阿尔兹海默病小鼠模型的磁共振影像学分析

目的分析和研究阿尔兹海默病（AD）转基因模型小鼠（APP/PS1）活体脑部影像学特征。方法本研究利用7.0 T高场强磁共振成像（MRI）技术,对1、3、5、7、9和11月龄AD转基因小鼠模型及对照组活体脑组织的微观结构变化进行对比研究。定量分析了脑组织顶叶皮层及海马区的横向弛豫时间（T2）、表观扩散系数（ADC）和各向异性分数（FA）随AD小鼠年龄变化情况。结果从9月龄开始AD转基因小鼠顶叶皮层及海马区可见散点状低信号区,并且随年龄增长逐渐增多;AD转基因小鼠顶叶皮层和海马区的T2磁豫时间在1～9月龄过程中有减小趋势,但与对照组无显著性差异;顶叶皮层及海马区ADC值的计算结果表明,7～11月龄AD转基因小鼠的ADC值明显下降（P≤0.05）;同样APP/PS1小鼠的FA值从5月龄就开始降低（P≤0.05）,并且这种差异一直持续到11月龄。结论高场强MRI能够显示AD病变出现早期小鼠顶叶皮层及海马区FA值的明显改变,揭示FA值对早期痴呆症临床诊断具有一定的参考价值。     

Peripheral Nerve Diffusion Tensor Imaging: Assessment of Axon and Myelin Sheath Integrity

Purpose

To investigate the potential of diffusion tensor imaging (DTI) parameters as in-vivo biomarkers of axon and myelin sheath integrity of the median nerve in the carpal tunnel as validated by correlation with electrophysiology.

Methods

MRI examinations at 3T including DTI were conducted on wrists in 30 healthy subjects. After manual segmentation of the median nerve quantitative analysis of fractional anisotropy (FA) as well as axial, radial and mean diffusivity (AD, RD, and MD) was carried out. Pairwise Pearson correlations with electrophysiological parameters comprising sensory nerve action potential (SNAP) and compound muscle action potential (CMAP) as markers of axon integrity, and distal motor latency (dml) and sensory nerve conduction velocity (sNCV) as markers of myelin sheath integrity were computed. The significance criterion was set at P=0.05, Bonferroni corrected for multiple comparisons.

Results

DTI parameters showed a distinct proximal-to-distal profile with FA, MD, and RD extrema coinciding in the center of the carpal tunnel. AD correlated with CMAP (r=0.50, p=0.04, Bonf. corr.) but not with markers of myelin sheath integrity. RD correlated with sNCV (r=-0.53, p=0.02, Bonf. corr.) but not with markers of axon integrity. FA correlated with dml (r=-0.63, p=0.002, Bonf. corr.) and sNCV (r=0.68, p=0.001, Bonf. corr.) but not with markers of axon integrity.

Conclusion

AD reflects axon integrity, while RD (and FA) reflect myelin sheath integrity as validated by correlation with electrophysiology. DTI parameters consistently indicate a slight decrease of structural integrity in the carpal tunnel as a physiological site of median nerve entrapment. DTI is particularly sensitive, since these findings are observed in healthy participants. Our results encourage future studies to evaluate the potential of DTI in differentiating axon from myelin sheath injury in patients with manifest peripheral neuropathies.     

Sexual dimorphism in healthy aging and mild cognitive impairment: a DTI study

Previous PET and MRI studies have indicated that the degree to which pathology translates into clinical symptoms is strongly dependent on sex with women more likely to express pathology as a diagnosis of AD, whereas men are more resistant to clinical symptoms in the face of the same degree of pathology. Here we use DTI to investigate the difference between male and female white matter tracts in healthy older participants (24 women, 16 men) and participants with mild cognitive impairment (21 women, 12 men). Differences between control and MCI participants were found in fractional anisotropy (FA), radial diffusion (DR), axial diffusion (DA) and mean diffusion (MD). A significant main effect of sex was also reported for FA, MD and DR indices, with male control and male MCI participants having significantly more microstructural damage than their female counterparts. There was no sex by diagnosis interaction. Male MCIs also had significantly less normalised grey matter (GM) volume than female MCIs. However, in terms of absolute brain volume, male controls had significantly more brain volume than female controls. Normalised GM and WM volumes were found to decrease significantly with age with no age by sex interaction. Overall, these data suggest that the same degree of cognitive impairment is associated with greater structural damage in men compared with women.     

