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Objectives Despite increasing evidence demonstrating structural and functional alterations within the central nervous system in diabetic peripheral neuropathy (DPN), the neuroanatomical correlates of Painful- and Painless-DPN have yet to be identified. Focusing on structural magnetic resonance (MR) imaging, the aims of this study were to 1) define the brain morphological alterations in Painful- and Painless-DPN and 2) explore the relationships between brain morphology and clinical/neurophysiological assessments. Research Design and Methods 277 participants with type 1 and 2 diabetes (No-DPN [n=57]; Painless-DPN [n=77]; and Painful-DPN [n=77]) and 66 healthy volunteers (HV) were enrolled. All underwent detailed clinical/neurophysiological assessment and brain MR imaging at 3-Tesla. Painful-DPN participants were subdivided into the irritable nociceptor (IR) and the non-irritable nociceptor (NIR) phenotype using the German Research Network on Neuropathic Painprotocol. Cortical reconstruction and volumetric segmentation were performed with FreeSurfer software and voxel-based morphometry implemented in FSL. Results Both Painful- and Painless-DPN had significant reduction in primary somatosensory and motor cortical thickness compared to HV and No-DPN [P=0.02; F(3,275)=3.36 and P=0.01; F(3,275)=3.80 respectively]. Somatomotor cortical thickness correlated with neurophysiological measures of DPN severity. There was also reduction in ventrobasal thalamic nuclei volume in both Painless- and Painful-DPN. Painful-DPN subjects with the NIR nociceptor phenotype had reduced primary somatosensory, posterior cingulate cortical and thalamic volume compared to the IR nociceptor phenotype. Conclusions In this, the largest neuroimaging study in DPN to date, we have demonstrated significant structural alterations in key somatomotor/nociceptive brain regions specific to Painless-DPN and Painful-DPN including the IR and NIR nociceptor phenotype.

IntroductionIn this study, we used proton Magnetic Resonance Spectroscopy (1H-MRS) to determine the neuronal function in the thalamus and primary somatosensory (S1) cortex in different subgroups of DPN, including subclinical- and painful-DPN.MethodOne-hundred and ten people with type 1 diabetes [20 without DPN (no-DPN); 30 with subclinical-DPN; 30 with painful-DPN; and 30 with painless-DPN] and 20 healthy volunteers, all of whom were right-handed men, were recruited and underwent detailed clinical and neurophysiological assessments. Participants underwent Magnetic Resonance Imaging at 1.5 Tesla with two 1H-MRS spectra obtained from 8 ml cubic volume voxels: one placed within left thalamus to encompass the ventro-posterior lateral sub-nucleus and another within the S1 cortex.ResultsIn the thalamus, participants with painless-DPN had a significantly lower NAA:Cr ratio [1.55 + 0.22 (mean ± SD)] compared to all other groups [HV (1.80 ± 0.23), no-DPN (1.85 ± 0.20), sub-clinical DPN (1.79 ± 0.23), painful-DPN (1.75 ± 0.19), ANOVA p ConclusionIn this largest cerebral MRS study in DPN, thalamic neuronal dysfunction was found in advanced painless-DPN with preservation of function in subclinical- and painful-DPN. Furthermore, there was a preservation of neuronal function within the S1 cortex in all subgroups of DPN. Therefore, there may be a proximo-distal gradient to central nervous system alterations in painless-DPN, with thalamic neuronal dysfunction occurring only in established DPN. Moreover, these results further highlight the manifestation of cerebral alterations between painful- and painless-DPN whereby preservation of thalamic function may be a prerequisite for neuropathic pain in DPN.

