Spatial patterns of the pathological changes in the temporal lobe of patients with neuronal intermediate filament inclusion disease

Neuronal intermediate filament inclusion disease (NIFID) is a new neurodegenerative disease characterized histologically by the presence of neuronal cytoplasmic inclusions (NI) immunopositive for intermediate filament proteins, neuronal loss, swollen achromatic neurons (SN), and gliosis. We studied the spatial patterns of these pathological changes parallel to the pia mater in gyri of the temporal lobe in four cases of NIFID. Both the NI and SN occurred in clusters that were regularly distributed parallel to the pia mater, the cluster sizes of the SN being significantly greater than those of the NI. In a significant proportion of areas studied, there was a spatial correlation between the clusters of NI and those of the SN and with the density of the surviving neurons. In addition, the clusters of surviving neurons were negatively correlated (out of phase) with the clusters of glial cell nuclei. The pattern of clustering of these histological features suggests that there is degeneration of the cortico-cortical projections in NIFID leading to the formation of NI and SN within the same vertical columns of cells. The glial cell reaction may be a response to the loss of neurons rather than to the appearance of the NI or SN.

The spectrum and severity of FUS-immunoreactive inclusions in the frontal and temporal lobes of ten cases of neuronal intermediate filament inclusion disease

Neuronal intermediate filament inclusion disease (NIFID), a rare form of frontotemporal lobar degeneration (FTLD), is characterized neuropathologically by focal atrophy of the frontal and temporal lobes, neuronal loss, gliosis, and neuronal cytoplasmic inclusions (NCI) containing epitopes of ubiquitin and neuronal intermediate filament proteins. Recently, the 'fused in sarcoma' (FUS) protein (encoded by the FUS gene) has been shown to be a component of the inclusions of familial amyotrophic lateral sclerosis with FUS mutation, NIFID, basophilic inclusion body disease, and atypical FTLD with ubiquitin-immunoreactive inclusions (aFTLD-U). To further characterize FUS proteinopathy in NIFID, and to determine whether the pathology revealed by FUS immunohistochemistry (IHC) is more extensive than a-internexin, we have undertaken a quantitative assessment of ten clinically and neuropathologically well-characterized cases using FUS IHC. The densities of NCI were greatest in the dentate gyrus (DG) and in sectors CA1/2 of the hippocampus. Anti-FUS antibodies also labeled glial inclusions (GI), neuronal intranuclear inclusions (NII), and dystrophic neurites (DN). Vacuolation was extensive across upper and lower cortical layers. Significantly greater densities of abnormally enlarged neurons and glial cell nuclei were present in the lower compared with the upper cortical laminae. FUS IHC revealed significantly greater numbers of NCI in all brain regions especially the DG. Our data suggest: (1) significant densities of FUS-immunoreactive NCI in NIFID especially in the DG and CA1/2; (2) infrequent FUS-immunoreactive GI, NII, and DN; (3) widely distributed vacuolation across the cortex, and (4) significantly more NCI revealed by FUS than a-internexin IHC.

Spatial patterns of FUS-immunoreactive neuronal cytoplasmic inclusions (NCI) in neuronal intermediate filament inclusion disease (NIFID)

Neuronal intermediate filament inclusion disease (NIFID), a rare form of frontotemporal lobar degeneration (FTLD), is characterized neuropathologically by focal atrophy of the frontal and temporal lobes, neuronal loss, gliosis, and neuronal cytoplasmic inclusions (NCI) containing epitopes of ubiquitin and neuronal intermediate filament (IF) proteins. Recently, the 'fused in sarcoma' (FUS) protein (encoded by the FUS gene) has been shown to be a component of the inclusions of NIFID. To further characterize FUS proteinopathy in NIFID, we studied the spatial patterns of the FUS-immunoreactive NCI in frontal and temporal cortex of 10 cases. In the cerebral cortex, sectors CA1/2 of the hippocampus, and the dentate gyrus (DG), the FUS-immunoreactive NCI were frequently clustered and the clusters were regularly distributed parallel to the tissue boundary. In a proportion of cortical gyri, cluster size of the NCI approximated to those of the columns of cells was associated with the cortico-cortical projections. There were no significant differences in the frequency of different types of spatial patterns with disease duration or disease stage. Clusters of NCI in the upper and lower cortex were significantly larger using FUS compared with phosphorylated, neurofilament heavy polypeptide (NEFH) or a-internexin (INA) immunohistochemistry (IHC). We concluded: (1) FUS-immunoreactive NCI exhibit similar spatial patterns to analogous inclusions in the tauopathies and synucleinopathies, (2) clusters of FUS-immunoreactive NCI are larger than those revealed by NEFH or ???, and (3) the spatial patterns of the FUS-immunoreactive NCI suggest the degeneration of the cortico-cortical projections in NIFID.

