Early identification of MCI converting to AD: a FDG PET study.

PURPOSE: Mild cognitive impairment (MCI) is a transitional pathological stage between normal ageing (NA) and Alzheimer's disease (AD). Although subjects with MCI show a decline at different rates, some individuals remain stable or even show an improvement in their cognitive level after some years. We assessed the accuracy of FDG PET in discriminating MCI patients who converted to AD from those who did not. METHODS: FDG PET was performed in 42 NA subjects, 27 MCI patients who had not converted to AD at 5 years (nc-MCI; mean follow-up time 7.5 ± 1.5 years), and 95 MCI patients who converted to AD within 5 years (MCI-AD; mean conversion time 1.8 ± 1.1 years). Relative FDG uptake values in 26 meta-volumes of interest were submitted to ANCOVA and support vector machine analyses to evaluate regional differences and discrimination accuracy. RESULTS: The MCI-AD group showed significantly lower FDG uptake values in the temporoparietal cortex than the other two groups. FDG uptake values in the nc-MCI group were similar to those in the NA group. Support vector machine analysis discriminated nc-MCI from MCI-AD patients with an accuracy of 89% (AUC 0.91), correctly detecting 93% of the nc-MCI patients. CONCLUSION: In MCI patients not converting to AD within a minimum follow-up time of 5 years and MCI patients converting within 5 years, baseline FDG PET and volume-based analysis identified those who converted with an accuracy of 89%. However, further analysis is needed in patients with amnestic MCI who convert to a dementia other than AD.

Predicting the transition from normal aging to Alzheimer's disease: A statistical mechanistic evaluation of FDG-PET data.

The assessment of the degree of order of brain metabolism by means of a statistical mechanistic approach applied to FDG-PET, allowed us to characterize healthy subjects as well as patients with mild cognitive impairment and Alzheimer's Disease (AD). The intensity signals from 24 volumes of interest were submitted to principal component analysis (PCA) giving rise to a major first principal component whose eigenvalue was a reliable cumulative index of order. This index linearly decreased from 77 to 44% going from normal aging to AD patients with intermediate conditions between these values (r=0.96, p<0.001). Bootstrap analysis confirmed the statistical significance of the results. The progressive detachment of different brain regions from the first component was assessed, allowing for a purely data driven reconstruction of already known maximally affected areas. We demonstrated for the first time the reliability of a single global index of order in discriminating groups of cognitively impaired patients with different clinical outcome. The second relevant finding was the identification of clusters of regions relevant to AD pathology progressively separating from the first principal component through different stages of cognitive impairment, including patients cognitively impaired but not converted to AD. This paved the way to the quantitative assessment of the functional networking status in individual patients.

Metabolic spatial connectivity in amyotrophic lateral sclerosis as revealed by independent component analysis.

OBJECTIVES: Positron emission tomography (PET) and volume of interest (VOI) analysis have recently shown in amyotrophic lateral sclerosis (ALS) an accuracy of 93% in differentiating patients from controls. The aim of this study was to disclose by spatial independent component analysis (ICA) the brain networks involved in ALS pathological processes and evaluate their discriminative value in separating patients from controls. EXPERIMENTAL DESIGN: Two hundred fifty-nine ALS patients and 40 age- and sex-matched control subjects underwent brain 18F-2-fluoro-2-deoxy-D-glucose PET (FDG-PET). Spatial ICA of the preprocessed FDG-PET images was performed. Intensity values were converted to z-scores and binary masks were used as data-driven VOIs. The accuracy of this classifier was tested versus a validated system processing intensity signals in 27 brain meta-VOIs. A support vector machine was independently applied to both datasets and the 'leave-one-out' technique verified the general validity of results. PRINCIPAL OBSERVATIONS: The 8 components selected as pathophysiologically meaningful discriminated patients from controls with 99.0% accuracy, the discriminating value of bilateral cerebellum/midbrain alone representing 96.3%. Among the meta-VOIs, right temporal lobe alone reached an accuracy of 93.7%. CONCLUSIONS: Spatial ICA identified in a very large cohort of ALS patients distinct spatial networks showing a high discriminatory value, improving substantially on the previously obtained accuracy. The cerebellar/midbrain component accounted for the highest accuracy in separating ALS patients from controls. Spatial ICA and multivariate analysis perform better than univariate semi-quantification methods in identifying the neurodegenerative features of ALS and pave the way for inclusion of PET in clinical trials and early diagnosis.