Painful diabetic neuropathy (DN) is a common and distressing complication. New approaches are required to identify novel targets that will serve as a catalyst for future drug discovery programmes. We have demonstrated that responders to neuropathic pain treatment have greater functional connectivity between the insula cortex and the corticolimbic system compared to non-responders. Activity within these networks is mediated by endogenous opioid receptor systems and may hold clues to possible future treatment targets. Methods: 43 painful-DN subjects [responders (VAS Disclosure K.Teh: None. G.P.Sloan: None. I.D.Wilkinson: None. S.Tesfaye: Advisory Panel; Astellas Pharma Inc., Bayer AG, Grünenthal Group, Nevro Corp., Wörwag Pharma GmbH & Co. KG, Speaker's Bureau; Eva Pharma, Pfizer Inc., Viatris Inc. D.Selvarajah: None. Funding National Institute of Health Research EME grant; European Foundation for the Study of Diabetes

Objective: We have previously demonstrated increased thalamic blood volume and preserved HMRS neuronal metabolite ratios in painful diabetic peripheral neuropathy (P-DPN) . We hypothesised that perfusion measures and neuronal function measured by metabolite ratios may be related. However, as brain metabolite ratios may also be affected by mood disorders, common in P-DPN, this may be a significant confounding factor. Methods: 52 type 1 diabetes (T1D) subjects (18 P-DPN, 23 DPN, 13 without neuropathy-DM-NN) and 18 healthy volunteers (HV) were recruited. 1HMRS was performed at 3T (Philips, Netherlands) . Single voxel spectra were obtained from a 2.25cm3 (15x10x15mm) volume of interest within the thalamus, TE=135ms, TR=1600ms, NSA=256 using point resolved (PRESS) technique. Metabolite ratios were calculated for choline, Creatine, and N-Acetyl Aspartate (NAA) . MR-DSC images were obtained at 3T using a T2*-weighted technique (TR/TE=1250/35ms; 72 dynamics) to assess the passage of bolus intravenous gadolinium-chelate through the thalamus. Results: There was significant negative correlation between NAA/Cr (measure of neuronal function) and measures of depression: Hospital Anxiety and Depression Scale R= -0.33 (p=0.01) , Becks Depression Inventory R= -0.25 (p=.048) ; and anxiety: State-Trait Anxiety inventory- State (STAI-S) R= -.37 (p=.002) , STAI- Trait (T) R= -.32 (p=0.01) and Behavioural Inhibition R= -0.25 (p=0.04) . There were no differences in metabolite ratios between groups; and no significant correlations between perfusion measures and metabolite ratios. Conclusion: This is the first study to show thalamic 1HMRS metabolite ratios are correlated with measures of mood disorders in T1D. The high prevalence of mood disorders in P-DPN and DPN have confounded previous 1HMRS studies and may explain conflicting reports in the literature. The link between neuropathy and mood disorders needs further exploration to understand whether both may arise from a common neurobiological pathway. Disclosure M.Greig: None. G.P.Sloan: None. P.Shillo: None. D.Selvarajah: None. I.D.Wilkinson: None. S.Tesfaye: Advisory Panel; Astellas Pharma Inc., Bayer AG, Grünenthal Group, Nevro Corp., Wörwag Pharma GmbH & Co. KG, Speaker's Bureau; Eva Pharma, Pfizer Inc., Viatris Inc. Funding European Foundation for the Study of Diabetes (EFSD)

Aim: Our study predicted treatment responses in patients with painful DPN (diabetic peripheral neuropathy) by developing a deep learning model using resting state functional magnetic resonance imaging (fMRI) neuroimaging datasets. Methods: Forty-three consecutive patients who received intravenous lidocaine treatment for painful DPN were assessed. All subjects (responders n=29 and non-responders n=14) underwent detailed clinical and neurophysiological assessments to phenotype their pain sensory profile. Subjects also underwent brain resting-state fMRI. After pre-processing we performed a group concatenated independent component analysis (ICA) set to 30 components and automatically chose 7 highly correlated (p Results: The deep learning treatment response classification in a ten-fold cross validation experiment using 7 ICA spatial maps has a mean AUC of 0.85 and an F1-Score of 0.90. However, with the extra information of all 30 ICA maps the mean AUROC increased to 0.97 with an F1-Score of 0.95. Using only pre-processed resting-state fMRI data achieved suboptimal F1-Score of 69% and AUC score of 44%. Conclusion: Through the use of our deep learning model, we have demonstrated high classification performance. Our method improves painful DPN treatment efficiency by stratifying patients to receive the correct treatment from the outset. We believe to our knowledge this is the first study utilising deep learning methods to classify treatment response in painful DPN. Disclosure K.Teh: None. I.D.Wilkinson: None. G.P.Sloan: None. S.Tesfaye: Advisory Panel; Astellas Pharma Inc., Bayer AG, Grünenthal Group, Nevro Corp., Wörwag Pharma GmbH & Co. KG, Speaker's Bureau; Eva Pharma, Pfizer Inc., Viatris Inc. D.Selvarajah: None. Funding National Instituteof Health Research Efficacy and Mechanism Evaluation Programme (NIHR 129921) European Foundation for the Study of Diabetes (Microvascular Complications Project Grant) University of Sheffield, Health Education England, Knowledge Exchange