Spatial patterns of the pathological changes in neuronal intermediate filament inclusion disease (NIFID):an α-internexin immunohistochemical study

Neuronal intermediate filament inclusion disease (NIFID) is characterized by α-internexin positive neuronal cytoplasmic inclusions (NCI), swollen achromatic neurons (SN), neuronal loss, and gliosis. This study tested: 1) whether the spatial patterns of the lesions was topographically organized in areas of the frontal and temporal lobe and 2) whether a spatial relationship exists between the NCI and SN. The NCI were distributed in regular clusters and in a quarter of these areas, the clusters were 400-800 μm in diameter approximating to the size of the cells of origin of the cortico-cortical pathways. Variations in the density of the NCI were positively correlated with the SN. Hence, cortical degeneration in NIFID appears to be topographically organized and may affect the cortico-cortical projections, the clusters of NCI and SN developing within the same vertical columns of cells. © 2007 Springer-Verlag.

Laminar degeneration of the frontal and temporal cortex in neuronal intermediate filament inclusion disease (NIFID): a study using a-internexin immunohistochemistry

Objective: To determine the laminar distribution of the pathological changes in the frontal and temporal lobe in neuronal intermediate filament inclusion disease (NIFID). Method: The distribution of the alpha-intenexin-positive neuronal cytoplasmic inclusions (NCI), surviving neurons, swollen achromatic neurons (SN) and glial cell nuclei was studied across the cortex in gyri of the frontal and temporal lobe in 10 cases of NIFID. Results: The distribution of the NCI was highly variable within different gyri, a peak in the upper cortex, a bimodal distribution with peaks of density in the upper and lower laminae, or no significant variation in density across the cortex. The surviving neurons were either bimodally distributed or exhibited no significant change in density across the cortex. The SN and glial cell nuclei were most abundant in the lower cortical laminae. In half of the gyri, variations in density of the NCI across the cortex were positively correlated with the SN. In some gyri, the surviving neurons were positively correlated with the SN and negatively correlated with the glial cell nuclei. In addition, the SN and glial cell nuclei were positively correlated in over half the gyri studied. Conclusion: The data suggest that frontal and temporal lobe degeneration in NIFID characterized by NCI, SN, neuronal loss and gliosis extends across the cortical laminae with considerable variation between cases and gyri. alpha-internexin-positive neurons in the upper laminae appear to be particularly vulnerable. The gliosis appears to be largely correlated with the appearance of SN and with neuronal loss and not related to the NCI.

Neuropathological changes in ten cases of neuronal intermediate filament inclusion disease (NIFID):A study using α-internexin immunohistochemistry and principal components analysis (PCA)

Ten cases of neuronal intermediate filament inclusion disease (NIFID) were studied quantitatively. The α-internexin positive neurofilament inclusions (NI) were most abundant in the motor cortex and CA sectors of the hippocampus. The densities of the NI and the swollen achromatic neurons (SN) were similar in laminae II/III and V/VI but glial cell density was greater in V/VI. The density of the NI was positively correlated with the SN and the glial cells. Principal components analysis (PCA) suggested that PC1 was associated with variation in neuronal loss in the frontal/temporal lobes and PC2 with neuronal loss in the frontal lobe and NI density in the parahippocampal gyrus. The data suggest: 1) frontal and temporal lobe degeneration in NIFID is associated with the widespread formation of NI and SN, 2) NI and SN affect cortical laminae II/III and V/VI, 3) the NI and SN affect closely related neuronal populations, and 4) variations in neuronal loss and in the density of NI were the most important sources of pathological heterogeneity. © Springer-Verlag 2005.