Involvement of Subcortical Brain Structures During Olfactory Stimulation in Multiple Chemical Sensitivity.

Multiple chemical sensitivity (MCS) patients usually react to odour compounds and the majority of neuroimaging studies assessed, especially at the cortical level, many olfactory-related correlates. The purpose of the present study was to depict sub-cortical metabolic changes during a neutral (NC) and pure (OC) olfactory stimulation by using a recently validated (18)F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computer tomography procedure in 26 MCS and 11 healthy (HC) resting subjects undergoing a battery of clinical tests. Twelve subcortical volumes of interest were identified by the automated anatomical labeling library and normalized to thalamus FDG uptake. In both groups, when comparing OC to NC, the within-subjects ANOVA demonstrated a relative decreased metabolism in bilateral putamen and hippocampus and a relative increased metabolism in bilateral amygdala, olfactory cortex (OLF), caudate and pallidum. The between-groups ANOVA demonstrated in MCS a significant higher metabolism in bilateral OLF during NC. As in HC subjects negative correlations were found in OC between FDG uptake in bilateral amygdala and hippocampus and odor pleasantness scale, the latter positively correlated with MCS subjects' bilateral putamen FDG uptake in OC. Besides FDG uptake resemblances in both groups were found, for the first time a relative higher metabolism increase in OLF in MCS subjects at rest with respect to HC was found. When merging this aspect to the different subcortical FDG uptake correlations patterns in the two groups, the present study demonstrated to describe a peculiar metabolic index of behavioral and neurological aspects of MCS complaints.

Vitamin D deficiency and lifestyle risk factors in a Norwegian adolescent population.

AIM: The aim was to study vitamin D status in a healthy adolescent Norwegian population at 69°N. METHODS: The data presented come from The Tromsø Study: Fit Futures, during the school year 2010/2011 (not including the summer months), where 1,038 (92% of those invited) participated. Physical examinations, questionnaires and blood samples were collected, and serum 25-hydroxyvitamin D (25(OH)D) were analyzed using LC-MS/MS. RESULTS: RESULTS are presented from 475 boys and 415 girls (15-18 years old) with available blood samples. A total of 60.2% had vitamin D deficiency or insufficiency (serum 25(OH)D <50 nmol/l), 16.5% were deficient (<25 nmol/l) and 1.6% had severe vitamin D deficiency (<12.5 nmol/l). Only 12.4% had levels >75 nmol/l. A significant gender difference with a mean (SD) serum 25(OH)D level of 40.5 (20.5) nmol/l in boys and 54.2 (23.2) nmol/l in girls (p <0.01) was present. Furthermore, 51.3% of girls had levels >50 nmol/l in comparison to 29.7% of boys (p <0.01). There was an inverse correlation between parathyroid hormone levels and 25(OH)D, rs= -0.30 (p<0.01). Explanatory factors that were significantly associated with serum 25(OH)D levels in multivariate models were use of snuff, consumption of vitamin D fortified milk, cod liver oil and vitamin/mineral supplements, physical activity, sunbathing holiday and use of solarium in boys, and vitamin/mineral supplements, physical activity, sunbathing holiday and use of solarium in girls . CONCLUSIONS: Vitamin D deficiency is prevalent during the school year among adolescents in northern Norway, particularly among boys.

Vitamin D Status During Adolescence and the Impact of Lifestyle Changes: 2 Years' Follow-up From the Fit Futures Study.