White Matter Changes in Patients with Amnestic Mild Cognitive Impairment Detected by Diffusion Tensor Imaging

Compared to normal aging adults, individuals with amnestic mild cognitive impairment (aMCI) have significantly increased risk for progressing into Alzheimer’s disease (AD). Autopsy studies found that most of the brains of aMCI cases showed anatomical features associated with AD pathology. The recent development of non-invasive neuroimaging technique, such as diffusion tensor imaging (DTI), makes it possible to investigate the microstructures of the cerebral white matter in vivo. We hypothesized that disrupted white matter (WM) integrity existed in aMCI. So we used DTI technique, by measuring fractional anisotropy (FA) and mean diffusivity (MD), to test the brain structures involved in patients with aMCI. DTI scans were collected from 40 patients with aMCI, and 28 normal controls (NC). Tract-based spatial statistics (TBSS) analyses of whole-brain FA and MD images in each individual and group comparisons were carried out. Compared to NC, aMCI patients showed significant FA reduction bilaterally, in the association and projection fibers of frontal, parietal, and temporal lobes, corpus callosum, bilateral corona radiation, right posterior thalamic radiation and right sagittal stratum. aMCI patients also showed significantly increased MD widespreadly in the association and projection fibers of frontal, parietal and temporal lobes, and corpus callosum. Assessment of the WM integrity of the frontal, parietal, temporal lobes, and corpus callosum by using DTI measures may aid early diagnosis of aMCI.     

Surface-Based Analysis on Shape and Fractional Anisotropy of White Matter Tracts in Alzheimer's Disease

Background

White matter disruption has been suggested as one of anatomical features associated with Alzheimer''s disease (AD). Diffusion tensor imaging (DTI), which has been widely used in AD studies, obtains new insights into the white matter structure.

Methods

We introduced surface-based geometric models of the deep white matter tracts extracted from DTI, allowing the characterization of their shape variations relative to an atlas as well as fractional anisotropy (FA) variations on the atlas surface through large deformation diffeomorphic metric mapping (LDDMM). We applied it to assess local shapes and FA variations of twenty-three deep white matter tracts in 13 patients with AD and 19 healthy control subjects.

Results

Our results showed regionally-specific shape abnormalities and FA reduction in the cingulum tract and the sagittal stratum tract in AD, suggesting that disruption in the white matter tracts near the temporal lobe may represent the secondary consequence of the medial temporal lobe pathology in AD. Moreover, the regionally-specific patterns of FA and shape of the white matter tracts were shown to be of sufficient sensitivity to robustly differentiate patients with AD from healthy comparison controls when compared with the mean FA and volumes within the regions of the white matter tracts. Finally, greater FA or deformation abnormalities of the white matter tracts were associated with lower MMSE scores.

Conclusion

The regionally-specific shape and FA patterns could be potential imaging markers for differentiating AD from normal aging.     

Arcuate fasciculus abnormalities and their relationship with psychotic symptoms in schizophrenia

