Cerebral glucose metabolism and cognition in newly diagnosed Parkinson's disease: ICICLE-PD study.

OBJECTIVE: To assess reductions of cerebral glucose metabolism in Parkinson's disease (PD) with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and their associations with cognitive decline. METHODS: FDG-PET was performed on a cohort of 79 patients with newly diagnosed PD (mean disease duration 8 months) and 20 unrelated controls. PD participants were scanned while on their usual dopaminergic medication. Cognitive testing was performed at baseline, and after 18 months using the Cognitive Drug Research (CDR) and Cambridge Neuropsychological Test Automated Battery (CANTAB) computerised batteries, the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment (MoCA). We used statistical parametric mapping (SPM V.12) software to compare groups and investigate voxelwise correlations between FDG metabolism and cognitive score at baseline. Linear regression was used to evaluate how levels of cortical FDG metabolism were predictive of subsequent cognitive decline rated with the MMSE and MoCA. RESULTS: PD participants showed reduced glucose metabolism in the occipital and inferior parietal lobes relative to controls. Low performance on memory-based tasks was associated with reduced FDG metabolism in posterior parietal and temporal regions, while attentional performance was associated with more frontal deficits. Baseline parietal to cerebellum FDG metabolism ratios predicted MMSE (ß=0.38, p=0.001) and MoCA (ß=0.3, p=0.002) at 18 months controlling for baseline score. CONCLUSIONS: Reductions in cortical FDG metabolism were present in newly diagnosed PD, and correlated with performance on neuropsychological tests. A reduced baseline parietal metabolism is associated with risk of cognitive decline and may represent a potential biomarker for this state and the development of PD dementia.

Relationship between baseline white-matter changes and development of late-life depressive symptoms: 3-year results from the LADIS study.

BACKGROUND: Growing evidence suggests that cerebral white-matter changes and depressive symptoms are linked directly along the causal pathway. We investigated whether baseline severity of cerebral white-matter changes predict longer-term future depressive outcomes in a community sample of non-disabled older adults. METHOD: In the Leukoaraiosis and Disability in the Elderly (LADIS) study, a longitudinal multi-centre pan-European study, 639 older subjects underwent baseline structural magnetic resonance imaging (MRI) and clinical assessments. Baseline severity of white-matter changes was quantified volumetrically. Depressive outcomes were assessed in terms of depressive episodes and depressive symptoms, as measured by the Geriatric Depression Scale (GDS). Subjects were clinically reassessed annually for up to 3 years. Regression models were constructed to determine whether baseline severity of white-matter changes predicted future depressive outcomes, after controlling for confounding factors. RESULTS: Baseline severity of white-matter changes independently predicted depressive symptoms at both 2 (p<0.001) and 3 years (p=0.015). Similarly, white-matter changes predicted incident depression (p=0.02). Over the study period the population became significantly more disabled (p<0.001). When regression models were adjusted to account for the influence of the prospective variable transition to disability, baseline severity of white-matter changes no longer predicted depressive symptoms at 3 years (p=0.09) or incident depression (p=0.08). CONCLUSIONS: Our results support the vascular depression hypothesis and strongly implicate white-matter changes in the pathogenesis of late-life depression. Furthermore, the findings indicate that, over time, part of the relationship between white-matter changes and depression may be mediated by loss of functional activity.

Combination peroxisome proliferator-activated receptor gamma and alpha agonist treatment in Type 2 diabetes prevents the beneficial pioglitazone effect on liver fat content.

AIMS: Peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-alpha agonists individually reduce intra-organ triglyceride content and improve insulin sensitivity. However, the precise effects of combined PPAR-gamma and PPAR-alpha therapy on intra-organ triglyceride content and insulin sensitivity in subjects with Type 2 diabetes have not yet been determined. METHODS: Diet-controlled Type 2 subjects (n = 9) were studied before and after 16 weeks of combined PPAR-gamma [pioglitazone (PIO), 45 mg daily] and PPAR-alpha [bezafibrate (BEZA), modified release 400 mg daily] agonist therapy. Glucose metabolism and endogenous glucose production were measured following a standard liquid test meal. Liver and muscle triglyceride levels were measured by (1)H magnetic resonance spectroscopy. RESULTS: Combined PIO and BEZA therapy reduced mean fasting (7.5 +/- 0.5 vs. 6.5 +/- 0.2 mmol/l, P = 0.04) and peak postprandial plasma glucose (15.3 +/- 1.1 vs. 11.7 +/- 0.6 mmol/l, P = 0.007). No significant change in hepatic or muscle triglyceride content was observed. Postprandial suppression of endogenous glucose production remained similar on both study days. Both subcutaneous and visceral fat content increased following therapy. CONCLUSIONS: Combined PIO and BEZA therapy in Type 2 diabetes does not decrease intrahepatic triglyceride content or postprandial endogenous glucose production. This study demonstrates an unexpected adverse interaction of PPAR-alpha with PPAR-gamma agonist therapy.

