Spatial arrangement patterns of senile plaques in post-mortem senile dementia of the Alzheimer type brains

We have studied the spatial distribution of plaques in coronal and tangential sections of the parahippocampal gyrus (PHG), the hippocampus, the frontal lobe and the temporal lobe of five SDAT patients. Sections were stained with cresyl violet and examined at two magnifications (x100 and x400). in all cases (and at both magnifications) statistical analysis using the Poisson distribution showed that the plaques were arranged in clumps (x100: V/M = 1.48 - 4.49; x400 V/M = 1.17 - 1.95). this indicates that both large scale and small scale clumping occurs. Application of the statistical techniques of pattern analysis to coronal sections of frontal and temporal cortex and PHG showed. furthermore, that both large (3200-6400 micron) and small scale (100 - 400 micron) clumps were arranged with a high degree of regularity in the tissue. This suggests that the clumps of plaques reflect underlying neural structure.

Are there two distinct populations of cored senile plaques in senile dementia of the Alzheimer type?

The relationship between plaque diameter (PD) and core diameter (CD) was studied in four brains from each of four SDAT brains. The regions studied were parahippocampal gyrus (PHG), hippocampus, frontal and inferior temporal lobes. The largest diameters of 100 cored classical plaques and their cores were measured. CD was positively correlated with PD (Pearson's 'r' 0.4 - 0.95) in all region studied. Significant linear regressions of CD on PD with positive slopes (0.10 - 0.65) were found. Two distinct types of regression were found. Type A had a steep slope and a negative intercept on the ordinate whereas Type B had a shallow slope and a positive intercept. Both types can be found within the same brain but Type A or B predominate in a particular tissue. The data suggest that core development may occur either early or late in the development of the plaque. The two types of plaque may thus have different aetiologies. Such an interpretation is consistent with current ideas of plaque formation.

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.

Tetrahydrobiopterin metabolism in dementia

The aim of this study was to establish levels of the enzymes involved in tetrahydrobiopterin (BH4) metabolism in human and rat brain preparations; to determine whether BH4 metabolism is altered in dementia, particularly in relation to senile dementia of the Alzheimer type (SDAT); and to examine the effect of aluminium on BH4 metabolism. Overall BH4 synthesis and dihydropteridine reductase (DHPR) activity were greater in the locus coeruleus than in the neocortex of elderly subjects. Sepiapterin reductase and DHPR activity showed a linear correlation with age in the temporal cortex. DHPR activity in the frontal cortex was relatively constant until the mid 60s and then fell with age. Overall BH4 synthesis showed a non-significant decline in temporal cortex and was significantly reduced in locus coeruleus preparations from SDAT subjects compared to control subjects. As DHPR, sepiapterin reductase and GTP cyclohydrolase activity were unaltered in SDAT we suggested that there is a lesion on the biosynthetic pathway between dihydroneopterin in triphosphate and BH4 in SDAT, possibly at the level of 6-pyruvoyl tetrahydropterin synthase. DHPR activity and BH4 synthesis capacity were unaltered in temporal cortex preparations from Huntingdon's disease subjects indicating that the defect in BH4 metabolism in SDAT is specific to the disease process and not a secondary consequence of dementia. The implications of altered BH4 metabolism in ageing and dementia are discussed. BH4 metabolism was examined in temporal and frontal cortex preparations from 4 subjects who had received peritoneal dialysis treatment. All patients had elevated serum aluminium levels. The data suggests that aluminium may inhibit DHPR activity in the frontal cortex resulting in diminished BH4 levels in the cells which leads to a compensatory increase in the activity of the biosynthetic pathway. Aluminium reversibly inhibited sepiapterin reductase activity in rat brain preparations but did not alter sepiapterin reductase activity in vivo. Overall BH4 synthesis and OTP cyclohydrolase activity were not affected by aluminium in vitro. The biosynthetic pathway was unaltered in rat brain preparations from animals receiving aluminium orally compared to control animals. DHPR activity was unaltered or increased in rat brain preparations from aluminium treated rats compared to the control group.

Behavioural and neuroimaging investigations of the relationship between visual attention, affordance and action

In this thesis the relationship between visual attention, affordance and action was investigated using a combination of neuroimaging and behavioural studies. Neuronal activity and movement construction were assessed when individuals passively viewed or produced action towards stimuli varying in their affordance and/or attentional attributes. The main findings were: (i) the passive perception of both object and abstract visual patterns was associated with decreased alpha and/or beta activity in sensori-motor cortex, occipito-temporal cortex and cerebellum. These are brain regions associated with the planning and production of visually guided action; (ii) for object patterns, decreased alpha and beta activity was also observed in regions of superior parietal and premotor cortex. These regions contain neurons argued to be essential for matching hand kinematics with manipulate objects; and (iii) in both control participants and a deafferented individual, studies of planned and unplanned pointing manoeuvres revealed that the attentional bias of a stimulus was critical for fast, efficient action production whereas the affordance bias was critical in determining end-point accuracy. Taken together, these findings demonstrate that affordance is not a necessary prerequisite for the potential of motor codes. Rather, affordance enables the construction of motor responses that reflect object functionality and/or manipulability. They further demonstrate that visual attention is associated with the potentiation of motor codes. Indeed, directed visual attention would appear critical for speeded responses. These findings provide new insights into the roles of directed visual attention and affordance upon action.