Disruption of fronto-temporal connections involving the arcuate fasciculus (AF) may underlie language processing anomalies and psychotic features such as auditory hallucinations in schizophrenia. No study to date has specifically investigated abnormalities of white matter integrity at particular loci along the AF as well as its regional lateralization in schizophrenia. We examined white matter changes (fractional anisotropy (FA), axial diffusivity (AD), asymmetry indices) along the whole extent of the AF and their relationship with psychotic symptoms in 32 males with schizophrenia and 44 healthy males. Large deformation diffeomorphic metric mapping and Fiber Assignment Continuous Tracking were employed to characterize FA and AD along the geometric curve of the AF. Our results showed that patients with schizophrenia had lower FA in the frontal aspects of the left AF compared with healthy controls. Greater left FA and AD lateralization in the temporal segment of AF were associated with more severe positive psychotic symptoms such as delusions and hallucinations in patients with schizophrenia. Disruption of white matter integrity of the left frontal AF and accentuation of normal left greater than right asymmetry of FA/AD in the temporal AF further support the notion of aberrant fronto-temporal connectivity in schizophrenia. AF pathology can affect corollary discharge of neural signals from frontal speech/motor initiation areas to suppress activity of auditory cortex that may influence psychotic phenomena such as auditory hallucinations and facilitate elaboration of delusional content.     

Longitudinal Assessment of Amyloid Pathology in Transgenic ArcAβ Mice Using Multi-Parametric Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) can be used to monitor pathological changes in Alzheimer''s disease (AD). The objective of this longitudinal study was to assess the effects of progressive amyloid-related pathology on multiple MRI parameters in transgenic arcAβ mice, a mouse model of cerebral amyloidosis. Diffusion-weighted imaging (DWI), T₁-mapping and quantitative susceptibility mapping (QSM), a novel MRI based technique, were applied to monitor structural alterations and changes in tissue composition imposed by the pathology over time. Vascular function and integrity was studied by assessing blood-brain barrier integrity with dynamic contrast-enhanced MRI and cerebral microbleed (CMB) load with susceptibility weighted imaging and QSM. A linear mixed effects model was built for each MRI parameter to incorporate effects within and between groups (i.e. genotype) and to account for changes unrelated to the disease pathology. Linear mixed effects modelling revealed a strong association of all investigated MRI parameters with age. DWI and QSM in addition revealed differences between arcAβ and wt mice over time. CMBs became apparent in arcAβ mice with 9 month of age; and the CMB load reflected disease stage. This study demonstrates the benefits of linear mixed effects modelling of longitudinal imaging data. Moreover, the diagnostic utility of QSM and assessment of CMB load should be exploited further in studies of AD.     

MRI of Neuronal Recovery after Low-Dose Methamphetamine Treatment of Traumatic Brain Injury in Rats

We assessed the effects of low dose methamphetamine treatment of traumatic brain injury (TBI) in rats by employing MRI, immunohistology, and neurological functional tests. Young male Wistar rats were subjected to TBI using the controlled cortical impact model. The treated rats (n = 10) received an intravenous (iv) bolus dose of 0.42 mg/kg of methamphetamine at eight hours after the TBI followed by continuous iv infusion for 24 hrs. The control rats (n = 10) received the same volume of saline using the same protocol. MRI scans, including T2-weighted imaging (T2WI) and diffusion tensor imaging (DTI), were performed one day prior to TBI, and at 1 and 3 days post TBI, and then weekly for 6 weeks. The lesion volumes of TBI damaged cerebral tissue were demarcated by elevated values in T₂ maps and were histologically identified by hematoxylin and eosin (H&E) staining. The fractional anisotropy (FA) values within regions-of-interest (ROI) were measured in FA maps deduced from DTI, and were directly compared with Bielschowsky’s silver and Luxol fast blue (BLFB) immunohistological staining. No therapeutic effect on lesion volumes was detected during 6 weeks after TBI. However, treatment significantly increased FA values in the recovery ROI compared with the control group at 5 and 6 weeks after TBI. Myelinated axons histologically measured using BLFB were significantly increased (p<0.001) in the treated group (25.84±1.41%) compared with the control group (17.05±2.95%). Significant correlations were detected between FA and BLFB measures in the recovery ROI (R = 0.54, p<0.02). Methamphetamine treatment significantly reduced modified neurological severity scores from 2 to 6 weeks (p<0.05) and foot-fault errors from 3 days to 6 weeks (p<0.05) after TBI. Thus, the FA data suggest that methamphetamine treatment improves white matter reorganization from 5 to 6 weeks after TBI in rats compared with saline treatment, which may contribute to the observed functional recovery.     