A comparison of two methods for measuring the signal to noise ratio on MR images.

The signal to noise ratio (SNR) is one of the important measures of the performance of a magnetic resonance imaging (MRI) system. The object of this study was to compare a single acquisition method, which estimates the noise from background pixels, with a dual acquisition method which estimates the noise from the subtraction of two sequentially acquired images. The dual acquisition method is more exact, but is slower to perform and requires image manipulation. A comparison between the two methods gave a good correlation, and a regression equation of SNRsingle = 1.1 + 0.94 SNRdual. The single acquisition method is therefore appropriate for use in a quality assurance programme, since it is quicker and simpler to perform and is a good indicator of the more exact measure.

Partial volume effects in MRI studies of multiple sclerosis.

We have estimated the accuracy of volume measurements of multiple sclerosis (MS) lesions made using magnetic resonance imaging (MRI) for lesions of comparable diameter to the image slice thickness. We used a phantom containing objects of known volume and obtained images using a range of slice thicknesses. Measurements on the phantom were used to assess a theoretical model, which was then employed to investigate the effects of image dimensions and geometry upon volume measurement accuracy. We observed measured volume to be dependent upon slice thickness. Thin slices gave the most accurate estimate of volume. As slice thickness increased relative to object diameter, the error in the volume measurement increased (to as much as 100%), the volume measured being dependent on the position of the object relative to the slice center. Using a signal intensity threshold value of 50% to outline objects gave results closest to the actual volume. As expected, a lower threshold value tended to give higher volume estimates (up to 100% larger), as did a semi-automated local edge detection technique. For accurate volume measurement, the slice thickness should be no more than a fifth of anticipated object diameter. For typical MS lesions (7 mm in diameter), this implies using a 1.5-mm slice thickness. For serial studies, a repositioning error of 1 mm could lead to differences in the volume measurement of individual lesions of up to 12% between studies for lesions of typical MS size and 5-mm slice thickness. These results emphasize the need for accurate patient repositioning, relatively thin slices, for regular quality assurance checks to ensure that pixel size and slice position are correct and stable over time, and that lesion outlining is performed in a consistent fashion. We would recommend the use of a 3D sequence with 1 mm cubic voxels for accurate measurements of MS lesions.

Measuring extraocular muscle volume using dynamic contours.

The effect of medical treatment on extraocular muscle enlargement in thyroid associated ophthalmopathy (TAO) may be monitored by measuring the change in volume of the extraocular muscles on serial orbital MRI examinations. In theory, 3D image sets offer the opportunity to minimise errors due to poor repositioning and partial volume effects. This study describes an automated technique for estimating extraocular muscle volumes from 3D datasets. Operator input is minimal and the technique is robust. Verification of the technique on both simulated and real datasets is described. For simulated image sets, both automated segmentation and manual outlining produced estimates of volume which were on average 4% less than "true" volume. For real patient data, extraocular muscle volumes measured by the automated technique were 1.6% (SD 13%) less than volumes measured by manual outlining. Coefficient of variation for repeat outlining of the same image dataset for the automated technique was 1.0%, compared with 4% for manual outlining. The manual technique took an experienced operator approximately 20 min to perform, compared to 7 min for the automated technique. The automated method is therefore rapid, reproducible and at least as accurate as other available methods.

Evaluation of a technique for estimation of extraocular muscle volume using 2D MRI.

