onset is between middle to late adulthood (51 +/- 7.1 years), disease duration varies between 8 and 72 months (18.4 +/- 17.3 months) and is ultimately fatal. We report the case of a 57-year-old man with a diagnosed FFI by molecular-genetic investigation who suffered from increasing memory- and sleep-disturbance as well as physical restlessness and impotence for 9 months. Clinical features were motor symptoms, generalized myoclonus and hyperactivity with reduced attention and concentration. The neuropsychological findings were a severe disturbance of attention and memory as well as incipient deficits in executive functions. The cranial MRI and repeated EEG were normal; in detailed laboratory tests including CSF no abnormalities were detected. The clinical course was characterized by rapid decline of the motor and cognitive skills; the patient died 15 months after onset. Histological analysis showed the typical changes of FFI (spongiform changes at hippocampus and regio entorhinalis, severe gliosis in the thalamus and mild deposits of abnormal prion protein).

Tyrosinase is not detected in human catecholaminergic neurons by immunohistochemistry and Western blot analysis.

Catecholaminergic neurons of the primate substantia nigra (SN) pars compacta (SNc) and the locus coeruleus contain neuromelanin (NM) granules as characteristic structures underlying the pigmentation of these brain areas. Due to a phylogenetic appearance NM granules are absent in the rodent brain, but gradually become present in primates until they reach a maximal expression in humans. Although a possible mechanism of pigment formation may be autoxidation of the NM precursors dopamine or noradrenalin, several groups have suggested an enzymatic formation of NM mediated by tyrosinase or a related enzyme. Since tyrosinase mRNA is suggested to be expressed in the SN of mice and humans, we reinvestigated the expression of tyrosinase in the human SNc and the locus coeruleus at the protein level by immunohistochemistry and Western blot analysis, but could not detect tyrosinase in these brain regions.

CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions.

CCL19 and CCL21 bind to CCR7, which is crucial for both inducing an immune response and establishing immunological tolerance. We report that in the normal human brain CCL19, but not CCL21, is transcribed, and detectable as a protein in tissue lysates and in cerebrospinal fluid. In both active and inactive multiple sclerosis (MS) lesions CCL19 transcripts were elevated. In cerebrospinal fluid from MS and OIND patients CCL19 protein was increased. In relapsing-remitting and secondary progressive MS patients CCL19 correlated with intrathecal IgG production. This study suggests that CCL19 plays a role in both the physiological immunosurveillance of the healthy CNS and the pathological maintenance of immune cells in the CNS of MS patients.

Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer's disease.

Excitatory neurotransmitter dysfunction has been discussed to be involved in the pathophysiology of Alzheimer's disease (AD). In the current study we investigated gene and protein expression patterns of glutamatergic receptors and transporters in brains of AD patients in various stages of disease using gene chip arrays, real time PCR and immunohistochemistry. We found marked impairment in the expression of excitatory amino acid transporters (EAAT1 and EAAT 2) at both gene and protein levels in hippocampus and gyrus frontalis medialis of AD patients, already in early clinical stages of disease. The loss of EAAT immunoreactivity was particularly obvious in the vicinity of amyloid plaques. In contrast, EAAT expression was up-regulated in the cerebellum of these patients. Furthermore, a significant up-regulation of the glutamatergic kainate (GRIK4) receptor observed by gene arrays was confirmed by quantitative RT-PCR in late stages in the hippocampus of AD patients. Moreover, there were down-regulations of other glutamatergic receptors such as NMDA (GRINL1A) and AMPA (GRIA4) receptors. Our data show marked changes in the functional elements of the glutamatergic synapses such as glutamatergic receptors and transporters and indicate impaired glutamate clearing rendering neurons susceptible to excess extracellular glutamate and support further the involvement of excitotoxic mechanisms in the pathogenesis of AD.

Neuronal and ependymal expression of selenoprotein P in the human brain.

Selenoprotein P (SePP) is central to selenium (Se) metabolism in the mammalian organism. Human SePP contains 10 Se atoms that are covalent constituents of the polypeptide chain incorporated as the rare amino acid selenocysteine (Sec). Since hepatocytes secrete SePP into plasma, SePP is commonly regarded as a Se transport protein, although SePP mRNA is expressed in many organs. Gene targeting of SePP in mice leads to neurological dysfunction resulting from Se deficiency and associated reduction of selenoenzyme activities in the brain. However, more recent data revealed that isolated hepatic SePP deficiency does not alter brain Se levels, suggesting a role for SePP locally expressed in the brain. Some of the best characterized and most abundant selenoenzymes, glutathione peroxidases, thioredoxin reductases, and methionine sulfoxide reductase B, play major roles in the cellular defense against reactive oxygen species. Therefore, it was hypothesized that reduced brain Se bioavailability may be involved in the pathogenesis of neurodegenerative disease and normal ageing. We present evidence that human CSF contains SePP and that the human brain expresses SePP mRNA. Moreover, SePP-like immunoreactivity localizes to neurons and ependymal cells and thus appears strategically situated for maintenance and control of Se-dependent anti-oxidative defense systems.

