Overweight/Obesity-related microstructural alterations of the fimbria-fornix in the ABCD study: The role of aerobic physical activity.

Childhood overweight/obesity has been associated with negative consequences related to brain function and may involve alterations in white matter pathways important for cognitive and emotional processing. Aerobic physical activity is a promising lifestyle factor that could restore white matter alterations. However, little is known about either regional white matter alterations in children with overweight/obesity or the effects of aerobic physical activity targeting the obesity-related brain alterations in children. Using a large-scale cross-sectional population-based dataset of US children aged 9 to 10 years (n = 8019), this study explored the associations between overweight/obesity and microstructure of limbic white matter tracts, and examined whether aerobic physical activity may reduce the overweight/obesity-related white matter alterations in children. The primary outcome measure was restriction spectrum imaging (RSI)-derived white matter microstructural integrity measures. The number of days in a week that children engaged in aerobic physical activity for at least 60 minutes per day was assessed. We found that females with overweight/obesity had lower measures of integrity of the fimbria-fornix, a major limbic-hippocampal white matter tract, than their lean peers, while this difference was not significant in males. We also found a positive relationship between the number of days of aerobic physical activity completed in a week and integrity measures of the fimbria-fornix in females with overweight/obesity. Our results provide cross-sectional evidence of sex-specific microstructural alteration in the fimbria-fornix in children with overweight/obesity and suggest that aerobic physical activity may play a role in reducing this alteration. Future work should examine the causal direction of the relationship between childhood overweight/obesity and brain alterations and evaluate potential interventions to validate the effects of aerobic physical activity on this relationship.

In vivo diffusion tensor imaging and histopathology of the fimbria-fornix in temporal lobe epilepsy.

While diffusion tensor imaging (DTI) has been extensively used to infer micro-structural characteristics of cerebral white matter in human conditions, correlations between human in vivo DTI and histology have not been performed. Temporal lobe epilepsy (TLE) patients with mesial temporal sclerosis (MTS) have abnormal DTI parameters of the fimbria-fornix (relative to TLE patients without MTS) which are presumed to represent differences in axonal/myelin integrity. Medically intractable TLE patients who undergo temporal lobe resection including the fimbria-fornix provide a unique opportunity to study the anatomical correlates of water diffusion abnormalities in freshly excised tissue. Eleven patients with medically intractable TLE were recruited (six with and five without MTS) for presurgical DTI followed by surgical excision of a small specimen of the fimbria-fornix which was processed for electron microscopy. Blinded quantitative analysis of the microphotographs included axonal diameter, density and area, cumulative axon membrane circumference, and myelin thickness and area. As predicted by DTI the fimbria-fornix of TLE patients with MTS had increased extra-axonal fraction, and reduced cumulative axonal membrane circumference and myelin area. Consistent with the animal literature, water diffusion anisotropy over the crus of the fimbria-fornix was strongly correlated with axonal membranes (cumulative membrane circumference) within the surgical specimen (approximately 15% of what was analyzed with DTI). The demonstration of a correlation between histology and human in vivo DTI, in combination with the observation that in vivo DTI accurately predicted white matter abnormalities in a human disease condition, provides strong validation of the application of DTI as a noninvasive marker of white matter pathology.

A preliminary study, using electron and light-microscopic methods, of axon numbers in the fornix in autopsies of patients with temporal lobe epilepsy.

Our objective was to show morphological changes of the fornix in autopsies of patients with temporal lobe epilepsy, which may potentially serve for post-mortem diagnosis. Epileptic and non-epileptic autopsy brains were obtained from the council of forensic medicine between the years 2005 and 2007. In both non-epileptic and epileptic autopsies the mean cross-sectional areas and fiber densities of the right and left fornices were calculated and analyzed. The numbers of myelinated and unmyelinated fibers, and the total number of fibers forming each fornix were counted. The total number of fibers in the right fornix was always greater than in the left fornix, in both epileptic and non-epileptic autopsies. The mean total number of fornix fibers was significantly reduced in epileptics compared with non-epileptics, in both the right (p = 0.043) and left (p = 0.043) sides. The electron-microscopic sections showed that myelinated axons outnumbered unmyelinated axons in both epileptic and non-epileptic autopsies. However, the reduction in the number of unmyelinated fibers was only statistically significant for the right fornix in right epileptic autopsies (p = 0.021). Although the reduction in the number of myelinated fibers was not statistically significant, electron-microscopic evaluations showed myelin degeneration of the myelinated fibers in the right fornix of the right temporal lobe in epileptic autopsies. In conclusion, our results suggest that unmyelinated fiber loss is functionally important, and may have functional consequences of diagnostic value.

Alpha-synuclein-positive structures induced in leupeptin-infused rats.

Abnormal accumulation of alpha-synuclein is regarded as a key pathological step in a wide range of neurodegenerative processes, not only in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) but also in multiple-system atrophy (MSA). Nevertheless, the mechanism of alpha-synuclein accumulation remains unclear. Leupeptin, a protease inhibitor, has been known to cause various neuropathological changes in vivo resembling those of aging or neurodegenerative processes in the human brain, including the accumulation of neuronal processes and neuronal cytoskeletal abnormalities leading to neurofibrillary tangle (NFT)-like formations. In the present study, we administered leupeptin into the rat ventricle and found that alpha-synuclein-positive structures appeared widely in the neuronal tissue, mainly in neuronal processes of the fimbria and alveus. Immunoelectron microscopic study revealed that alpha-synuclein immunoreactivity was located in the swollen axons of the fimbria and alveus, especially in the dilated presynaptic terminals. In addition colocalization of alpha-synuclein with ubiquitin was rarely observed in confocal laser-scan image. This is the first report of experimentally induced in vivo accumulation of alpha-synuclein in non-transgenic rodent brain injected with a well-characterized protease inhibitor by an infusion pump. The present finding suggests that the local accumulation of alpha-synuclein might be induced by the impaired metabolism of alpha-synuclein, which are likely related to lysosomal or ubiquitin-independent proteasomal systems.

Three-dimensional electron microscopic studies of the transitional oligodendrocyte associated with the initial stage of myelination in developing rat hippocampal fimbria.

We identified the transitional oligodendrocyte and their processes of rat hippocampal fimbria associated with the initial stage of myelination in both the morphological and functional classifications by means of three-dimensional ultrastructural analysis. Transitional oligodendrocytes appeared around P7, and their cell bodies were morphologically an intermediate form between the light and medium oligodendrocytes described by Mori and Leblond [J. Comp. Neurol. 139 (1970) 1]. Three phenotypes of the transitional oligodendrocytic processes were recognized. Spiral wrapping processes were ensheathing processes, club-like processes were nonensheathing processes, and sheet-like processes were possibly the transmuting form between the nonensheathing and ensheathing processes. Club-like processes were the major part of the nonensheathing processes, and most likely function as sensors to perceive axon maturation and find target axons. Multivesicular bodies that appeared to be associated with the initial ensheathment were observed in the transitional oligodendrocytic processes, suggesting that their roles are crucial in myelinogenesis.