Genetic risk for Alzheimer disease in children: Evidence from early‐life IQ and brain white‐matter microstructure

It remains unclear whether the genetic risk for late‐onset Alzheimer disease (AD) is linked to premorbid individual differences in general cognitive ability and brain structure. The objective of the present study was to determine whether the genetic risk of late‐onset AD is related to premorbid individual differences in intelligence quotient (IQ) and characteristics of the cerebral white‐matter in children. The study sample included children of the Generation R Study from Rotterdam, The Netherlands. IQ was measured using a well‐validated Dutch nonverbal IQ test (n = 1908) at ages 5 to 9 years. White‐matter microstructure was assessed by measuring fractional anisotropy (FA) of white‐matter tracts using diffusion tensor imaging (DTI) (n = 919) at ages 9 to 12 years. Genetic risk was quantified using three biologically defined genetic risk scores (GRSs) hypothesized to be related to the pathophysiology of late‐onset AD: immune response, cholesterol/lipid metabolism and endocytosis. Higher genetic risk for late‐onset AD that included genes associated with immune responsivity had a negative influence on cognition and cerebral white‐matter microstructure. For each unit increase in the immune response GRS, IQ decreased by 0.259 SD (95% CI [?0.500, ?0.017]). For each unit increase in the immune response GRS, global FA decreased by 0.373 SD (95% CI [?0.721, ?0.026]). Neither cholesterol/lipid metabolism nor endocytosis GRSs were associated with IQ or cerebral white‐matter microstructure. Our findings suggest that elevated genetic risk for late‐onset AD may in part be manifest during childhood neurodevelopment through alterations in immune responsivity.     

Independent Component Analysis-Based Identification of Covariance Patterns of Microstructural White Matter Damage in Alzheimer’s Disease

The existing DTI studies have suggested that white matter damage constitutes an important part of the neurodegenerative changes in Alzheimer’s disease (AD). The present study aimed to identify the regional covariance patterns of microstructural white matter changes associated with AD. In this study, we applied a multivariate analysis approach, independent component analysis (ICA), to identify covariance patterns of microstructural white matter damage based on fractional anisotropy (FA) skeletonised images from DTI data in 39 AD patients and 41 healthy controls (HCs) from the Alzheimer’s Disease Neuroimaging Initiative database. The multivariate ICA decomposed the subject-dimension concatenated FA data into a mixing coefficient matrix and a source matrix. Twenty-eight independent components (ICs) were extracted, and a two sample t-test on each column of the corresponding mixing coefficient matrix revealed significant AD/HC differences in ICA weights for 7 ICs. The covariant FA changes primarily involved the bilateral corona radiata, the superior longitudinal fasciculus, the cingulum, the hippocampal commissure, and the corpus callosum in AD patients compared to HCs. Our findings identified covariant white matter damage associated with AD based on DTI in combination with multivariate ICA, potentially expanding our understanding of the neuropathological mechanisms of AD.     

Obesity is associated with reduced white matter integrity in otherwise healthy adults

Existing work demonstrates that obesity is independently associated with cognitive dysfunction and macrostructural brain changes; however, little is known about the association between obesity and white matter (WM) integrity. We explore this relationship in a large cohort of otherwise healthy subjects. The present study classified 103 adult participants from the Brain Resource International Database between 21 and 86 years of age without history of neurological, medical, or psychiatric illness according to BMI (normal weight, overweight, obese) and subjected them to diffusion tensor imaging (DTI). Resulting fractional anisotropy (FA) indexes for the corpus callosum and fornix were examined in relation to BMI and age in a multiple regression framework. Results indicated that increasing BMI was independently associated with lower FA in the genu, splenium, and fornix, and a BMI × age interaction emerged for FA in the splenium and body of the corpus callosum. When categorized, obese persons demonstrated lower FA than normal and overweight persons for all WM indexes, but no FA differences emerged between overweight and normal persons. Results indicate both a direct association between obesity and reduced WM tract integrity and an interaction between obesity and aging processes on certain WM tracts in otherwise healthy adults. While such findings suggest a possible role for adiposity in WM dysfunction and associated cognitive deficits, prospective studies are needed to clarify the nature of these relationships and elucidate underlying mechanisms.     