We report a consanguineous family in which schizophrenia segregates in a manner consistent with recessive inheritance of a rare, partial-penetrance susceptibility allele. From 4 marriages between 2 sets of siblings who are half first cousins, 6 offspring have diagnoses of psychotic disorder. Homozygosity mapping revealed a 6.1-Mb homozygous region on chromosome 13q22.2-31.1 shared by all affected individuals, containing 13 protein-coding genes. Microsatellite analysis confirmed homozygosity for the affected haplotype in 12 further apparently unaffected members of the family. Psychiatric reports suggested an endophenotype of milder psychiatric illness in 4 of these individuals. Exome and genome sequencing revealed no potentially pathogenic coding or structural variants within the risk haplotype. Filtering for noncoding variants with a minor allele frequency of

Painful diabetic peripheral neuropathy (DPN) is difficult to manage, as treatment response is often varied. The primary aim of this study was to examine differences in pain phenotypes between responders and nonresponders to intravenous lidocaine treatment using quantitative sensory testing. The secondary aim was to explore differences in brain structure and functional connectivity with treatment response. Forty-five consecutive patients who received intravenous lidocaine treatment for painful DPN were screened. Twenty-nine patients who met the eligibility criteria (responders, n = 14, and nonresponders, n = 15) and 26 healthy control subjects underwent detailed sensory profiling. Subjects also underwent multimodal brain MRI. A greater proportion of patients with the irritable (IR) nociceptor phenotype were responders to intravenous lidocaine treatment compared with nonresponders. The odds ratio of responding to intravenous lidocaine was 8.67 times greater (95% CI 1.4–53.8) for the IR nociceptor phenotype. Responders to intravenous lidocaine also had significantly greater mean primary somatosensory cortex cortical volume and functional connectivity between the insula cortex and the corticolimbic circuitry. This study provides preliminary evidence for a mechanism-based approach for individualizing therapy in patients with painful DPN.

Background Clinical phenotypic heterogeneity represents a major barrier to trials in motor neuron disease (MND) and objective surrogate outcome measures are required, especially for slowly progressive patients. We assessed responsiveness of clinical, electrophysiological and radiological muscle-based assessments to detect MND-related progression. Materials and methods A prospective, longitudinal cohort study of 29 MND patients and 22 healthy controls was performed. Clinical measures, electrophysiological motor unit number index/size (MUNIX/MUSIX) and relative T2- and diffusion-weighted whole-body muscle magnetic resonance (MR) were assessed three times over 12 months. Multi-variable regression models assessed between-group differences, clinico-electrophysiological associations, and longitudinal changes. Standardized response means (SRMs) assessed sensitivity to change over 12 months. Results MND patients exhibited 18% higher whole-body mean muscle relative T2-signal than controls (95% CI 7–29%, p p p Conclusion MUNIX and relative T2-weighted MR represent objective surrogate markers of progressive denervation in MND. Radiological changes were maximal in leg muscles, irrespective of clinical onset-site.

