Chlorinated lipids and fatty acids:an emerging role in pathology

Although the existence of halogenated lipids in lower organisms has been known for many years, it is only since the 1990s that interest in their occurrence in mammalian systems has developed. Chlorinated (and other halogenated) lipids can arise from oxidation by hypohalous acids, such as HOCl, which are products of the phagocytic enzyme myeloperoxidase and are generated during inflammation. The major species of chlorinated lipids investigated to date are chlorinated sterols, fatty acid and phospholipid chlorohydrins, and a-chloro fatty aldehydes. While all of these chlorinated lipids have been shown to be produced in model systems from lipoproteins to cells subjected to oxidative stress, as yet only a-chloro fatty aldehydes, such as 2-chlorohexadecanal, have been detected in clinical samples or animal models of disease. a-Chloro fatty aldehydes and chlorohydrins have been found to have a number of potentially pro-inflammatory effects ranging from toxicity to inhibition of nitric oxide synthesis and upregulation of vascular adhesion molecules. Thus evidence is building for a role of chlorinated lipids in inflammatory disease, although much more research is required to establish the contributions of specific compounds in different disease pathologies. Preventing chlorinated lipid formation and indeed other HOCl-induced damage, via the inhibition of myeloperoxidase, is an area of growing interest and may lead in the future to antimyeloperoxidase-based antiinflammatory therapy. However, other chlorinated lipids, such as punaglandins, have beneficial effects that could offer novel therapies for cancer.

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.

Corticobasal degeneration and dementia

Corticobasal degeneration is a rare, progressive neurodegenerative disorder which significantly impairs movement. The most common initial symptom is asymmetric limb clumsiness with or without accompanying rigidity or tremor. Subsequently, the disease progresses to affect gait and there is a slow progression to influence ipsilateral arms and legs. Apraxia and dementia are the most common cortical signs. Clinical diagnosis of the disorder is difficult as the symptoms resemble those of related neurodegenerative disorders. Histopathologically, there is widespread neuronal and glial pathology including tau-immunoreactive neuronal cytoplasmic inclusions, neuropil threads, oligodendroglial inclusions, astrocytic plaques, together with abnormally enlarged ‘ballooned’ neurons. Corticobasal degeneration has affinities both with the parkinsonian syndromes including Parkinson’s disease, progressive supranuclear palsy, and multiple system atrophy and with the fronto-temporal dementias. Treatment of corticobasal degeneration involves managing and reducing the effect of symptoms.

Balance and gait in children with dyslexia

Tests of postural stability have provided some evidence of a link between deficits in gross motor skills and developmental dyslexia. The ordinal-level scales used previously, however, have limited measurement sensitivity, and no studies have investigated motor performance during walking in participants with dyslexia. The purpose of this study was to investigate if continuous-scaled measures of standing balance and gait could discriminate between groups of impaired and normal readers when investigators were blind to group membership during testing. Children with dyslexia (n=22) and controls (n=18), aged 10-12 years, performed walking tests at four different speeds (slow-preferred-fast-very fast) on an even and an uneven surface, and tests of unperturbed and perturbed body sway during standing. Body movements were registered by a triaxial accelerometer over the lower trunk, and measures of reaction time, body sway, walking speed, step length and cadence were calculated. Results were controlled for gender differences. Tests of standing balance with eyes closed did not discriminate between groups. All unperturbed standing tests with eyes open showed significant group differences (P<0.05) and classified correctly 70-77.5% of the subjects into their respective groups. Mean walking speed during very fast walking on both flat and uneven surface was ≥0.2 m/s (P≤0.01) faster for controls than for the group with dyslexia. This test classified 77.5% and 85% of the subjects correctly on flat and uneven surface, respectively Cadence at preferred or very fast speed did not differ statistically between groups, but revealed significant group differences when all subjects were compared at a normalised walking speed (P≤0.04). Very fast walking speed as well as cadence at a normalised speed discriminated better between groups when subjects were walking on an uneven surface compared to a flat floor. Continuous-scaled walking tests performed in field settings may be suitable for motor skill assessment as a component of a screening tool for developmental dyslexia.

Oxidiative lipidomics coming of age:advances in analysis of oxidized phospholipids in physiology and pathology

Significance: Oxidized phospholipids are now well-recognized as markers of biological oxidative stress and bioactive molecules with both pro-inflammatory and anti-inflammatory effects. While analytical methods continue to be developed for studies of generic lipid oxidation, mass spectrometry (MS) has underpinned the advances in knowledge of specific oxidized phospholipids by allowing their identification and characterization, and is responsible for the expansion of oxidative lipidomics. Recent Advances: Studies of oxidized phospholipids in biological samples, both from animal models and clinical samples, have been facilitated by the recent improvements in MS, especially targeted routines that depend on the fragmentation pattern of the parent molecular ion and improved resolution and mass accuracy. MS can be used to identify selectively individual compounds or groups of compounds with common features, which greatly improves the sensitivity and specificity of detection. Application of these methods have enabled important advances in understanding the mechanisms of inflammatory diseases such as atherosclerosis, steatohepatitis, leprosy and cystic fibrosis, and offer potential for developing biomarkers of molecular aspects of the diseases. Critical Issues and Future Directions: The future in this field will depend on development of improved MS technologies, such as ion mobility, novel enrichment methods and databases and software for data analysis, owing to the very large amount of data generated in these experiments. Imaging of oxidized phospholipids in tissue MS is an additional exciting direction emerging that can be expected to advance understanding of physiology and disease.