CONTEXT: Longitudinal data regarding vitamin D status in adolescence is scarce. This study presents population-based data from an Arctic adolescent population (n = 589) at 16 and 18 years. OBJECTIVE: The aims of this study were to investigate changes in vitamin D status during 2 years in adolescence, and whether lifestyle changes were associated with serum 25-hydroxyvitamin D (s-25(OH)D) at follow-up. METHODS: Fit Futures is a longitudinal study at 69°N in Norway. Participants had their s-25(OH)D levels analyzed in their first and third year of upper secondary school (median age 16 and 18 years), in Fit Futures 1 (FF1) and Fit Futures 2 (FF2), respectively. Self-reported lifestyle habits were registered through questionnaires. The association between lifestyle changes and s-25(OH)D levels at follow-up were calculated by regression analyses, controlling for baseline s-25(OH)D levels. RESULTS: Longitudinal data were available for 309 girls and 280 boys. The proportion of adolescents with s-25(OH)D <50 nmol/L were 73.7% in FF1 and 77.1% in FF2, while the proportion <30 nmol/L constituted 35.7% in FF1 and 40.9% in FF2. Of those with s-25(OH)D <30 nmol/L (severe vitamin D deficiency) in FF1, 73.3% remained severely deficient in FF2. Among boys, an increase in UV exposure was significantly associated with higher s-25(OH)D levels in FF2 (beta; CI [nmol/L] 12.9; 9.1, 16.7). In girls, decreased vitamin/mineral supplement intake was significantly associated with lower s-25(OH)D at FF2 (-6.7; -10.2, -3.1), while increased UV (10.8; 7.0, 14.7) and combined hormonal contraceptive exposure (12.1; 6.0, 18.1) in FF2 was significantly associated with higher s-25(OH)D levels in FF2. CONCLUSION: Severe vitamin D deficiency was prevalent throughout adolescence. Lifestyle changes may alter s-25(OH)D levels in this age group.

High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio.

At present, there are few means to track symptomatic stages of CNS aging. Thus, although metabolic changes are implicated in mtDNA mutation-driven aging, the manifestations remain unclear. Here, we used normally aging and prematurely aging mtDNA mutator mice to establish a molecular link between mitochondrial dysfunction and abnormal metabolism in the aging process. Using proton magnetic resonance spectroscopy and HPLC, we found that brain lactate levels were increased twofold in both normally and prematurely aging mice during aging. To correlate the striking increase in lactate with tissue pathology, we investigated the respiratory chain enzymes and detected mitochondrial failure in key brain areas from both normally and prematurely aging mice. We used in situ hybridization to show that increased brain lactate levels were caused by a shift in transcriptional activities of the lactate dehydrogenases to promote pyruvate to lactate conversion. Separation of the five tetrameric lactate dehydrogenase (LDH) isoenzymes revealed an increase of those dominated by the Ldh-A product and a decrease of those rich in the Ldh-B product, which, in turn, increases pyruvate to lactate conversion. Spectrophotometric assays measuring LDH activity from the pyruvate and lactate sides of the reaction showed a higher pyruvate → lactate activity in the brain. We argue for the use of lactate proton magnetic resonance spectroscopy as a noninvasive strategy for monitoring this hallmark of the aging process. The mtDNA mutator mouse allows us to conclude that the increased LDH-A/LDH-B ratio causes high brain lactate levels, which, in turn, are predictive of aging phenotypes.

Effect of standardised surgical assessment and shared decision-making on morbidity and patient satisfaction after breast conserving therapy: A cross-sectional study.

BACKGROUND: The role of oncoplastic breast conserving therapy (OPBCT) on physical function, morbidity and patient satisfaction has yet to be defined. Additionally, technique selection should be individualised and incorporate patient preference. The study aim was to investigate differences between "standard" (sBCT) and oncoplastic breast conservation (OPBCT) in patient-reported outcomes (PROs) when patients have been assessed in a standardised manner and technique selection has been reached through shared decision-making (SDM). METHODS: This is a cross-sectional study of 215 women treated at a tertiary referral centre. Standardised surgical assessment included breast and lesion volumetry, definition of resection ratio, patient-related risk factors and patient preference. Postoperative morbidity and patient satisfaction were assessed by validated PROs tools (Diseases of the Arm, Shoulder and Hand-DASH and Breast-Q). Patient experience was assessed by semi-structured interviews. RESULTS: There was no difference of the median values between OPBCT and sBCT in postoperative morbidity of the upper extremity (DASH 3.3 vs 5, p = 0.656) or the function of the chest wall (Breast-Q 82 vs 82, p = 0.758). Postoperative satisfaction with breasts did not differ either (Breast-Q 65 vs 61, p = 0.702). On the individual level, women that opted for OPBCT after SDM had improved satisfaction when compared to baseline (+3 vs -1, p = 0.001). Shared decision-making changed patient attitude in 69.8% of patients, leading most often to de-escalation from mastectomy. CONCLUSIONS: These findings support that a combination of standardised surgical assessment and SDM allows for tailored treatment and de-escalation of oncoplastic surgery without negatively affecting patient satisfaction and morbidity.