Reduced Right Frontal Fractional Anisotropy Correlated with Early Elevated Plasma LDL Levels in Obese Young Adults

Objective

To investigate the underlying physiological mechanisms of the structural differences in gray matter (GM) and white matter (WM) associated with obesity in young Chinese adults.

Materials and Methods

A total of 49 right-handed obese or overweight (n = 22, mean age 31.72±8.04 years) and normal weight (n = 27, mean age 29.04±7.32 years) Han Chinese individuals were recruited. All participants underwent voxel-based morphometry analysis of T1-weighted MRI and tract-based spatial statistics analysis of diffusion tensor imaging. Partial correlation analysis was performed between the physiological data obtained and the abnormal structural alterations.

Results

In the OO group, GM atrophy occurred in the left prefrontal cortex, bilateral cingulate gyrus, and the right temporal lobe, while enlargement was observed in the bilateral putamen. WM atrophy was observed predominantly in the regions that regulate food intake, such as the bilateral basal ganglia, the right amygdala, and the left insula. The OO group exhibited lower fractional anisotropy (FA) in bilateral frontal corticospinal tracts and the right brainstem. Significant negative correlations were observed between FA values of those three clusters and BMI, and waist circumference, while the volume of bilateral putamen positively correlated with both BMI and waist circumference. High plasma LDL levels were correlated with low FA values in the right frontal corticospinal tract. Interestingly, the negative correlation was limited to male participants.

Conclusions

Obesity-related alterations of GM and WM volumes were observed predominantly in food reward circuit, which may motivate abnormal dietary intake. Further, early elevated plasma LDL might contribute to low right frontal FA values of male adults, which requires further demonstration by larger-scale and longitudinal studies.     

Identification of Neonatal White Matter on DTI: Influence of More Inclusive Thresholds for Atlas Segmentation

Purpose

Semi-automated diffusion tensor imaging (DTI) analysis of white matter (WM) microstructure offers a clinically feasible technique to assess neonatal brain development and provide early prognosis, but is limited by variable methods and insufficient evidence regarding optimal parameters. The purpose of this research was to investigate the influence of threshold values on semi-automated, atlas-based brain segmentation in very-low-birth-weight (VLBW) preterm infants at near-term age.

Materials and Methods

DTI scans were analyzed from 45 VLBW preterm neonates at near-term-age with no brain abnormalities evident on MRI. Brain regions were selected with a neonatal brain atlas and threshold values: trace <0.006 mm²/s, fractional anisotropy (FA)>0.15, FA>0.20, and FA>0.25. Relative regional volumes, FA, axial diffusivity (AD), and radial diffusivity (RD) were compared for twelve WM regions.

Results

Near-term brain regions demonstrated differential effects from segmentation with the three FA thresholds. Regional DTI values and volumes selected in the PLIC, CereP, and RLC varied the least with the application of different FA thresholds. Overall, application of higher FA thresholds significantly reduced brain region volume selected, increased variability, and resulted in higher FA and lower RD values. The lower threshold FA>0.15 selected 78±21% of original volumes segmented by the atlas, compared to 38±12% using threshold FA>0.25.

Conclusion

Results indicate substantial and differential effects of atlas-based DTI threshold parameters on regional volume and diffusion scalars. A lower, more inclusive FA threshold than typically applied for adults is suggested for consistent analysis of WM regions in neonates.     

A Pilot Study of the Effect of Sodium Thiosulfate on Urinary Lithogenicity and Associated Metabolic Acid Load in Non-Stone Formers and Stone Formers with Hypercalciuria

Background and Objectives

Sodium thiosulfate (STS) reduced calcium stone formation in both humans and genetic hypercalciuric stone forming (GHS) rats. We sought to measure urine chemistry changes resulting from STS administration in people.