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.

Gait Measurements and Motor Recovery after Stroke

2000 Mathematics Subject Classification: 62P10, 92C20

TDP-43-immunoreactive pathology in frontotemporal lobar degeneration with TDP proteinopathy (FTLD-TDP) with and without associated motor neuron disease (MND)

A proportion of patients with motor neuron disease (MND) exhibit frontotemporal dementia (FTD) and some patients with FTD develop the clinical features of MND. Frontotemporal lobar degeneration (FTLD) is the pathological substrate of FTD and some forms of this disease (referred to as FTLD-U) share with MND the common feature of ubiquitin-immunoreactive, tau-negative cellular inclusions in the cerebral cortex and hippocampus. Recently, the transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) has been found to be a major protein of the inclusions of FTLD-U with or without MND and these cases are referred to as FTLD with TDP-43 proteinopathy (FTLD-TDP). To clarify the relationship between MND and FTLD-TDP, TDP-43 pathology was studied in nine cases of FTLD-MND and compared with cases of familial and sporadic FTLD-TDP without associated MND. A principal components analysis (PCA) of the nine FTLD-MND cases suggested that variations in the density of surviving neurons in the frontal cortex and neuronal cytoplasmic inclusions (NCI) in the dentate gyrus (DG) were the major histological differences between cases. The density of surviving neurons in FTLD-MND was significantly less than in FTLD-TDP cases without MND, and there were greater densities of NCI but fewer neuronal intranuclear inclusions (NII) in some brain regions in FTLD-MND. A PCA of all FTLD-TDP cases, based on TDP-43 pathology alone, suggested that neuropathological heterogeneity was essentially continuously distributed. The FTLD-MND cases exhibited consistently high loadings on PC2 and overlapped with subtypes 2 and 3 of FTLD-TDP. The data suggest: (1) FTLD-MND cases have a consistent pathology, variations in the density of NCI in the DG being the major TDP-43-immunoreactive difference between cases, (2) there are considerable similarities in the neuropathology of FTLD-TDP with and without MND, but with greater neuronal loss in FTLD-MND, and (3) FTLD-MND cases are part of the FTLD-TDP 'continuum' overlapping with FTLD-TDP disease subtypes 2 and 3. © 2012 Nova Science Publishers, Inc. All rights reserved.

Oligodendrocyte pathology in neurodegenerative disease

Oligodendrocytes have multiple functions in the central nervous system including mechanical support of neurons, production of myelin sheaths, and uptake and inactivation of chemical neurotransmitters released by neurons. Consequently, oligodendrocytes could be involved in the pathology of a number of neurodegenerative diseases. Although, the molecular mechanisms involved require further elucidation, it is likely that oligodendrocyte dysfunction is important in Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). In addition, abnormal protein aggregates in the form of oligodendrocyte inclusions (OI) have been observed in several other disorders, most notable in multiple system atrophy (MSA), in which the glial cytoplasmic inclusion (GCI) is the ‘signature’ pathology of the disease. OI have also been identified in argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP) (Armstrong et al 2007), and various forms of frontotemporal lobar degeneration (FTLD) (Armstrong et al 2010), although their role in the pathology of these disorders is less clear. It is likely that future research will expand the range of disorders in which oligodendrocytes play a significant role in neurodegeneration.

A quantitative study of tau pathology in eleven cases of chronic traumatic encephalopathy

AIMS: To quantify tau pathology of chronic traumatic encephalopathy (CTE) and investigate influence of dot-like lesions (DL), brain region, co-morbidity, and sporting career length. METHODS: Densities of neurofibrillary tangles (NFT), astrocytic tangles (AT), DL, oligodendroglial inclusions (GI), neuropil threads (NT), vacuoles, neurons, and enlarged neurons (EN) were measured in tau-immunoreactive sections of upper cortical laminae of frontal and temporal lobe, hippocampus (HC), amygdala, and substantia nigra (SN) of eleven cases of CTE. RESULTS: DL were a consistent finding in CTE. Densities of NFT, NT and DL were greatest in sectors CA1 and CA2 of the HC. Densities of AT were lower than NFT, small numbers of GI were recorded in temporal lobe, and low densities of vacuoles and EN were consistently present. β-amyloid containing neuritic plaques (NP) also occurred at low density. Densities of NFT, NT, DL, and AT were greater in sulci than gyri while vacuole density was greater in gyri. Principal components analysis (PCA) suggested that sporting career length and densities of NFT in entorhinal cortex, NT in CA2 and SN, and vacuolation in the DG were significant sources of variation among cases. CONCLUSION: DL are frequent in CTE suggesting affinity with argyrophilic grain disease (AGD) and Parkinson's disease dementia (PD-Dem). Densities of AT in all regions and NT/DL in sectors CA2/4 were consistent features of CTE. The eleven cases are neuropathologically heterogeneous which may result from genetic diversity, and variation in anatomical pathways subjected to trauma. This article is protected by copyright. All rights reserved.