Measurements of extraocular muscle volume may be useful as an outcome indicator in the assessment of treatment options in thyroid-associated ophthalmopathy. In this study, a technique for estimating extraocular muscle volume from two-dimensional T1 weighted MR images acquired in the coronal plane is described. For each image slice, the cross-sectional area of individual extraocular muscles was estimated using a combination of semi-automated outlining based on a local thresholding technique and manual outlining where thresholding was not possible. The technique was assessed using three sets of images: a computer-generated virtual image set with "extraocular muscles" of known volumes; a set of images from 19 biochemically and clinically euthyroid patients; and images from 7 patients with thyroid-associated ophthalmopathy. From the computer-generated images, the accuracy was determined as 7.6%. Intraobserver agreement was investigated using repeated MRI scans on a single subject and repeat outlining of muscles on five sets of images from different subjects. The mean difference between repeat measurements was 2% (SD 5.9%). We conclude that two-dimensional MR images can be used to determine changes in muscle volume of greater than 12% during treatment of thyroid-associated ophthalmopathy.

Quality assurance for MRI: practical experience.

The aim of this study is to propose guidelines for quality assurance (QA) in MRI, based on a comprehensive assessment of QA parameters undertaken on a busy clinical MRI scanner over the course of 1 year. QA phantoms supplied by the scanner manufacturer were used together with the Eurospin MRI phantom set. Signal-to-noise ratio (SNR) and image uniformity were measured daily from spin echo images acquired using a quadrature send-receive head coil and from a gradient echo sequence using the Helmholtz body coil. The voltage of the transmit radiofrequency (RF) amplifier was noted. Monthly measurements of slice thickness, geometric distortion, slice position, image resolution and image ghosting were acquired using the head coil. In addition, SNR was measured monthly on a selection of commonly used coils. Apart from some drift of the RF amplifier voltage, all measurements were within acceptable limits and were stable over the course of 1 year. Satisfactory measurements of SNR were possible using the simple phantom supplied with the scanner. The SNR, geometric distortion and RF amplifier voltage are simple to determine and can be measured in less than 15 min by the scanner operator, using the scanner software. Weekly recording of these parameters is recommended for busy clinical MRI scanners, as this should allow deviations from acceptable limits to be identified early. Such in-house checks can usefully be compared with the less frequent estimations performed by the service engineer. Comprehensive QA routines are discussed for systems used for quantitative measurements.

White matter hyperintensities in mild lewy body dementia.

BACKGROUND: The objective of this study was to explore the load of white matter hyperintensities (WMH) in patients with Lewy body dementia (LBD) and compare to Alzheimer's disease (AD) and normal controls (NC). METHODS: Diagnosis of LBD and AD was made according to consensus criteria and cognitive tests were administered. MRI scans for 77 (61 AD and 16 LBD) patients and 37 healthy elderly control subjects were available for analysis. We segmented WMH from FLAIR images using an automatic thresholding technique and calculated the volume of WMH in several regions of the brain, using non-parametric tests to compare groups. Multivariate regression was applied. RESULTS: There were no significant differences in WMH between AD and LBD. We found a significant correlation between total and frontal WMH and Mini-Mental State Examination (MMSE) and verbal fluency scores in the AD group, but not in the LBD group. CONCLUSION: The WMH load in LBD was similar to that of AD. A correlation between WMH load and cognition was found in the AD group, but not in the LBD group, suggesting that vascular disease contributes to cognitive impairment in AD but not LBD.

Cerebral blood flow by arterial spin labeling in poststroke dementia.

OBJECTIVE: To investigate the relationship between cerebral blood flow and dementia in older stroke survivors and subjects with Alzheimer disease (AD). METHODS: This cohort study used arterial spin labeling MRI at 3 T to examine cerebral blood flow (CBF). We scanned 39 patients 6 years after stroke. They were older than 75 years at the time of stroke and free of dementia 3 months poststroke, with 8 subsequently developing dementia. We also scanned 17 subjects with AD and 29 healthy control subjects. We determined the perfusion in regions of interest (ROIs). Hippocampal volume was also measured using a previously validated automated procedure. RESULTS: The gray matter/white matter CBF ratio was reduced globally in the poststroke dementia (PSD) group (1.55 SD = 0.12) relative to control subjects (1.78 SD = 0.18; p = 0.03). The CBF ratio in a parietal ROI was reduced in the AD (1.34 SD = 0.31; p = 0.003), PSD (1.32 SD = 0.22; p = 0.041), and poststroke no-dementia (PSND) (1.44 SD = 0.34; p = 0.014) groups relative to that of control subjects (1.70 SD = 0.32). In subjects without stroke, the best predictor of dementia was hippocampus volume, whereas in the stroke group, it was the global CBF gray matter/white matter ratio. Hippocampus volume was not significantly different between the AD and PSD groups, and both had reduced hippocampi relative to those of control subjects and the PSND group. CONCLUSIONS: We found evidence for both vascular and AD pathology in PSD, suggesting that both the direct impact of the stroke and subsequent development of AD-type changes play a role in the etiology of PSD.