Cortical activity during rotational and linear transformations

Neuroimaging studies of cortical activation during image transformation tasks have shown that mental rotation may rely on similar brain regions as those underlying visual perceptual mechanisms. The V5 complex, which is specialised for visual motion, is one region that has been implicated. We used functional magnetic resonance imaging (fMRI) to investigate rotational and linear transformation of stimuli. Areas of significant brain activation were identified for each of the primary mental transformation tasks in contrast to its own perceptual reference task which was cognitively matched in all respects except for the variable of interest. Analysis of group data for perception of rotational and linear motion showed activation in areas corresponding to V5 as defined in earlier studies. Both rotational and linear mental transformations activated Brodman Area (BA) 19 but did not activate V5. An area within the inferior temporal gyrus, representing an inferior satellite area of V5, was activated by both the rotational perception and rotational transformation tasks, but showed no activation in response to linear motion perception or transformation. The findings demonstrate the extent to which neural substrates for image transformation and perception overlap and are distinct as well as revealing functional specialisation within perception and transformation processing systems.

Spatial patterns of TDP-43 neuronal cytoplasmic inclusions (NCI) in fifteen cases of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP)

Neuronal cytoplasmic inclusions (NCI) immunoreactive for transactive response DNA-binding protein (TDP-43) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). We studied the spatial patterns of the TDP-43 immunoreactive NCI in the frontal and temporal cortex of 15 cases of FTLD-TDP. The NCI were distributed parallel to the tissue boundary predominantly in regular clusters 50-400 µm in diameter. In five cortical areas, the size of the clusters approximated to the cells of the cortico-cortical pathways. In most regions, cluster size was smaller than 400 µm. There were no significant differences in spatial patterns between familial and sporadic cases. Cluster size of the NCI was not correlated with disease duration, brain weight, Braak stage, or disease subtype. The spatial pattern of the NCI was similar to that of neuronal inclusions in other neurodegenerative diseases and may reflect a common pattern of degeneration involving the cortico-cortical projections.

Spatial patterns of phosphorylation-dependent TDP-43-immunoreactive neuronal cytoplasmic inclusions (NCI) in frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP)

The transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) is an RNA binding protein encoded by the TARDPB gene. Abnormal aggregations of TDP-43 in neurons in the form of neuronal cytoplasmic inclusions (NCI) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of TDP-43 in FTLD-TDP, the spatial patterns of the NCI were studied in frontal and temporal cortex of FTLD-TDP cases using a phosphorylation dependent anti-TDP-43 antibody (pTDP-43). In many regions, the NCI formed clusters and the clusters were distributed regularly parallel to the tissue boundary. In about 35% of cortical regions, cluster size of the NCI was within the size range of the modular columns of the cortex. The spatial patterns of the pTDP-immunoreactive inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody and also similar to inclusions characterized by other molecular pathologies such as tau, ?-synuclein and ‘fused in sarcoma’ (FUS). In conclusion, the data suggest degeneration of cortical and hippocampal anatomical pathways associated with accumulation of cellular pTDP-43 is characteristic of FTLD-TDP. In addition, the data are consistent with the hypothesis of cell to cell transfer of pTDP-43 within the brain.

Do simple intransitive finger movements consistently activate frontoparietal mirror neuron areas in humans?

The posterior inferior frontal gyrus (pIFG) and anterior inferior parietal lobule (aIPL) form the core regions of the human “mirror neuron system” that matches an observed movement onto its internal motor representation. We used event-related functional MRI to examine whether simple intransitive finger movements evoke “mirror activity” in the pIFG and aIPL. In separate sessions, participants either merely observed visuospatial stimuli or responded to them as quickly as possible with a spatially compatible finger movement. A picture of a relaxed hand with static dots on the tip of the index and little finger was continuously presented as high-level baseline. Four types of stimuli were presented in a pseudorandom order: a color change of a dot, a moving finger, a moving dot, or a simultaneous finger-dot movement. Dot movements were spatially and kinematically matched to finger movements. Participants were faster at imitating a finger movement than performing the same movement in response to a moving dot or a color change of a dot. Though imitative responses were facilitated, fMRI revealed no additional “mirror activity” in the pIFG and aIPL during the observation or imitation of finger movements as opposed to observing or responding to a moving dot. Mere observation of a finger movement alone failed to induce significant activation of the pIFG and aIPL. The lack of a signature of “mirror neuron activity” in the inferior frontoparietal cortex is presumably due to specific features of the task which may have favored stimulus–response mapping based on common spatial coding. We propose that the responsiveness of human frontoparietal mirror neuron areas to simple intransitive movements critically depends on the experimental context.