Topography of α-internexin-positive neuronal aggregates in 10 patients with neuronal intermediate filament inclusion disease

Abnormal neuronal intermediate filament (IF) inclusions immunopositive for the type IV IF α-internexin have been identified as the pathological hallmark of neuronal intermediate filament inclusion disease (NIFID). We studied the topography of these inclusions in the frontal and temporal lobe in 68 areas from 10 cases of NIFID. In the cerebral cortex, CA sectors of the hippocampus, and dentate gyrus granule cell layer, the inclusions were distributed mainly in regularly distributed clusters, 50-800 μm in diameter. In seven cortical areas, there was a more complex pattern in which the clusters of inclusions were aggregated into larger superclusters. In 11 cortical areas, the size of the clusters approximated to those of the cells of origin of the cortico-cortical pathways but in the majority of the remaining areas, cluster size was smaller than 400 μm. The topography of the lesions suggests that there is degeneration of the cortico-cortical projections in NIFID with the formation of α-internexin-positive aggregates within vertical columns of cells. Initially, only a subset of cells within a vertical column develops inclusions but as the disease progresses, the whole of the column becomes affected. The corticostriate projection appears to have little effect on the cortical topography of the inclusions. © 2006 EFNS.

Spatial correlations between the neuronal inclusions, swollen achromatic neurons, and glial cells in neuronal intermediate filament inclusion disease (NIFID)

Neuronal intermediate filament (IF) inclusion disease (NIFID) is characterized by neuronal loss, neuronal cytoplasmic IF-positive inclusions (NI), swollen neurons (SN), and a glial cell reaction. We studied the spatial correlations between the clusters of NI, SN, and glial cells in four gyri of the temporal lobe (superior temporal gyrus, inferior temporal gyrus, lateral occipitotemporal gyrus, and parahippocampal gyrus) in four cases of NIFID. The densities of histological features (per 50x250 μ sample field) were as follows: NI (mean = 0.41, range 0.28-0.68), SN (mean = 1.41, range 0.47-2.65), glial cell nuclei (mean = 5.21, range 3.63-8.17). The NI and the SN were positively correlated in half of the brain regions examined, the correlations being present at the smallest field size (50x250 μm). The NI were also positively or negatively correlated with the glial cell nuclei in different areas, the negative correlations being present at the smallest field size. Glial cell nuclei were positively or negatively correlated with the SN in different brain areas, mainly at the larger field sizes (400x250 and 800x250 μm). The spatial correlation between the clusters of NI and SN in the cortex suggests their development within the same columns of cells. At first, the glial cell reaction is also confined to these columns but later becomes more generally distributed across the cortex. © Springer-Verlag 2004.

Different molecular pathologies result in similar spatial patterns of cellular inclusions in neurodegenerative disease:a comparative study of eight disorders

Recent research suggests cell-to-cell transfer of pathogenic proteins such as tau and α-synuclein may play a role in neurodegeneration. Pathogenic spread along neural pathways may give rise to specific spatial patterns of the neuronal cytoplasmic inclusions (NCI) characteristic of these disorders. Hence, the spatial patterns of NCI were compared in four tauopathies, viz., Alzheimer's disease, Pick's disease, corticobasal degeneration, and progressive supranuclear palsy, two synucleinopathies, viz., dementia with Lewy bodies and multiple system atrophy, the 'fused in sarcoma' (FUS)-immunoreactive inclusions in neuronal intermediate filament inclusion disease, and the transactive response DNA-binding protein (TDP-43)-immunoreactive inclusions in frontotemporal lobar degeneration, a TDP-43 proteinopathy (FTLD-TDP). Regardless of molecular group or morphology, NCI were most frequently aggregated into clusters, the clusters being regularly distributed parallel to the pia mater. In a significant proportion of regions, the regularly distributed clusters were in the size range 400-800 μm, approximating to the dimension of cell columns associated with the cortico-cortical pathways. The data suggest that cortical NCI in different disorders exhibit a similar spatial pattern in the cortex consistent with pathogenic spread along anatomical pathways. Hence, treatments designed to protect the cortex from neurodegeneration may be applicable across several different disorders. © 2012 Springer-Verlag.