How a neuropsychiatric brain bank should be run: a consensus paper of Brainnet Europe II.

The development of new molecular and neurobiological methods, computer-assisted quantification techniques and neurobiological investigation methods which can be applied to the human brain, all have evoked an increased demand for post-mortem tissue in research. Psychiatric disorders are considered to be of neurobiological origin. Thus far, however, the etiology and pathophysiology of schizophrenia, depression and dementias are not well understood at the cellular and molecular level. The following will outline the consensus of the working group for neuropsychiatric brain banking organized in the Brainnet Europe II, on ethical guidelines for brain banking, clinical diagnostic criteria, the minimal clinical data set of retrospectively analyzed cases as well as neuropathological standard investigations to perform stageing for neurodegenerative disorders in brain tissue. We will list regions of interest for assessments in psychiatric disorder, propose a dissection scheme and describe preservation and storage conditions of tissue. These guidelines may be of value for future implementations of additional neuropsychiatric brain banks world-wide.

Expression of epidermal growth factor receptor in neoplastic pituitary cells: evidence for a role in corticotropinoma cells.

The oncogenic effects of epidermal growth factor (EGF) have long been established. EGF receptor (EGFr) is overexpressed in many types of tumors and constitutes a target for cancer treatment. The pituitary gland is a target of EGF action and it is very likely that EGFr plays a role in pituitary tumor formation and progression. However, there is a controversy in the literature concerning EGFr expression in the different types of pituitary adenomas. In the present study we investigated the expression pattern of the wild type EGFr (EGFrWT) and the constitutively active variant III (EGFrvIII) at the mRNA and protein levels in a large series of pituitary tumors. EGFrWT was found in a high percentage of hormone-secreting tumors, but only in a small fraction of non-functioning pituitary adenomas, while no expression of the EGFrvIII could be detected by nested RT-PCR in any tumor. Among the hormone-secreting adenomas, the highest incidence of EGFr expression was found in Cushing's pituitary adenomas. Furthermore, immunohistochemistry for the phosphorylated EGFr revealed the presence of activated EGFr in most Cushing's adenomas, compared with most pituitary adenomas. Taking into account that downregulation of p27/Kip1 plays a significant role in corticotrope tumorigenesis and that EGFr mitogenic signaling results in decreased p27/Kip1, we searched for a correlation between EGFr expression and p27/Kip1 levels in corticotropinomas. Low p27/Kip1 immunoreactivity was observed in corticotropinomas expressing EGFr. On the other hand, somatotropinomas expressing EGFr had high p27/Kip1 immunoreactivity. These data suggest a corticotrope-specific phenomenon and indicate that EGFr may have a role in the unbalanced growth of corticotrope tumoral cells.

Differential expression of menin in sporadic pituitary adenomas.

Pituitary adenomas represent one of the key features of multiple endocrine neoplasia type 1. The gene involved in this syndrome (MEN1) is a putative tumor suppressor, that codes for a 610-amino acid nuclear protein termed 'menin'. Analyses of sporadic pituitary adenomas have so far failed to reveal MEN1 mutations or defects in MEN1 transcription in these tumors. In the present study we detected menin protein expression in a panel of normal and tumoral pituitary tissues, using a monoclonal antibody against the carboxy-terminus of menin. In the normal human pituitary gland, strong nuclear staining for menin was detectable in the majority of the endocrine cells of the anterior lobe, without a clear association with a particular hormone-producing type. In sporadic pituitary adenomas, menin expression was variable, with a high percentage of cases demonstrating a significant decrease in menin immunoreactivity when compared with the normal pituitary. Interestingly, metastatic tissues derived from one pituitary carcinoma had no detectable menin levels. Altogether, our data provide the first information regarding the status of menin expression in human normal and neoplastic pituitary as determined by immunohistochemistry (IHC).

Dopamine receptor agonists in current clinical use: comparative dopamine receptor binding profiles defined in the human striatum.