Background: Apathy is a common and early symptom in Alzheimer’s disease (AD) and is linked to poorer prognosis. Theoretical interpretations of apathy implicate alterations of connections amongst fronto-striatal and limbic regions. Objective: To test the association between presence of apathy and patterns of brain functional connectivity in patients with clinically-established AD. Methods: Seventy AD patients were included. Thirty-five patients experienced apathy as defined by the screening question of the Neuropsychiatric Inventory, and thirty-five did not. All patients agreed to undergo an MRI protocol inclusive of resting-state acquisitions. The hemodynamic-dependent signal was extracted bilaterally from five regions of interest: ventromedial prefrontal cortices, anterior cingulate cortices, dorsolateral prefrontal cortices, insulae and amygdalae. t tests were run to compare connectivity maps of apathetic and non-apathetic patients. Age, education, Mini Mental State Examination score, gray matter volumes and gray matter fractions served as covariates. Results: At a pFWE < 0.05 threshold, apathetic patients had reduced connectivity between the left insula and right superior parietal cortex. Apathetic patients had also increased connectivity between the right dorsolateral prefrontal seed and the right superior parietal cortex. Patients with apathy were significantly more likely to experience other psychiatric symptoms. Conclusion: Our findings support a role of frontal and insular connections in coordinating value-based decisions in AD. Both down-regulation and maladaptive up-regulation mechanisms appear to be at play in these regions.

BackgroundSporadic Parkinson’s disease (sPD) is an aetiologically heterogeneous disorder. Identification of distinct pathogenic mechanisms causing sPD will be crucial to develop future “Precision Medicine” approaches. 31P-MRS is a non-invasive tool that can quantify key bionenergetic metabolites in individual patients.ObjectiveTo determine whether 31P-MRS can identify mitochondrial dysfunction in the midbrain/sub- stantia nigra of individual PD patients and correlates with trial-relevant clinical aspects of PD.Methods31P-MRS spectra were obtained from 35 sPD patients and 25 healthy, age-matched controls. Spectra were analysed using the jMRUI software package and AMARES spectral fitting algorithm. Clinical assessment included widely utilised clinical rating scales, genetic analysis and the calculation of predicted risk of rapid disease progression.ResultsThere was a significantly broader variance in 31P-MRS midbrain ATP with 1/3 of all PD patients having ATP levels > 2 standard deviations outside the mean control values (p=0.0030). Higher midbrain phosphocreatine was associated with greater risk of rapid disease progression (p= 0.0384).Conclusions31P-MRS may help to identify a subgroup of sPD with significant mitochondrial dysfunction or at higher risk of more rapid progression and facilitate stratification for future precision medicine neu- roprotective trials. Longitudinal studies are required to characterise if changes 31P-MRS measures mirror clinical progression.

Background Glutathione (GSH) is an important brain antioxidant and a number of studies have reported its measurement by edited and nonedited localized 1 H spectroscopy techniques within a range of applications in healthy volunteers and disease states. Good test-retest reproducibility is key when assessing the efficacy of treatments aimed at modulating GSH levels within the central nervous system or when noninvasively assessing changes in GSH content over time. Purpose To evaluate the intraday (in vitro and in vivo) and 1-month apart (in vivo) test-retest reproducibility of GSH measurements from GSH-edited MEGA-PRESS acquisitions at 3 T in a phantom and in the brain of a cohort of middle-aged and older healthy volunteers. Study type Prospective. Subjects/phantoms A phantom containing physiological concentrations of GSH and metabolites with overlapping spectral signatures and 10 healthy volunteers (4 F, 6 M, 55 ± 14 years old). Field strength/sequence GSH-edited spectra were acquired at 3 T using the MEGA-PRESS sequence. Assessment The phantom was scanned twice and the healthy subjects were scanned three times (on two separate days, 1 month apart). GSH was quantified from each acquisition, with the in vivo voxels placed at the primary motor cortex (PMC) and the occipital cortex (OCC). Statistical tests Mean coefficients of variation (CV) were used to assess short-term (in vitro and in vivo) and longer-term (in vivo) test-retest reproducibility. Results In vitro, the CV was 2.3%. In vivo, the mean intraday CV was 3.3% in the PMC and 2.4% in the OCC, while the CVs at 1 month apart were 4.6% in the PMC and 7.8% in the OCC. Data conclusion GSH-edited MEGA-PRESS spectroscopy allows measurement of GSH with excellent precision. Evidence level 1 TECHNICAL EFFICACY: Stage 2.