Conversational interaction in the scanner:mentalizing during language processing as revealed by MEG

Humans are especially good at taking another's perspective-representing what others might be thinking or experiencing. This "mentalizing" capacity is apparent in everyday human interactions and conversations. We investigated its neural basis using magnetoencephalography. We focused on whether mentalizing was engaged spontaneously and routinely to understand an utterance's meaning or largely on-demand, to restore "common ground" when expectations were violated. Participants conversed with 1 of 2 confederate speakers and established tacit agreements about objects' names. In a subsequent "test" phase, some of these agreements were violated by either the same or a different speaker. Our analysis of the neural processing of test phase utterances revealed recruitment of neural circuits associated with language (temporal cortex), episodic memory (e.g., medial temporal lobe), and mentalizing (temporo-parietal junction and ventromedial prefrontal cortex). Theta oscillations (3-7 Hz) were modulated most prominently, and we observed phase coupling between functionally distinct neural circuits. The episodic memory and language circuits were recruited in anticipation of upcoming referring expressions, suggesting that context-sensitive predictions were spontaneously generated. In contrast, the mentalizing areas were recruited on-demand, as a means for detecting and resolving perceived pragmatic anomalies, with little evidence they were activated to make partner-specific predictions about upcoming linguistic utterances.

How the brain blinks:towards a neurocognitive model of the attentional blink

When people monitor a visual stream of rapidly presented stimuli for two targets (T1 and T2), they often miss T2 if it falls into a time window of about half a second after T1 onset—the attentional blink (AB). We provide an overview of recent neuroscientific studies devoted to analyze the neural processes underlying the AB and their temporal dynamics. The available evidence points to an attentional network involving temporal, right-parietal and frontal cortex, and suggests that the components of this neural network interact by means of synchronization and stimulus-induced desynchronization in the beta frequency range. We set up a neurocognitive scenario describing how the AB might emerge and why it depends on the presence of masks and the other event(s) the targets are embedded in. The scenario supports the idea that the AB arises from ‘‘biased competition’’, with the top–down bias being generated by parietal–frontal interactions and the competition taking place between stimulus codes in temporal cortex.

Optimal time following fluorescein instillation to evaluate rigid gas permeable contact lens fit

PURPOSE: To examine the optimum time at which fluorescein patterns of gas permeable lenses (GPs) should be evaluated. METHODS: Aligned, 0.2mm steep and 0.2mm flat GPs were fitted to 17 patients (aged 20.6±1.1 years, 10 male). Fluorescein was applied to their upper temporal bulbar conjunctiva with a moistened fluorescein strip. Digital slit lamp images (CSO, Italy) at 10× magnification of the fluorescein pattern viewed with blue light through a yellow filter were captured every 15s. Fluorescein intensity in central, mid peripheral and edge regions of the superior, inferior, temporal and nasal quadrants of the lens were graded subjectively using a +2 to -2 scale and using ImageJ software on the simultaneously captured images. RESULTS: Subjectively graded and objectively image analysed fluorescein intensity changed with time (p<0.001), lens region (centre, mid-periphery and edge: p<0.05) and there was interaction between lens region with lens fit (p<0.001). For edge band width, there was a significant effect of time (F=118.503, p<0.001) and lens fit (F=5.1249, p=0.012). The expected alignment, flat and steep fitting patterns could be seen from approximately after 30 to 180s subjectively and 15 to 105s in captured images. CONCLUSION: Although the stability of fluorescein intensity can start to decline in as little as 45s post fluorescein instillation, the diagnostic pattern of alignment, steep or flat fit is seen in each meridian by subjective observation from about 30s to 3min indicating this is the most appropriate time window to evaluate GP lenses in clinical practice.