100 YEARS OF VITAMIN D: Combined hormonal contraceptives and vitamin D metabolism in adolescent girls.

Objective: Combined hormonal contraceptive (CHC) use has been associated with higher total 25-hydroxyvitamin D (25(OH)D) levels. Here, we investigate the relation between CHC use and vitamin D metabolism to elucidate its clinical interpretation. Methods: The cross-sectional Fit Futures 1 included 1038 adolescents. Here, a subgroup of 182 girls with available 25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)2D), 24,25-dihydroxyvitamin D (24,25(OH)2D), vitamin D-binding protein (DBP) and measured free 25(OH)D levels, in addition to parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), was investigated. Vitamin D metabolites were compared between girls using (CHC+) and not using CHC (CHC-). Further, the predictability of CHC on 25(OH)D levels was assessed in a multiple regression model including lifestyle factors. The ratios 1,25(OH)2D/25(OH)D and 24,25(OH)2D/25(OH)D (vitamin D metabolite ratio (VMR)) in relation to 25(OH)D were presented in scatterplots. Results: CHC+ (n = 64; 35% of the girls) had higher 25(OH)D levels (mean ± s.d., 60.3 ± 22.2) nmol/L) than CHC- (n = 118; 41.8 ± 19.3 nmol/L), P -values <0.01. The differences in 25(OH)D levels between CHC+ and CHC- were attenuated but remained significant after the adjustment of lifestyle factors. CHC+ also had higher levels of 1,25(OH)2D, 24,25(OH)2D, DBP and calcium than CHC-, whereas 1,25(OH)2D/25(OH)D, PTH, FGF23 and albumin were significantly lower. Free 25(OH)D and VMR did not statistically differ, and both ratios appeared similar in relation to 25(OH)D, irrespective of CHC status. Conclusion: This confirms a clinical impact of CHC on vitamin D levels in adolescents. Our observations are likely due to an increased DBP-concentration, whereas the free 25(OH)D appears unaltered.

1H-MRS in spinal cord injury: acute and chronic metabolite alterations in rat brain and lumbar spinal cord.

A variety of tests of sensorimotor function are used to characterize outcome after experimental spinal cord injury (SCI). These tests typically do not provide information about chemical and metabolic processes in the injured CNS. Here, we used (1) H-magnetic resonance spectroscopy (MRS) to monitor long-term and short-term chemical changes in the CNS in vivo following SCI. The investigated areas were cortex, thalamus/striatum and the spinal cord distal to injury. In cortex, glutamate (Glu) decreased 1 day after SCI and slowly returned towards normal levels. The combined glutamine (Gln) and Glu signal was similarly decreased in cortex, but increased in the distal spinal cord, suggesting opposite changes of the Glu/Gln metabolites in cortex and distal spinal cord. In lumbar spinal cord, a marked increase of myo-inositol was found 3 days, 14 days and 4 months after SCI. Changes in metabolite concentrations in the spinal cord were also found for choline and N-acetylaspartate. No significant changes in metabolite concentrations were found in thalamus/striatum. Multivariate data analysis allowed separation between rats with SCI and controls for spectra acquired in cortex and spinal cord, but not in thalamus/striatum. Our findings suggest MRS could become a helpful tool to monitor spatial and temporal alterations of metabolic conditions in vivo in the brain and spinal cord after SCI. We provide evidence for dynamic temporal changes at both ends of the neuraxis, cortex cerebri and distal spinal cord, while deep brain areas appear less affected.

Cognitive impairment in the Tg6590 transgenic rat model of Alzheimer's disease.