Design, Setting, Participants & Measurements

STS was given to healthy and hypercalciuric stone forming adults. Five normal non-stone forming adults (mean age 33 years), and 5 people with idiopathic hypercalciuria and calcium kidney stones (mean age 66 years) participated. Two baseline 24-hour urine collections were performed on days 2 and 3 of 3 days of self-selected diets. Subjects then drank STS 10 mmol twice a day for 7 days and did urine collections while repeating the self-selected diet. Results were compared by non-parametric Wilcoxon signed rank test. The primary outcome was the resulting change in urine chemistry.

Results

STS administration did not cause a significant change in urinary calcium excretion in either group. In both groups, 24 hour urinary ammonium (P = 0.005) and sulfate excretion (P = 0.007) increased, and urinary pH fell (P = 0.005); citrate excretion fell (P<0.05) in hypercalciuric participants but not in non-stone formers. Among stone formers with hypercalciuria, 3 of 5 patients had measurement of serum HCO₃ concentration after the STS period: it did not change. The net effect was an increase in supersaturation of uric acid, and no change in supersaturation of calcium oxalate or calcium phosphate.

Conclusions

The basis for studies demonstrating that STS prevented stones in rats and people was not reflected by the changes in urine chemistry reported here. Although serum HCO₃ did not change, urine tests suggested an acid load in both non-stone forming and hypercalciuric stone-forming participants. The long term safety of STS needs to be determined before the drug can be tested in humans for long-term prevention of stone recurrence.     

Apathy and White Matter Integrity in Alzheimer’s Disease: A Whole Brain Analysis with Tract-Based Spatial Statistics

The aim of this study was to investigate the microstructural alterations of white matter (WM) in Alzheimer’s disease (AD) patients with apathy and to observe the relationships with the severity of apathy. Sixty drug-naïve subjects took part in this study (30 apathetic and 30 nonapathetic subjects with AD). The loss of integrity in WM was compared in AD patients with and without apathy through measurement of fractional anisotropy (FA) using by tract-based spatial statistics (TBSS). In addition, we explored the correlation pattern between FA values and the severity of apathy in AD patients with apathy. The apathy group had significantly reduced FA values (p_corrected<0.05) in the genu of the corpus callosum compared to the nonapathy group. The severity of apathy was negatively correlated with FA values of the left anterior and posterior cingulum, right superior longitudinal fasciculus, splenium, body and genu of the corpus callosum and bilateral uncinate fasciculusin the apathy group (p_corrected<0.05). This study was the first to explore FA values in whole brain WM in AD patients with apathy. The findings of these microstructural alterations of WM may be the key to the understanding of underlying neurobiological mechanism and clinical significances of apathy in AD.     

Sodium tanshinone IIA sulfonate protects against Aβ-induced cell toxicity through regulating Aβ process

Sodium tanshinone IIA sulfonate (STS) has been reported to prevent Alzheimer's disease (AD). However, the mechanism is still unknown. In this study, two in vitro models, Aβ-treated SH-SY5Y cells and SH-SY5Y human neuroblastoma cells transfected with APPsw (SH-SY5Y-APPsw cells), were employed to investigate the neuroprotective of STS. The results revealed that pretreatment with STS (1, 10 and 100 µmol/L) for 24 hours could protect against Aβ (10 µmol/L)-induced cell toxicity in a dose-dependent manner in the SH-SY5Y cells. Sodium tanshinone IIA sulfonate decreased the concentrations of reactive oxygen species, malondialdehyde, NO and iNOS, while increased the activities of superoxide dismutase and glutathione peroxidase in the SH-SY5Y cells. Sodium tanshinone IIA sulfonate decreased the levels of inflammatory factors (IL-1β, IL-6 and TNF-α) in the SH-SY5Y cells. In addition, Western blot results revealed that the expressions of neprilysin and insulin-degrading enzyme were up-regulated in the SH-SY5Y cells after STS treatment. Furthermore, ELISA and Western blot results showed that STS could decrease the levels of Aβ. ELISA and qPCR results indicated that STS could increase α-secretase (ADAM10) activity and decrease β-secretase (BACE1) activity. In conclusion, STS could protect against Aβ-induced cell damage by modulating Aβ degration and generation. Sodium tanshinone IIA sulfonate could be a promising candidate for AD treatment.     