Alterations in nicotinic α4ß2 receptor binding in vascular dementia using ¹²³I-5IA-85380 SPECT: comparison with regional cerebral blood flow.

OBJECTIVE: To investigate differences in distribution of α4ß2 subtypes of nicotinic acetylcholine receptors (nAChRs) using the ligand ¹²³I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) and single photon emission computed tomography (SPECT) in subjects with vascular dementia and age-matched controls. ¹²³I-5IA-85380 binding was compared to corresponding regional cerebral blood flow (rCBF) changes in the same subjects. METHODS: Thirty subjects (14 vascular dementia and 16 controls) underwent ¹²³I-5IA-85380 and rCBF ((99m)Tc-exametazime) SPECT scanning. Image analysis was performed on voxel basis using statistical parametric mapping (SPM2). RESULTS: Compared to controls, reductions in relative ¹²³I-5IA-85380 uptake were identified in dorsal thalamus and right caudate in vascular dementia. Increase in scaled ¹²³I-5IA-85380 uptake in cuneus was also demonstrated in vascular dementia relative to controls. Perfusion deficits in anterior cingulate were apparent in the patient group and did not appear to be associated with ¹²³I-5IA-85380 changes. CONCLUSIONS: Reduced ¹²³I-5IA-85380 uptake in vascular dementia was confined to sub-cortical regions, unlike the cortical reductions previously described in Alzheimer's disease. Elevation of normalised ¹²³I-5IA-85380 uptake in cuneus in vascular dementia could be a compensatory response to reduced cholinergic activity in dorsal thalamus.

White matter changes and late-life depressive symptoms: longitudinal study.

BACKGROUND: Evidence from cross-sectional studies suggests a link between cerebral age-related white matter changes and depressive symptoms in older people, although the temporal association remains unclear. AIMS: To investigate age-related white matter changes on magnetic resonance imaging (MRI) as an independent predictor of depressive symptoms at 1 year after controlling for known confounders. METHOD: In a pan-European multicentre study of 639 older adults without significant disability, MRI white matter changes and demographic and clinical variables, including cognitive scores, quality of life, disability and depressive symptoms, were assessed at baseline. Clinical assessments were repeated at 1 year. RESULTS: Using logistic regression analysis, severity of white matter changes was shown to independently and significantly predict depressive symptoms at 1 year after controlling for baseline depressive symptoms, quality of life and worsening disability (P<0.01). CONCLUSIONS: White matter changes pre-date and are associated with the development of depressive symptoms. This has implications for treatment and prevention of depression in later life.

Longitudinal change in 99mTcHMPAO cerebral perfusion SPECT in Parkinson's disease over one year.

BACKGROUND: Brain perfusion deficits have been reported previously in subjects with Parkinson's disease in comparison with healthy controls. OBJECTIVE: To carry out a longitudinal study of perfusion in patients with Parkinson's disease and controls to find areas showing a reduction in perfusion over one year. METHODS: Two HMPAO cerebral perfusion scans were acquired one year apart in 30 subjects with Parkinson's disease (mean (SD) age, 76 (5) years) and 34 healthy comparison subjects (76 (7) years). Scans were normalised to the mean intensity in the cerebellum. RESULTS: Using SPM99 within groups to investigate regions that showed a decrease in perfusion between scans, it was found that in Parkinson's disease subjects but not controls there was a significant cluster in the frontal lobe (Brodmann area 10) where perfusion decreased over the year. CONCLUSIONS: The progressive frontal perfusion deficits in Parkinson's disease are consistent with results from previous structural and neuropsychological studies suggesting frontal lobe involvement and executive dysfunction even in early Parkinson's disease.

Real-time assessment of postprandial fat storage in liver and skeletal muscle in health and type 2 diabetes.