Recently, interest in the rat as an animal model of Alzheimer's disease (AD) has been growing. We have previously described the Tg6590 transgenic rat line expressing the amyloid precursor protein containing the Swedish AD mutation (K670M/N671L) that shows early stages of Abeta deposition, predominantly in cerebrovascular blood vessels, after 15 months of age. Here we show that by the age of 9 months, that is long before the appearance of Abeta deposits, the Tg6590 rats exhibit deficits in the Morris water maze spatial navigation task and altered spontaneous behaviour in the open-field test. The levels of soluble Abeta were elevated both in the hippocampus and cortex of transgenic animals. Magnetic resonance imaging showed no major changes in the brains of transgenic animals, although they tended to have enlarged lateral ventricles when compared to control animals. The Tg6590 transgenic rat line should prove a suitable model of early AD for advanced studies including serial cerebrospinal fluid sampling, electrophysiology, neuroimaging or complex behavioural testing.

In vivo 1H-magnetic resonance spectroscopy can detect metabolic changes in APP/PS1 mice after donepezil treatment.

BACKGROUND: Donepezil improves cognitive functions in AD patients. Effects on the brain metabolites N-acetyl-L-aspartate, choline and myo-inositol levels have been reported in clinical studies using this drug. The APP/PS1 mouse coexpresses the mutated forms of human beta-amyloid precursor protein (APP) and mutated human presenilin 1 (PS1). Consequently, the APP/PS1 mouse model reflects important features of the neurochemical profile in humans. In vivo magnetic resonance spectroscopy (1H-MRS) was performed in fronto-parietal cortex and hippocampus (ctx/hipp) and in striatum (str). Metabolites were quantified using the LCModel and the final analysis was done using multivariate data analysis. The aim of this study was to investigate if multivariate data analysis could detect changes in the pattern of the metabolic profile after donepezil treatment. RESULTS: Significant differences were observed in the metabolic pattern of APP/PS1 mice in both str and ctx/hipp before and after donepezil treatment using multivariate data analysis, evidencing a significant treatment effect. A treatment effect was also seen in wild type (wt) mice in str. A significant decrease in the metabolic ratio taurine/creatine (Tau/tCr) was related to donepezil treatment (p < 0.05) in APP/PS1 mice in both brain regions. Furthermore, a significant influence on the choline/creatine (tCho/tCr) level was observed in treated APP/PS1 mice compared to untreated in str (p = 0.011). Finally, there was an increase in glutamate/creatine (Glu/tCr) in str in wt mice treated with donepezil. CONCLUSION: Multivariate data analysis can detect changes in the metabolic profile in APP/PS1 mice after donepezil treatment. Effects on several metabolites that are measurable in vivo using MR spectroscopy were observed. Changes in Tau/tCr and tCho/tCr could possibly be related to changed cholinergic activity caused by donepezil treatment.

High dose vitamin D may improve lower urinary tract symptoms in postmenopausal women.

Lower urinary tract symptoms (LUTS) are common in postmenopausal women, and have been reported inversely associated with vitamin D intake and serum 25-hydroxyvitamin D (25(OH)D) levels. The aim of this study was to investigate if high dose vitamin D supplementation would affect LUTS in comparison to standard dose. In a randomized controlled study including 297 postmenopausal women with low bone mineral density, the participants were allocated to receive capsules of 20 000IU of vitamin D3 twice a week (high dose group) or similar looking placebo (standard dose group). In addition, all the participants received 1g of calcium and 800IU of vitamin D daily. A validated questionnaire regarding LUTS was filled in at baseline and after 12 months. At baseline, 76 women in the high dose group and 82 in the standard dose group reported any LUTS. Levels of serum 25(OH)D increased significantly more in the high dose group (from 64.7 to 164.1nmol/l compared to from 64.1 to 81.8nmol/l, p<0.01). No differences between the groups were seen regarding change in LUTS except for a statistically significant reduction in the reported severity of urine incontinence in the high dose group as compared to the standard dose group after one year (p<0.05). The results need confirmation in a study specifically designed for this purpose.

Progressive Disintegration of Brain Networking from Normal Aging to Alzheimer Disease: Analysis of Independent Components of 18F-FDG PET Data.