Aims: Neuroimaging studies have found structural alterations in brain regions involved in the somatomotor system in diabetic peripheral neuropathy (DPN) and painful-DPN (pDPN). However, most of these studies have had small cohorts of subjects, without consideration of pDPN phenotypes. Here we present the largest DPN neuroimaging study, which examines differences in brain morphology in DPN and phenotypes of painful-DPN. Methods: 229 participants were enrolled, 177 with diabetes (46 no-DPN, 56 painless-DPN and 75 pDPN; 25 irritable [IR] and 50 non-irritable [NIR] phenotype), and 52 healthy volunteers underwent detailed clinical, neurophysiological and quantitative sensory testing (DFNS) assessments, and 3-dimensional T1-weighted brain MRI (3.0T, Phillips). Brain volumetry was performed using Freesurfer. Results: At the post-central gyrus, in comparison with HV (1.92mm±0.11) and NoDPN (1.90mm±0.14), there was a significantly reduced cortical thickness in DPN (1.85mm±0.14), in pDPN (1.87mm±0.12) cortical thickness was reduced compared with HV. At the precentral gyrus, both DPN (2.29mm±0.16) and pDPN (2.28mm±0.16) had significantly reduced cortical thickness compared with HV (2.37mm±0.14) and NoDPN (2.36mm±0.13). At the insula, compared with HV (2.93mm±0.15) the cortical thickness was reduced in DPN (2.85mm±0.18) and pDPN (2.84mm±0.17). The cortical thickness at the pre and postcentral gyrus, and insula correlated with measures of nerve conduction. Moreover, the mean anterior cingulate cortical (ACC) thickness was significantly reduced in the IR- (2.40mm±0.23) compared to NIR-pDPN (2.58mm±0.20; p=0.003). Conclusions: Key somatomotor brain regions have a reduced cortical thickness in patients with DPN and pDPN, which correlate with neurophysiological measures suggestive of an ascending axonopathy. Moreover, the cortical thickness at the ACC differentiated IR and NIR, suggesting neuroplasticity in this region may play a role determining clinical phenotypes in pDPN. Disclosure G. P. Sloan: None. D. Selvarajah: None. K. Teh: None. P. Shillo: None. I. D. Wilkinson: None. S. Tesfaye: Advisory Panel; Self; Angellini, Bayer AG, Eva Pharma, Wörwag Pharma, Speaker’s Bureau; Self; Abbott, AstraZeneca, Grunenthal Group, MSD Corporation, Novo Nordisk, Pfizer Inc.

Objective: We have previously reported increased thalamic vascularity in painful diabetic peripheral neuropathy (PDPN) but the microvascular perfusion characteristics of the other pain processing areas of the brain (Pain Matrix - PM) with or without pain at the time of scanning have not been assessed. The aim thus was to measure the cerebral perfusion of the PM areas using MR-Dynamic Susceptibility Contrast (MR-DSC). Methods: 55 T1DM subjects (20 PDPN, 23 painless-DPN, 13 no-DPN) and 19 healthy volunteers (HV) underwent clinical, neurophysiological and MR-DSC of the passage of IV-gadolinium-chelate through the cerebral vascular bed (3-Tesla, Philips, Netherlands) at rest. The PDPN group was further divided into those that had neuropathic pain during scan - P+ and no pain - P-) and the intensity of pain at the time of scanning was recorded. The Mean Transit Time -MTT and the time-to-peak -TTP concentrations of gadolinium in PM areas (Thalamus, Insular Cortex - IC, Anterior Cingulate Cortex - ACC) were measured. Results: Subjects experiencing spontaneous neuropathic pain (P+, n=10, VAS score≥4) during scanning had shorter mean TTP at the Right-Thalamus: P+ vs. painless-DPN p=0.017, P+ vs. HV p=0.033; Right-IC: P+ vs. painless-DPN p=0.048; and POWM: P+ vs. P- p=0.009, P+ vs. painless-DPN p=0.034, P+ vs. HV p=0.011. The MTT at the Right-Thalamus: P+ vs. HV p=0.043 and at the Left-IC: HV vs. No-DPN p=036, were also significant. Conclusion: This is the first study to show there is altered cerebral perfusion in the pain processing areas of of the brain, with shorter TTP during spontaneous pain at the time of scanning. This seems to be related to a bolus dispersal factor as MTT, and CBF do not match the TTP and the control area is also affected. However, whether this altered perfusion is primary or secondary to the experience of pain is yet to be determined. This novel finding may serve as objective marker of spontaneous neuropathic pain, and a target for the development of novel treatments. Disclosure M. Greig: None. G. P. Sloan: None. P. Shillo: None. D. Selvarajah: None. I. D. Wilkinson: None. S. Tesfaye: Advisory Panel; Self; Angellini, Bayer AG, Eva Pharma, Wörwag Pharma, Speaker’s Bureau; Self; Abbott, AstraZeneca, Grunenthal Group, MSD Corporation, Novo Nordisk, Pfizer Inc. Funding European Foundation for the Study of Diabetes