Pathology of the superior colliculus in chronic traumatic encephalopathy

PURPOSE: To investigate neuropathological changes in the superior colliculus in chronic traumatic encephalopathy. METHODS: The densities of the tau-immunoreactive neurofibrillary tangles, neuropil threads, dot-like grains, astrocytic tangles, and neuritic plaques, together with abnormally enlarged neurons, typical neurons, vacuolation, and frequency of contacts with blood vessels, were studied across the superior colliculus from pia mater to the periaqueductal gray in eight chronic traumatic encephalopathy and six control cases. RESULTS: Tau-immunoreactive pathology was absent in the superior colliculus of controls but present in varying degrees in all chronic traumatic encephalopathy cases, significant densities of tau-immunoreactive neurofibrillary tangles, NT, or dot-like grains being present in three cases. No significant differences in overall density of the tau-immunoreactive neurofibrillary tangles, neuropil threads, dot-like grains, enlarged neurons, vacuoles, or contacts with blood vessels were observed in control and chronic traumatic encephalopathy cases, but chronic traumatic encephalopathy cases had significantly lower mean densities of neurons. The distribution of surviving neurons across the superior colliculus suggested greater neuronal loss in intermediate and lower laminae in chronic traumatic encephalopathy. Changes in density of the tau-immunoreactive pathology across the laminae were variable, but in six chronic traumatic encephalopathy cases, densities of tau-immunoreactive neurofibrillary tangles, neuropil threads, or dot-like grains were significantly greater in intermediate and lower laminae. Pathological changes were not correlated with the distribution of blood vessels. CONCLUSIONS: The data suggest significant pathology affecting the superior colliculus in a proportion of chronic traumatic encephalopathy cases with a laminar distribution which could compromise motor function rather than sensory analysis.

Validation of Coded Aperture Coherent Scatter Spectral Imaging for Differentiation of Normal and Neoplastic Breast Tissues via Surgical Pathology

This study intends to validate the sensitivity and specificity of coded aperture coherent scatter spectral imaging (CACSSI) by comparison to clinical histological preparation and pathologic analysis methods currently used for the differentiation of normal and neoplastic breast tissues. A composite overlay of the CACSSI rendered image and pathologist interpreted, stained sections validate the ability of coherent scatter imaging to differentiate cancerous tissues from normal, healthy breast structures ex-vivo. Via comparison to the pathologist annotated slides, the CACSSI system may be further optimized to maximized sensitivity and specificity for differentiation of breast carcinomas.

Improved Accuracy in Optical Motion Capture Measurements Leads to Increased Sensitivity to Kinematic Changes

Clinical optical motion capture allows us to obtain kinematic and kinetic outcome measures that aid clinicians in diagnosing and treating different pathologies affecting healthy gait. The long term aim for gait centres is for subject-specific analyses that can predict, prevent, or reverse the effects of pathologies through gait retraining. To track the body, anatomical segment coordinate systems are commonly created by applying markers to the surface of the skin over specific, bony anatomy that is manually palpated. The location and placement of these markers is subjective and precision errors of up to 25mm have been reported [1]. Additionally, the selection of which anatomical landmarks to use in segment models can result in large angular differences; for example angular differences in the trunk can range up to 53o for the same motion depending on marker placement [2]. These errors can result in erroneous kinematic outcomes that either diminish or increase the apparent effects of a treatment or pathology compared to healthy data. Our goal was to improve the accuracy and precision of optical motion capture outcome measures. This thesis describes two separate studies. In the first study we aimed to establish an approach that would allow us to independently quantify the error among trunk models. Using this approach we determined if there was a best model to accurately track trunk motion. In the second study we designed a device to improve precision for test, re-test protocols that would also reduce the set-up time for motion capture experiments. Our method to compare a kinematically derived centre of mass velocity to one that was derived kinetically was successful in quantifying error among trunk models. Our findings indicate that models that use lateral shoulder markers as well as limit the translational degrees of freedom of the trunk through shared pelvic markers result in the least amount of error for the tasks we studied. We also successfully reduced intra- and inter-operator anatomical marker placement errors using a marker alignment device. The improved accuracy and precision resulting from the methods established in this thesis may lead to increased sensitivity to changes in kinematics, and ultimately result in more consistent treatment outcomes.

On covariate factor detection and removal for robust gait recognition

We propose a novel bolt-on module capable of boosting the robustness of various single compact 2D gait representations. Gait recognition is negatively influenced by covariate factors including clothing and time which alter the natural gait appearance and motion. Contrary to traditional gait recognition, our bolt-on module remedies this by a dedicated covariate factor detection and removal procedure which we quantitatively and qualitatively evaluate. The fundamental concept of the bolt-on module is founded on exploiting the pixel-wise composition of covariate factors. Results demonstrate how our bolt-on module is a powerful component leading to significant improvements across gait representations and datasets yielding state-of-the-art results.