Liver and skeletal muscle triglyceride stores are elevated in type 2 diabetes and correlate with insulin resistance. As postprandial handling of dietary fat may be a critical determinant of tissue triglyceride levels, we quantified postprandial fat storage in normal and type 2 diabetes subjects. Healthy volunteers (n = 8) and diet-controlled type 2 diabetes subjects (n = 12) were studied using a novel 13C magnetic resonance spectroscopy protocol to measure the postprandial increment in liver and skeletal muscle triglyceride following ingestion of 13C-labeled fatty acids given with a standard mixed meal. The postprandial increment in hepatic triglyceride was rapid in both groups (peak increment controls: +7.3 +/- 1.5 mmol/l at 6 h, P = 0.002; peak increment diabetics: +10.8 +/- 3.4 mmol/l at 4 h, P = 0.009). The mean postprandial incremental AUC of hepatic 13C enrichment between the first and second meals (0 and 4 h) was significantly higher in the diabetes group (6.1 +/- 1.4 vs. 1.7 +/- 0.6 mmol x l(-1) x h(-1), P = 0.019). Postprandial increment in skeletal muscle triglyceride in the control group was small compared with the diabetic group, the mean 24-h postprandial incremental AUC being 0.2 +/- 0.3 vs. 1.7 +/- 0.4 mmol x l(-1) x h(-1) (P = 0.009). We conclude that the postprandial uptake of fatty acids by liver and skeletal muscle is increased in type 2 diabetes and may underlie the elevated tissue triglyceride stores and consequent insulin resistance.

Changes in DWI and MRS associated with white matter hyperintensities in elderly subjects.

OBJECTIVE: To assess normal-appearing white matter (NAWM) characteristics by magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI) in elderly subjects. METHODS: The authors studied 60 volunteers (mean age 72.6 years; SD 4.7; range 64 to 84 years) without signs of neurologic illness. They used DWI and spectroscopic imaging to investigate whether there were changes in the NAWM that related to the presence of white matter hyperintensities (WMH). RESULTS: The authors found a correlation (p < 0.001) between the apparent diffusion coefficient in the NAWM and the total volume of WMH. The metabolite ratios N-acetylaspartate/creatine and N-acetylaspartate/choline of the NAWM also correlated significantly with total WMH volume. These correlations were independent of age. CONCLUSIONS: Damage associated with WMH is detectable in NAWM.

A comprehensive review of proton magnetic resonance spectroscopy studies in dementia and Parkinson's disease.

We reviewed the literature of proton magnetic resonance spectroscopy (MRS) in dementia and Parkinson's disease (PD) and quantitatively compared the reported values of the markers N-acetyl aspartate (NAA), choline, and myo-Inositol between control and disease groups. We analysed a total of 27 reports in dementia. Combining the quantitative data from these showed a relative decrease of 15% in NAA level in the temporal lobe tissue in patients with Alzheimer's disease (AD) compared with controls. The rest of the brain showed a seemingly uniform 10% decrease in NAA levels in AD compared with controls. myo-Inositol was raised by about 15%, again uniformly throughout the brain, but there was no evidence for changed levels of choline. We found 15 reports of MRS in PD, which show a small decrease (5%) in the NAA level in the lentiform nucleus compared with controls. In progressive supranuclear palsy (PSP), there is a greater decrease in NAA levels in the frontal region and the lentiform nucleus. This may aid in the diagnosis of PSP. Further research is needed to determine spectroscopic changes in other dementias, to monitor how markers change with disease progression and to establish clinical utility.

Regional cerebral blood flow in Parkinson's disease with and without dementia.

Tc99 HMPAO SPECT and T1 weighted 3D MRI scans were acquired in cognitively intact subjects with Parkinson's disease (PD) (n = 31), and in PD subjects with dementia (PDD) (n = 34), healthy controls (n = 37), those with Alzheimer's disease (AD) (n = 32), and those with dementia with Lewy bodies (DLB) (n = 15). We used SPM99 to look for regions which showed a reduction in perfusion on SPECT not related to associated structural brain changes assessed by a MRI scan. The precuneus and inferior lateral parietal regions showed a perfusion deficit in Parkinson's disease with dementia, similar to the pattern observed in DLB. In comparison, AD showed a perfusion deficit in the midline parietal region, in a more anterior and inferior location than in PDD, involving the posterior cingulate as well as the precuneus. The perfusion deficits in PDD are similar those in DLB, and in a location associated with visual processing, and may be associated with the visuospatial perception deficits which are present in persons with DLB and PDD.