Painful diabetic neuropathy (DN) is a common, distressing complication of diabetes that is discordant with the degree of peripheral nerve pathology. Very little is known about the cerebral processes involved in pain processing in painful DN. Here we investigated resting-state brain connectivity associated with prolonged pain in DN. Methods: 58 subjects and 36 matched controls were compared with regard to both behavioural measures of pain perception and resting-resting state functional Magnetic Resonance Imaging. The resting-state fMRI brain connectivity was investigated using 20 seed regions located in cardinal pain processing brain regions. Resting-state fMRI analysis was performed using the NITRC Functional Connectivity (CONN) Toolbox and SPM8 (welcome Trust Centre for Neuroimaging London, UK) in Matlab 2014a (the MathWorks, Natick, MA, USA). Functional connectivity matrices between the pre-specified seeds were calculated and the HV versus painful DN phenotype interaction examined. Results: Relative to controls, painful DPN patients displayed increased brain connectivity predominately for the supplementary motor areas (p Conclusion: Our study provides experimental evidence of increased connectivity between frontal midline regions that are implicated in affective pain processing and bilateral sensorimotor regions in painful DPN patients. Disclosure K. Teh: None. I. D. Wilkinson: None. P. Shillo: None. G. P. Sloan: None. S. Tesfaye: Advisory Panel; Self; Angellini, Bayer AG, Eva Pharma, Wörwag Pharma, Speaker’s Bureau; Self; Abbott, AstraZeneca, Grunenthal Group, MSD Corporation, Novo Nordisk, Pfizer Inc. D. Selvarajah: None. Funding Health Education England/University of Sheffield Knowledge Exchange Fund; National Institute for Health Research; EME

Copyright © 2021– The authors. Background: How the relationship between obesity and MRI-defined neural properties varies across distinct stages of cognitive impairment due to Alzheimer’s disease is unclear. Objective: We used multimodal neuroimaging to clarify this relationship. Methods: Scans were acquired from 47 patients clinically diagnosed with mild Alzheimer’s disease dementia, 68 patients with mild cognitive impairment, and 57 cognitively healthy individuals. Voxel-wise associations were run between maps of gray matter volume, white matter integrity, and cerebral blood flow, and global/visceral obesity. Results: Negative associations were found in cognitively healthy individuals between obesity and white matter integrity and cerebral blood flow of temporo-parietal regions. In mild cognitive impairment, negative associations emerged in frontal, temporal, and brainstem regions. In mild dementia, a positive association was found between obesity and gray matter volume around the right temporoparietal junction. Conclusion: Obesity might contribute toward neural tissue vulnerability in cognitively healthy individuals and mild cognitive impairment, while a healthy weight in mild Alzheimer’s disease dementia could help preserve brain structure in the presence of age and disease-related weight loss. European Union Seventh Framework Programme (FP7/2007– 2013) under grant agreement no. 601055, VPH-DARE@IT; Neurocare; University of Sheffield, Faculty of Medicine, Dentistry and Health PhD scholarship.