Variations in dentate gyrus pathology in neurodegenerative disease

The dentate gyrus (DG) is an important part of the hippocampal formation and is believed to be involved in a variety of brain functions including episodic and spatial memory and the exploration of novel environments. In several neurodegenerative disorders, significant pathology occurs in the DG which may be involved in the development of clinical dementia. Based on the abundance of pathological change, neurodegenerative disorders could be divided into three groups: (1) those in which high densities of neuronal cytoplasmic inclusions (NCI) were present in DG granule cells, e.g., Pick’s disease (PiD), frontotemporal lobar degeneration with TDP-43-immunoreactive inclusions (FTLD-TDP), and neuronal intermediate filament inclusion disease (NIFID), (2) those in which aggregated protein deposits were distributed throughout the hippocampal formation including the molecular layer of the DG, e.g., Alzheimer’s disease (AD), Down’s syndrome (DS), and variant Creutzfeldt-Jakob disease (vCJD), and (3) those in which in there was significantly less pathology in the DG, e.g., Parkinson’s disease dementia (PD-Dem), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA), and sporadic CJD (sCJD). Hence, DG pathology varied significantly among disorders which could contribute to differences in clinical dementia. Pathological differences among disorders could reflect either differential vulnerability of the DG to specific molecular pathologies or variation in the degree of spread of pathological proteins into the hippocampal formation from adjacent regions.

Pathology of the dentate gyrus in neurodegenerative disease

The dentate gyrus (DG) is an important part of the hippocampal formation and is believed to be involved in a variety of brain functions including episodic and spatial memory and the exploration of novel environments. In several neurodegenerative disorders, significant pathology occurs in the DG which may be involved in the development of clinical dementia. Based on the abundance of pathological change, neurodegenerative disorders can be divided into three groups: (1) those in which high densities of neuronal cytoplasmic inclusions (NCI) are present in DG granule cells, e.g., Pick’s disease (PiD), frontotemporal lobar degeneration with TDP-43-immunoreactive inclusions (FTLD-TDP), and neuronal intermediate filament inclusion disease (NIFID), (2) those in which aggregated protein deposits are distributed throughout the hippocampal formation including the molecular layer of the DG, e.g., Alzheimer’s disease (AD), Down’s syndrome (DS), and variant Creutzfeldt-Jakob disease (vCJD), and (3) those in which in there is significantly less pathology in the DG, e.g., Parkinson’s disease dementia (PD-Dem), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA), and sporadic CJD (sCJD). Hence, DG pathology varies significantly among disorders which could contribute to differences in clinical dementia. Pathological differences among disorders could reflect either differential vulnerability of the DG to specific molecular pathologies or variation in the degree of spread of pathological proteins into the hippocampal formation from adjacent regions.

Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders

The hippocampus (HC) and adjacent gyri are implicated in dementia in several neurodegenerative disorders. To compare HC pathology among disorders, densities of ‘signature’ pathological lesions were measured at a standard location in eight brain regions of 12 disorders. Principal components analysis of the data suggested that the disorders could be divided into three groups: (1) Alzheimer’s disease (AD), Down’s syndrome (DS), sporadic Creutzfeldt–Jakob disease, and variant Creutzfeldt–Jakob disease in which either β-amyloid (Aβ) or prion protein deposits were distributed in all sectors of the HC and adjacent gyri, with high densities being recorded in the parahippocampal gyrus and subiculum; (2) Pick’s disease, sporadic frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions, and neuronal intermediate filament inclusion disease in which relatively high densities of neuronal cytoplasmic inclusions were present in the dentate gyrus (DG) granule cells; and (3) Parkinson’s disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy in which densities of signature lesions were relatively low. Variation in density of signature lesions in DG granule cells and CA1 were the most important sources of neuropathological variation among disorders. Hence, HC and adjacent gyri are differentially affected in dementia reflecting either variation in vulnerability of hippocampal neurons to specific molecular pathologies or in the spread of pathological proteins to the HC. Information regarding the distribution of pathology could ultimately help to explain variations in different cognitive domains, such as memory, observed in various disorders.