A comparison of spatial patterns of TDP-43 cellular inclusions in familial and sporadic frontotemporal lobar degeneration with TDP-43 proteinopathy

Abnormal protein aggregates of transactive response (TAR) DNA-binding protein (TDP-43) in the form of neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), neuronal internuclear inclusions (NII), and dystrophic neurites (DN) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of phosphorylated TDP-43 (pTDP-43) in neurodegeneration in FTLD-TDP, the spatial patterns of the pTDP-43-immunoreactive NCI, GI, NII, and DN were studied in frontal and temporal cortex in three groups of cases: (1) familial FTLD-TDP caused by progranulin (GRN) mutation, (2) a miscellaneous group of familial cases containing cases caused by valosin-containing protein (VCP) mutation, ubiquitin associated protein 1 (UBAP1) mutation, and cases not associated with currently known genes, and (3) sporadic FTLD-TDP. In a significant number of brain regions, the pTDP-43-immunoreactive inclusions developed in clusters and the clusters were distributed regularly parallel to the tissue boundary. The spatial patterns of the inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody. The spatial patterns and cluster sizes of the pTDP-43-immunoreactive inclusions were similar in GRN mutation cases, remaining familial cases, and in sporadic FTLD-TDP. Hence, pathological changes initiated by different genetic factors in familial cases and by unknown causes in sporadic FTLD-TDP appear to follow a parallel course resulting in very similar patterns of degeneration of frontal and temporal lobes.

Measurement of scleral thickness in humans using anterior segment optical coherent tomography

Anterior segment optical coherent tomography (AS-OCT, Visante; Zeiss) is used to examine meridional variation in anterior scleral thickness (AST) and its association with refractive error, ethnicity and gender. Scleral cross-sections of 74 individuals (28 males; 46 females; aged between 18-40 years (27.7±5.3)) were sampled twice in random order in 8 meridians: [superior (S), inferior (I), nasal (N), temporal (T), superior-temporal (ST), superior-nasal (SN), inferior-temporal (IT) and inferior-nasal (IN)]. AST was measured in 1mm anterior-toposterior increments (designated the A-P distance) from the scleral spur (SS) over a 6mm distance. Axial length and refractive error were measured with a Zeiss IOLMaster biometer and an open-view binocular Shin-Nippon autorefractor. Intra- And inter-observer variability of AST was assessed for each of the 8 meridians. Mixed repeated measures ANOVAs tested meridional and A-P distance differences in AST with refractive error, gender and ethnicity. Only right eye data were analysed. AST (mean±SD) across all meridians and A-P distances was 725±46μm. Meridian SN was the thinnest (662±57μm) and I the thickest (806 ±60μm). Significant differences were found between all meridians (p<0.001), except S:ST, IT:IN, IT:N and IN:N. Significant differences between A-P distances were found except between SS and 6 mm and between 2 and 4mm. AST measurements at 1mm (682±48 μm) were the thinnest and at 6mm (818±49 μm) the thickest (p<0.001); a significant interaction occurred between meridians and A-P distances (p<0.001). AST was significantly greater (p<0.001) in male subjects but no significant differences were found between refractive error or ethnicity. Significant variations in AST occur with regard to meridian and distance from the SS and may have utility in selecting optimum sites for pharmaceutical or surgical intervention.

Functional near infrared spectroscopy study of language, joint attention and motor skills

Near infrared spectroscopy (NIRS) is an emerging non-invasive optical neuro imaging technique that monitors the hemodynamic response to brain activation with ms-scale temporal resolution and sub-cm spatial resolution. The overall goal of my dissertation was to develop and apply NIRS towards investigation of neurological response to language, joint attention and planning and execution of motor skills in healthy adults. Language studies were performed to investigate the hemodynamic response, synchrony and dominance feature of the frontal and fronto-temporal cortex of healthy adults in response to language reception and expression. The mathematical model developed based on granger causality explicated the directional flow of information during the processing of language stimuli by the fronto-temporal cortex. Joint attention and planning/ execution of motor skill studies were performed to investigate the hemodynamic response, synchrony and dominance feature of the frontal cortex of healthy adults and in children (5-8 years old) with autism (for joint attention studies) and individuals with cerebral palsy (for planning/execution of motor skills studies). The joint attention studies on healthy adults showed differences in activation as well as intensity and phase dependent connectivity in the frontal cortex during joint attention in comparison to rest. The joint attention studies on typically developing children showed differences in frontal cortical activation in comparison to that in children with autism. The planning and execution of motor skills studies on healthy adults and individuals with cerebral palsy (CP) showed difference in the frontal cortical dominance, that is, bilateral and ipsilateral dominance, respectively. The planning and execution of motor skills studies also demonstrated the plastic and learning behavior of brain wherein correlation was found between the relative change in total hemoglobin in the frontal cortex and the kinematics of the activity performed by the participants. Thus, during my dissertation the NIRS neuroimaging technique was successfully implemented to investigate the neurological response of language, joint attention and planning and execution of motor skills in healthy adults as well as preliminarily on children with autism and individuals with cerebral palsy. These NIRS studies have long-term potential for the design of early stage interventions in children with autism and customized rehabilitation in individuals with cerebral palsy.