Fatty acid control of nitric oxide production by macrophages

Modulation of macrophage functions by fatty acids (FA) has been studied by several groups, but the effect of FA on nitric oxide production by macrophages has been poorly examined. In the present study the effect of palmitic, stearic, oleic, linoleic, arachidonic, docosahexaenoic and eicosapentaenoic acids on NF-kappaB activity and NO production in J774 cells (a murine macrophage cell line) was investigated. All FA tested stimulated NO production at low doses (1-10 microM) and inhibited it at high doses (50-200 microM). An increase of iNOS expression and activity in J774 cells treated with a low concentration of FA (5 microM) was observed. The activity of NF-kappaB was time-dependently enhanced by the FA treatment. The inhibitory effect of FA on NO production may be due to their cytotoxicity, as observed by loss of membrane integrity and/or increase of DNA fragmentation in cells treated for 48 h with high concentrations. The results indicate that, at low concentrations FA increase NO production by J774 cells, whereas at high concentrations they cause cell death.     

Alzheimer’s Disease Susceptibility Genes APOE and TOMM40, and Hippocampal Volumes in the Lothian Birth Cohort 1936

The APOE ε and TOMM40 rs10524523 (‘523’) variable length poly-T repeat gene loci have been significantly and independently associated with Alzheimer’s disease (AD) related phenotypes such as age of clinical onset. Hippocampal atrophy has been significantly associated with memory impairment, a characteristic of AD. The current study aimed to test for independent effects of APOE ε and TOMM40 ‘523’ genotypes on hippocampal volumes as assessed by brain structural MRI in a relatively large sample of community-dwelling older adults. As part of a longitudinal study of cognitive ageing, participants in the Lothian Birth Cohort 1936 underwent genotyping for APOE ε2/ε3/ε4 status and TOMM40 ‘523’ poly-T repeat length, and detailed structural brain MRI at a mean age of 72.7 years (standard deviation = 0.7, N range = 624 to 636). No significant effects of APOE ε or TOMM40 523 genotype were found on hippocampal volumes when analysed raw, or when adjusted for either intracranial or total brain tissue volumes. In summary, in a large community-dwelling sample of older adults, we found no effects of APOE ε or TOMM40 523 genotypes on hippocampal volumes. This is discrepant with some previous reports of significant association between APOE and left/right hippocampal volumes, and instead echoes other reports that found no association. Previous significant findings may partly reflect type 1 error. Future studies should carefully consider: 1) their specific techniques in adjusting for brain size; 2) assessing more detailed sub-divisions of the hippocampal formation; and 3) testing whether significant APOE-hippocampal associations are independent of generalised brain atrophy.     

Ischemic preconditioning enhances fatty acid-dependent mitochondrial uncoupling

This study tests the hypothesis that ischemic preconditioning (IP) changes fatty acid (FA)-dependent uncoupling between mitochondrial respiration and oxidative phosphorylation. We found that IP does not alter mitochondrial membrane integrity or FA levels, but enhances membrane potential decreases when FA are present, in an ATP-sensitive manner. FA hydroperoxides had equal effects in control and preconditioned mitochondria, and GTP did not abrogate the IP effect, suggesting uncoupling proteins were not involved. Conversely, thiol reductants and atractyloside, which inhibits the adenine nucleotide translocator, eliminated the differences in responses to FA. Together, our results suggest that IP leads to thiol oxidation and activation of the adenine nucleotide translocator, resulting in enhanced FA transport and mild mitochondrial uncoupling.