Brain connectivity has been assessed in several neurodegenerative disorders investigating the mutual correlations between predetermined regions or nodes. Selective breakdown of brain networks during progression from normal aging to Alzheimer disease dementia (AD) has also been observed. Methods: We implemented independent-component analysis of 18F-FDG PET data in 5 groups of subjects with cognitive states ranging from normal aging to AD-including mild cognitive impairment (MCI) not converting or converting to AD-to disclose the spatial distribution of the independent components in each cognitive state and their accuracy in discriminating the groups. Results: We could identify spatially distinct independent components in each group, with generation of local circuits increasing proportionally to the severity of the disease. AD-specific independent components first appeared in the late-MCI stage and could discriminate converting MCI and AD from nonconverting MCI with an accuracy of 83.5%. Progressive disintegration of the intrinsic networks from normal aging to MCI to AD was inversely proportional to the conversion time. Conclusion: Independent-component analysis of 18F-FDG PET data showed a gradual disruption of functional brain connectivity with progression of cognitive decline in AD. This information might be useful as a prognostic aid for individual patients and as a surrogate biomarker in intervention trials.

Towards mapping the brain connectome in depression: functional connectivity by perfusion SPECT.

Several studies have demonstrated altered brain functional connectivity in the resting state in depression. However, no study has investigated interregional networking in patients with persistent depressive disorder (PDD). The aim of this study was to assess differences in brain perfusion distribution and connectivity between large groups of patients and healthy controls. Participants comprised 91 patients with PDD and 65 age- and sex-matched healthy controls. Resting state perfusion was investigated by single photon emission computed tomography, and group differences were assessed by Statistical Parametric Mapping. Brain connectivity was explored through a voxel-wise interregional correlation analysis using as covariate of interest the normalized values of clusters of voxels in which perfusion differences were found in group analysis. Significantly increased regional brain perfusion distribution covering a large part of the cerebellum was observed in patients as compared with controls. Patients showed a significant negative functional connectivity between the cerebellar cluster and caudate, bilaterally. This study demonstrated inverse relative perfusion between the cerebellum and the caudate in PDD. Functional uncoupling may be associated with a dysregulation between the role of the cerebellum in action control and of the caudate in action selection, initiation and decision making in the patients. The potential impact of the resting state condition and the possibility of mitochondrial impairment are discussed.

Cerebellar metabolic involvement and its correlations with clinical parameters in vestibular neuritis.

Although vestibular neuritis (VN) cortical models are described in the literature, there is lack of knowledge regarding the exclusive cerebellar involvement. The aim of the present study was to analyze, by [18F] fluorodeoxyglucose-positron emission tomography (FDG-PET)/computer tomography, regional cerebellar FDG uptake in eight right-handed VN patients (five females; three males; mean age 48 ± 7 years) during the first few days (PET0) and after 1 month (PET1) since symptoms onset. At both phases, patients underwent otoneurological examination and filled in a battery of validated questionnaires. Twenty-six cerebellar volumes of interest (VOI) were identified by the automated anatomical labeling library and normalized to thalamus FDG-PET uptake. Mean intensity within VOIs was calculated in both phases and processed by within-subjects ANOVA. A significantly lower (p < 0.005) FDG uptake distribution was found in bilateral lobules III, VI and X and in vermis 1-2, 3, 6 and 10 at PET0 as compared to PET1 and a significant higher FDG uptake distribution was found in right crus I in the same comparison. Significant (p < 0.05) positive correlations were found between Anxiety and Bucket test scores, and normalized metabolism in right crus I (at PET0) and vermis 10 (at PET1), respectively. A negative correlation was found at PET0 between slow-phase velocity scores and normalized metabolism in right lobule X. These data show relevant changes in the pattern of cerebellar metabolism that might unravel additional central aspects of early and late VN associated to bilateral cortical responses to sensory conflict during the acute VN-related controversial inflow.

Functional pattern of brain FDG-PET in amyotrophic lateral sclerosis.