Quantification of white matter abnormalities in neurodegenerative disease

Degeneration of white matter fibre tracts occurs in several neurodegenerative disorders and results in various histological abnormalities including loss of axons, vacuolation, gliosis, axonal varicosities and spheroids, corpora amylacea, extracellular protein deposits, and glial inclusions (GI). This chapter describes quantitative studies that have been carried out on white matter pathology in a variety of neurodegenerative disease. First, in Alzheimer’s disease (AD), axonal loss quantified in histological sections stained with toluidine blue, occurs in several white matter fibre tracts including the optic nerve, olfactory tract, and corpus callosum. Second, in Creutzfeldt-Jakob disease (CJD), sections of cerebral cortex stained with haematoxylin and eosin (H/E) or immunolabelled with antibodies against the disease form of prion protein (PrPsc), reveal extensive vacuolation, gliosis of white matter, and deposition of PrPsc deposits. Third, GI immunolabelled with antibodies against various pathological proteins including tau, -synuclein, TDP-43, and FUS, have been recorded in white matter of a number of disorders including frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and neuronal intermediate filament inclusion disease (NIFID). Axonal varicosities have also been observed in NIFID. There are two important questions regarding white matter pathology that need further investigation: (1) what is the relative importance of white and gray matter pathologies in different disorders and (2) do white matter abnormalities precede or are they the consequence of gray matter pathology?

Temporal lobe pathology in neurodegenerative disease:a comparative study of eight disorders with special reference to the hippocampus

The temporal lobe is a major site of pathology in a number of neurodegenerative diseases. In this chapter, the densities of the characteristic pathological lesions in various regions of the temporal lobe were compared in eight neurodegenerative disorders, viz., Alzheimer’s disease (AD), Down’s syndrome (DS), dementia with Lewy bodies (DLB), Pick’s disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), sporadic Creutzfeldt-Jakob disease (sCJD), and neuronal intermediate filament inclusion disease (NIFID). Temporal lobe pathology was observed in all of these disorders most notably in AD, DS, PiD, sCJD, and NIFID. The regions of the temporal lobe affected by the pathology, however, varied between disorders. In AD and DS, the greatest densities of ?-amyloid (A?) deposits were recorded in cortical regions adjacent to the hippocampus (HC), DS exhibiting greater densities of A? deposits than AD. Similarly, in sCJD, greatest densities of prion protein (PrPsc) deposits were recorded in cortical areas of the temporal lobe. In AD and PiD, significant densities of neurofibrillary tangles (NFT) and Pick bodies (PB) respectively were present in sector CA1 of the HC while in CBD, the greatest densities of tau-immunoreactive neuronal cytoplasmic inclusions (NCI) were present in the parahippocampal gyrus (PHG). Particularly high densities of PB were present in the DG in PiD, whereas NFT in AD and Lewy bodies (LB) in DLB were usually absent in this region. These data confirm that the temporal lobe is an important site of pathology in the disorders studied regardless of their molecular ‘signature’. However, disorders differ in the extent to which the pathology spreads to affect the HC which may account for some of the observed differences in clinical dementia.

Intermediate pyrolysis studies of aquatic biomass and potential applications in the BtVB-process

Aquatic biomass is seen as one of the major feedstocks to overcome difficulties associated with 1st generation biofuels, such as competition with food production, change of land use and further environmental issues. Although, this finding is widely accepted only little work has been carried out to investigate thermo-chemical conversion of algal specimen to produce biofuels, power and heat. This work aims at contributing fundamental knowledge for thermo-chemical processing of aquatic biomass via intermediate pyrolysis. Therefore, it was necessary to install and commission an analytical pyrolysis apparatus which facilitates intermediate pyrolysis process conditions as well as subsequent separation and detection of pyrolysates (Py- GC/MS). In addition, a methodology was established to analyse aquatic biomass under intermediate conditions by Thermo-Gravimetric Analysis (TGA). Several microalgae (e.g. Chlamydomonas reinhardtii, Chlorella vulgaris) and macroalgae specimen (e.g. Fucus vesiculosus) from main algal divisions and various natural habitats (fresh and saline water, temperate and polar climates) were chosen and their thermal degradation under intermediate pyrolysis conditions was studied. In addition, it was of interest to examine the contribution of biochemical constituents of algal biomass onto the chemical compounds contained in pyrolysates. Therefore, lipid and protein fractions were extracted from microalgae biomass and analysed separately. Furthermore, investigations of residual algal materials obtained by extraction of high valuable compounds (e.g. lipids, proteins, enzymes) were included to evaluate their potential for intermediate pyrolysis processing. On basis of these thermal degradation studies, possible applications of algal biomass and from there derived materials in the Bio-thermal Valorisation of Biomass-process (BtVB-process) are presented. It was of interest to evaluate the combination of the production of high valuable products and bioenergy generation derived by micro- and macro algal biomass.