Aims/hypothesis The aim of this work was to investigate whether different clinical pain phenotypes of diabetic polyneuropathy (DPN) are distinguished by functional connectivity at rest. Methods This was an observational, cohort study of 43 individuals with painful DPN, divided into irritable (IR, n = 10) and non-irritable (NIR, n = 33) nociceptor phenotypes using the German Research Network of Neuropathic Pain quantitative sensory testing protocol. In-situ brain MRI included 3D T1-weighted anatomical and 6 min resting-state functional MRI scans. Subgroup differences in resting-state functional connectivity in brain regions involved with somatic (thalamus, primary somatosensory cortex, motor cortex) and non-somatic (insular and anterior cingulate cortices) pain processing were examined. Multidimensional reduction of MRI datasets was performed using a machine-learning approach to classify individuals into each clinical pain phenotype. Results Individuals with the IR nociceptor phenotype had significantly greater thalamic–insular cortex (p false discovery rate [FDR] = 0.03) and reduced thalamus–somatosensory cortex functional connectivity (p-FDR = 0.03). We observed a double dissociation such that self-reported neuropathic pain score was more associated with greater thalamus–insular cortex functional connectivity (r = 0.41; p = 0.01) whereas more severe nerve function deficits were more related to lower thalamus–somatosensory cortex functional connectivity (r = −0.35; p = 0.03). Machine-learning group classification performance to identify individuals with the NIR nociceptor phenotype achieved an accuracy of 0.92 (95% CI 0.08) and sensitivity of 90%. Conclusions/interpretation This study demonstrates differences in functional connectivity in nociceptive processing brain regions between IR and NIR phenotypes in painful DPN. We also establish proof of concept for the utility of multimodal MRI as a biomarker for painful DPN by using a machine-learning approach to classify individuals into sensory phenotypes. Graphical abstract

Aims: The management of painful diabetic peripheral neuropathy (pDPN) is inadequate because the disease mechanisms are not fully understood. We assessed cerebral cellular bioenergetics using phosphorus magnetic resonance spectroscopy (31P-MRS) to determine whether high energy phosphate metabolite levels are altered in the pain processing regions of the brain in pDPN. Methods: A total of 66 subjects, 44 with type 2 diabetes (12 no-DPN, 13 painless-DPN and 19 pDPN) and 12 healthy volunteers (HV), underwent detailed clinical and neurophysiological assessments, and 31P-MRS brain imaging at 3-Tesla (Ingenia, Phillips Healthcare) with voxels placed over the right somatosensory cortex and the thalamus (TR 4s, TR 0.26ms, voxel size 21 x 21 x 40mm3). Measures reflecting cellular bioenergetics (mitochondrial function), ATP to phosphocreatine (PCr) and inorganic phosphate (Pi) ratios (ATP:PCr and ATP:Pi) were calculated. Results: There was a significant group effect in the ATP:PCr ratio at the thalamus (p=0.016) and somatosensory cortex (p=0.025). The ATP:PCr at the thalamus was significantly higher in the pDPN group (0.50±0.06) compared to HV (0.44±0.04, p=0.024) and no-DPN (0.42±0.07, p=0.006). Moreover, the ATP:PCr ratio at the somatosensory cortex was significantly higher in pDPN (0.48 ±0.1) compared to HV (0.38 ±0.1, p=0.035). In addition, the ratio correlated with the numeric pain score ratings during the MRI scan at both brain regions. Conclusions: This is the first study to use 31P-MRS to study cerebral energetics in human-DPN and peripheral painful neuropathies. We demonstrated significantly higher ATP:PCr ratios in patients with pDPN in the somatosensory cortex and thalamus, which correlated with pain severity. This is suggestive of increased cellular energy usage in pain processing regions of the brain, perhaps due to continuous nociceptive inputs. Altered cerebral phosphorus metabolite ratios may serve as a biomarker of neuropathic pain in diabetes. Disclosure G.P. Sloan: None. A. Anton: None. D. Selvarajah: None. S. Tesfaye: Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation, Wörwag Pharma. Speaker’s Bureau; Self; Abbott, AstraZeneca, Grunenthal Group, Napp Pharmaceuticals, Novo Nordisk Inc., Pfizer Inc. I.D. Wilkinson: None.