OBJECTIVE: We investigated a large sample of patients with amyotrophic lateral sclerosis (ALS) at rest in order to assess the value of (18)F-2-fluoro-2-deoxy-d-glucose ((18)F-FDG) PET as a biomarker to discriminate patients from controls. METHODS: A total of 195 patients with ALS and 40 controls underwent brain (18)F-FDG-PET, most within 5 months of diagnosis. Spinal and bulbar subgroups of ALS were also investigated. Twenty-five bilateral cortical and subcortical volumes of interest and cerebellum were taken into account, and (18)F-FDG uptakes were individually normalized by whole-brain values. Group analyses investigated the ALS-related metabolic changes. Discriminant analysis investigating sensitivity and specificity was performed using the 51 volumes of interest as well as age and sex. Metabolic connectivity was explored by voxel-wise interregional correlation analysis. RESULTS: Hypometabolism was found in frontal, motor, and occipital cortex and hypermetabolism in midbrain, temporal pole, and hippocampus in patients with ALS compared to controls. A similar metabolic pattern was also found in the 2 subgroups. Discriminant analysis showed a sensitivity of 95% and a specificity of 83% in separating patients from controls. Connectivity analysis found a highly significant positive correlation between midbrain and white matter in corticospinal tracts in patients with ALS. CONCLUSIONS: (18)F-FDG distribution changes in ALS showed a clear pattern of hypometabolism in frontal and occipital cortex and hypermetabolism in midbrain. The latter might be interpreted as the neurobiological correlate of diffuse subcortical gliosis. Discriminant analysis resulted in high sensitivity and specificity in differentiating patients with ALS from controls. Once validated by diseased-control studies, the present methodology might represent a potentially useful biomarker for ALS diagnosis. CLASSIFICATON OF EVIDENCE: This study provides Class III evidence that (18)F-FDG-PET accurately distinguishes patients with ALS from normal controls (sensitivity 95.4%, specificity 82.5%).

Age related changes in brain metabolites observed by 1H MRS in APP/PS1 mice.

Translational biomarkers in Alzheimer's disease based on non-invasive in vivo methods are highly warranted. (1)H magnetic resonance spectroscopy (MRS) is non-invasive and applicable in vivo in both humans and experimental animals. In vivo(1)H MRS and 3D MRI were performed on brains of double transgenic (tg) mice expressing a double mutant human beta-amyloid precursor protein APP(K670N,M671L) and human mutated presenilin gene PS1M146L, and wild-type (wt) littermates at 2.5, 6.5 and 9 months of age using a 9.4T magnet. For quantification, LCModel was used, and the data were analyzed using multivariate data analysis (MVDA). MVDA evidenced a significant separation, which became more pronounced with age, between tg and wt mice at all time points. While myo-inositol and guanidoacetate were important for group separation in young mice, N-acetylaspartate, glutamate and macrolipids were important for separation of aged tg and wt mice. Volume segmentation revealed that brain and hippocampus were readily smaller in tg as compared to wt mice at the age of 2.5 months. Amyloid plaques were seen in 6.5 and 9 months, but not in 2.5 months old animals. In conclusion, differences in brain metabolites could be accurately depicted in tg and wt mice in vivo by combining MRS with MVDA. First differences in metabolite content were readily seen at 2.5 months, when volume defects in tg mice were present, but no amyloid plaques.

Recovery from spinal cord injury differs between rat strains in a major histocompatibility complex-independent manner.

Inflammation is a common characteristic of spinal cord injury. The nature of this response, whether it is beneficial or detrimental, has been the subject of debate. It has been reported that susceptibility to autoimmunity is correlated with increased functional impairment following spinal cord injury. As the ability to mount an autoimmune response has most consistently been associated with certain haplotypes of the major histocompatibility complex (MHC), we analysed the possible effects of the MHC haplotype on functional impairment and recovery following spinal cord injury. A contusion injury was induced in experimental autoimmune encephalomyelitis-susceptible and -resistant rats [Dark Agouti, Lewis and Piebald Viral Glaxo (PVG), respectively]. We found that locomotion recovered significantly better in Dark Agouti rats compared with PVG and Lewis rats but an F2 intercross (PVG x PVG-RT1(av1)) excluded the possibility that this difference was MHC haplotype-dependent. Thus, we conclude that recovery following spinal cord injury is subject to considerable genetic heterogeneity that is not coupled to the MHC haplotype region. Continued research of genetic variants regulating recovery following spinal cord injury is warranted.