Negative C-11-PIB PET Predicts Lack of Alzheimer's Disease Pathology in Postmortem Examination

Our aim was to assess whether in vivo C-11-PIB negative memory-impaired subjects may nonetheless exhibit brain Alzheimer's disease (AD) pathology. We re-evaluated the PET images and systematically characterized the postmortem neuropathology of six individuals who had undergone clinically indicated amyloid PET. The single case with negligible amyloid-beta (A beta) pathology had Lewy body disease, where concomitant AD changes are often seen. Further, the subject's plaques were predominantly diffuse. The predictive value of a negative C-11-PIB scan appears to be good, even in memory-impaired populations. Our results suggest that considerable neuritic A beta plaque pathology in the absence of specific/cortical C-11-PIB binding upon PET is unlikely

Protective distal side-to-side neurorrhaphy in proximal nerve injury-an experimental study with rats

Background Side-to-side neurorrhaphy may protect the denervated end organ and preserve the initial connection with proximal stump. We examined the effect of protective side-to-side anastomosis on nerve and end organ regeneration in proximal nerve injury model.Methods The left common peroneal nerve of 24 Sprague Dawley rats was proximally transected. In groups B and C, side-to-side neurorrhaphy was performed distally between the peroneal and tibial nerves without (group B) and with (group C) partial donor nerve axotomy inside the epineural window. Group A served as an unprotected control. After 26 weeks, the proximal transection was repaired with end-to-end neurorrhaphy on all animals. Regeneration was followed during 12 weeks with the walk track analysis. Morphometric studies and wet muscle mass calculations were conducted at the end of the follow-up period.Results The results of the walk track analysis were significantly better in groups B and C compared to group A. Groups B and C showed significantly higher wet mass ratios of the tibialis anterior and extensor digitorum longus muscle compared to group A. Group C showed significantly higher morphometric values compared to group A. Group B reached higher values of the fibre count, fibre density, and percentage of the fibre area compared to group A.Conclusions Protective distal side-to-side neurorrhaphy reduced muscle atrophy and had an improving effect on the morphometric studies and walk track analysis. Distal side-to-side neurorrhaphy does not prevent the regenerating axons to grow from the proximal stump to achieve distal nerve stump

Increased Energy Expenditure, Lipolysis and Hyperinsulinemia Confer Resistance to Central Obesity and Type 2 Diabetes in Mice Lacking Alpha2α-Adrenoceptors

The α2A-adrenoceptors (ARs) are Gi-coupled receptors, which prejunctionally inhibit the release of norepinephrine (NE) and epinephrine (Epi), and postjunctionally insulin secretion and lipolysis. We have earlier shown that α2A-/- mice display sympathetic hyperactivity, hyperinsulinemia and improved glucose tolerance. Here we employed α2A-/- mice and placed the mice on a high-fat diet (HFD) to test the hypothesis that lack of α2A-ARs protects from diet-induced obesity (DIO) and type 2 diabetes (T2D). In addition, high caloric diet was combined with running wheel exercise to test the interaction of diet and exercise. HFD was obesogenic in both genotypes, but α2A-/- mice accumulated less visceral fat than their WT controls, were protected from T2D, and their insulin secretion was unaltered by the diet. Lack of α2A-ARs associated with increased sympatho-adrenal tone, which resulted in increased energy expenditure and fat oxidation rate potentiated by HFD. Fittingly, α2A-/- mice displayed enhanced lipolytic responses to Epi, and increased fecal lipids suggesting altered fat mobilization and absorption. Subcutaneous white fat appeared to be thermogenically more active (measured as Ucp1 mRNA expression) in α2A-/- mice, and brown fat showed an increased response to norepinephrine. Exercise was effective in reducing total body adiposity and increasing lean mass in both genotypes, but there was a significant diet-genotype interaction, as even modestly increased physical activity combined with lack of α2A-AR signalling promoted weight loss more efficiently than exercise with normal α2A-AR function. These results suggest that blockade of α2A-ARs may be exploited to reduce visceral fat and to improve insulin secretion.

Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer's disease

Background Alzheimer's disease results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. Environmental and lifestyle factors largely modulate the disease risk and may influence the pathogenesis through epigenetic mechanisms, such as DNA methylation. As environmental and lifestyle factors may affect multiple tissues of the body, we hypothesized that the disease-associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs. Results Comparison of 23 disease discordant Finnish twin pairs with reduced representation bisulfite sequencing revealed peripheral blood DNA methylation differences in 11 genomic regions with at least 15.0% median methylation difference and FDR adjusted p value Conclusions DNA methylation differences can be detected in the peripheral blood of twin pairs discordant for Alzheimer's disease. These DNA methylation signatures may have value as disease markers and provide insights into the molecular mechanisms of pathogenesis. We found no evidence that the DNA methylation marks would be associated with gene expression in blood. Further studies are needed to elucidate the potential importance of the associated genes in neuronal functions and to validate the prognostic or diagnostic value of the individual marks or marker panels.</p

MODERN STEREOLOGICAL EVALUATION IN THE AGING HUMAN SUBSTANTIA NIGRA

Quantitative estimation of neuronal numbers in the human substantia nigra (SN) can be achieved by a conventional single section (SS) count or by the more modern stereological disector (DS) count. However, counting results from SS counts are potentially biased and might not accurately reflect the total neuronal number in the SN or the changes in the total number of neurons occurring during aging or with neurodegenerative disease. Potential sources of bias include the lack of linearity between cell number per area of section and cell number per volume; the variation in the counting level and orientation of tissue sections; and shrinkage of tissue. Modern stereological DS counting overcomes these problems and has played a crucial role in many recent studies in neuropathology, neuroanatomy, neuropharmacology and neurogenetics. Over the past decades, four stereology based counting methods including physical DS, physical fractionator, optical DS and optical fractionator, have been established for quantitative measurement. Recently, stereological estimates have revealed a linear reduction rate of total nigral neuronal numbers with age of about 10% per decade. These findings suggest that the surviving nigral neurons undergo a degenerative change leading to neuronal dysfunction with aging. Furthermore, as an advanced quantitative tool, modern stereological evaluation may provide new insights into the aging of the human SN thereby enabling us to better understand the pathophysiological processes in aging brain

Image Anal Stereol 2003;22:73-80 Review Article MODERN STEREOLOGICAL EVALUATION IN THE AGING HUMAN

Quantitative estimation of neuronal numbers in the human substantia nigra (SN) can be achieved by a conventional single section (SS) count or by the more modern stereological disector (DS) count. However, counting results from SS counts are potentially biased and might not accurately reflect the total neuronal number in the SN or the changes in the total number of neurons occurring during aging or with neurodegenerative disease. Potential sources of bias include the lack of linearity between cell number per area of section and cell number per volume; the variation in the counting level and orientation of tissue sections; and shrinkage of tissue. Modern stereological DS counting overcomes these problems and has played a crucial role in many recent studies in neuropathology, neuroanatomy, neuropharmacology and neurogenetics. Over the past decades, four stereology based counting methods including physical DS, physical fractionator, optical DS and optical fractionator, have been established for quantitative measurement. Recently, stereological estimates have revealed a linear reduction rate of total nigral neuronal numbers with age of about 10 % per decade. These findings suggest that the surviving nigral neurons undergo a degenerative change leading to neuronal dysfunction with aging. Furthermore, as an advanced quantitative tool, modern stereological evaluation may provide new insights into the aging of the human SN thereby enabling us to better understand the pathophysiological processes in aging brain

Protective distal side-to-side neurorrhaphy in proximal nerve injury-an experimental study with rats

publishedVersionPeer reviewe