The aim of this study was to compare dopamine receptor binding affinities of all currently approved dopamine receptor agonist treatments for Parkinson's disease (PD) in human brain tissue. Alpha-dihydroergocryptine and lisuride displayed higher comparative affinities (Ki=35.4 and 56.7 nM, respectively) for D1 receptors, than the D1/D2 dopamine agonist pergolide (Ki=447 nM). The second generation non-ergot dopamine receptors agonists pramipexole and ropinirole demonstrated no affinity for D1 receptors at concentrations up to 10(-4) M. The ergoline dopamine agonists cabergoline and lisuride displayed the highest affinities for the D2 receptor (Ki=0.61 and 0.95 nM, respectively). Surprisingly, the second generation non-ergot dopamine receptors agonists pramipexole and ropinirole only weakly inhibited binding to D2 receptors (Ki=79.5 and 98.7 microM, respectively using [3H]spiperone). Interestingly we also found that the affinities of cabergoline (Ki=1.27 nM), lisuride (Ki=1.08 nM) and pergolide (Ki=0.86 nM) for the D3 receptor subtype were comparable to that of pramipexole (Ki=0.97 nM). The present results thus support the hypothesis that the antiparkinsonian effect of dopamine receptor agonists is mediated by a more complex interactions with dopamine receptor subtypes than currently believed.

Characterization of the human and mouse genes encoding the tuberoinfundibular peptide of 39 residues, a ligand of the parathyroid hormone receptor family.

The polypeptide TIP39 (tuberoinfundibular peptide of 39 residues) is a potent activator of the parathyroid hormone (PTH)-2 receptor (P2R) and an antagonist of the PTH-1 receptor (P1R). To clarify its possible physiological function(s), we studied its interaction with the human P1R and P2R and examined the expression of TIP39 in man and mouse. To find out possible sites of this ligand interaction in the organism, we identified the genes encoding the TIP39 protein precursors of Homo sapiens and Mus musculus in the databases of the human and mouse genome projects respectively. We then obtained the full-length cDNAs of both species by RACE-PCR. The deduced TIP39 preprohormones consist of an N-terminal 30 amino acid (aa) signal peptide followed by a 29 aa TIP39 precursor-related peptide, an Arg-Arg processing site, and the actual 39 aa TIP39 sequence. The first 23 aa of the actual TIP39 sequence, thought to contain the P2R receptor activation site, are identical in man and mouse and thus phylogenetically conserved. By contrast, the 16 aa C-terminal portion showed a higher degree of diversity (75% aa identity). By using RT-PCR, TIP39 was found to be highly expressed in human central nervous system tissues, trachea, fetal liver, and, to a lesser degree, in human heart and kidney. Using in situ hybridization, TIP39 mRNA expression was revealed in various areas of the mouse brain. In a homologous human cell model using human embryonic kidney 293 cells stably transfected with human P1R and P2R, human TIP39 did bind to P1R with moderate affinity (IC(50) approximately 10(-7)-10(-6 )M), but showed higher affinity binding to P2R (IC(50) approximately 10(-8)M), comparable to the affinity of human N-terminal PTH (hPTH(1-34)) to this receptor. In P2R-transfected cells, the cAMP pathway was activated more efficiently ( approximately 10-fold) by TIP39 as a ligand compared to hPTH(1-34). In P1R-transfected cells, only hPTH(1-34) but not TIP39 was able to elicit a cAMP response, but TIP39 was able to directly antagonize the cAMP-stimulating effect of hPTH(1-34) on this receptor. In conclusion, we could show a possible function of TIP39 for the human organism as a potent activator of P2R (e.g. in brain) as well as an antagonist of the action of PTH and/or PTH-related protein on P1R (e.g. in bone and kidney). The physiological role of TIP39 in calcium metabolism with regard to these actions remains to be determined. The tools developed in this work will allow us to investigate the possible role of TIP39 as a locally or systemically secreted ligand modulating the function of the PTH receptor family.

The role of endothelins in the regulation of pituitary function.

The different members of the endothelin peptide family exhibit potent, long-lasting vasoconstrictive effects and thus play a central role in blood pressure regulation. However, endothelins have also been shown to modulate renal, cardiac and immune functions under physiological and pathophysiological conditions. In addition, endothelins are thought to be involved in the progression of some types of tumours. Soon after their discovery in 1988, it was shown that endothelins affect hormone release in the pituitary. Moreover, the intrapituitary production and expression of both endothelins and endothelin receptors have been described. This review summarises the present day knowledge concerning the expression and regulation of intrapituitary endothelins and their receptors. In addition, the effects of endothelins on hormone production by anterior, intermediate and posterior pituitary cell types are reviewed and their importance for pituitary physiology and pathophysiology is discussed.