Diabetic distal symmetrical peripheral polyneuropathy (DSP) results in decreased somatosensory cortical gray matter volume, indicating that the disease process may produce morphological changes in the brains of those affected. However, no study has examined whether changes in brain volume alter the functional organization of the somatosensory cortex and how this relates to the various painful DSP clinical phenotypes. In this case-controlled, multimodal brain MRI study of 44 carefully phenotyped subjects, we found significant anatomical and functional changes in the somatosensory cortex. Subjects with painful DSP insensate have the lowest somatosensory cortical thickness, with expansion of the area representing pain in the lower limb to include face and lip regions. Furthermore, there was a significant relationship between anatomical and functional changes within the somatosensory cortex and severity of the peripheral neuropathy. These data suggest a dynamic plasticity of the brain in DSP driven by the neuropathic process. It demonstrates, for the first time in our knowledge, a pathophysiological relationship between a clinically painful DSP phenotype and alterations in the somatosensory cortex.

Mitochondrial dysfunction is postulated to be central to amyotrophic lateral sclerosis pathophysiology. Evidence comes primarily from disease models and conclusive data to support bioenergetic dysfunction in vivo in patients is currently lacking. This study is the first to assess mitochondrial dysfunction in brain and muscle in people living with amyotrophic lateral sclerosis using phosphorus-31 magnetic resonance spectroscopy, the modality of choice to assess energy metabolism in vivo. We recruited twenty patients and 10 healthy age and gender-matched controls in this cross-sectional clinico-radiological study. Phosphorus-31 magnetic resonance spectroscopy was acquired from cerebral motor regions and from tibialis anterior during rest and exercise. Bioenergetic parameter estimates were derived including: adenosine triphosphate, phosphocreatine, inorganic phosphate, adenosine diphosphate, Gibbs free energy of adenosine triphosphate hydrolysis, phosphomonoesters, phosphodiesters, pH, free magnesium concentration, and muscle dynamic recovery constants. Linear regression was used to test for associations between brain data and clinical parameters (revised amyotrophic functional rating scale, slow vital capacity, and upper motor neuron score) and between muscle data and clinico-neurophysiological measures (motor unit number and size indices, force of contraction, and speed of walking). Evidence for primary dysfunction of mitochondrial oxidative phosphorylation was detected in brainstem where Gibbs free energy of adenosine triphosphate hydrolysis and phosphocreatine were reduced. Alterations were also detected in skeletal muscle in patients where resting inorganic phosphate, pH, and phosphomonoesters were increased, whereas resting Gibbs free energy of adenosine triphosphate hydrolysis, magnesium, and dynamic phosphocreatine to inorganic phosphate recovery were decreased. Phosphocreatine in brainstem correlated with respiratory dysfunction and disability; in muscle, energy metabolites correlated with motor unit number index, muscle power, and speed of walking. This study provides in vivo evidence for bioenergetic dysfunction in amyotrophic lateral sclerosis in brain and skeletal muscle, which appears clinically and electrophysiologically relevant. Phosphorus-31 magnetic resonance spectroscopy represents a promising technique to assess the pathophysiology of mitochondrial function in vivo in amyotrophic lateral sclerosis and a potential tool for future clinical trials targeting bioenergetic dysfunction.

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted Pboot). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N-acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol (Pboot > .90), N-acetylaspartate and N-acetylaspartylglutamate (Pboot = .13), or glutamate and glutamine (Pboot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (Pboot = .08), aspartate (Pboot > .90), glutathione (Pboot > .90), or lactate (Pboot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article. ispartof: RADIOLOGY vol:295 issue:1 pages:171-180 ispartof: location:United States status: published

Aim: Recent studies have reported an association between low vitamin D levels and diabetic peripheral neuropathy. However, many of these did not differentiate between people with painful diabetic peripheral neuropathy and those with painless diabetic peripheral neuropathy, or assess major confounding factors including sunlight exposure and daily activity. Our study addressed these limitations and evaluated vitamin D levels in people with carefully phenotyped diabetic peripheral neuropathy and controls. Methods: Forty-five white Europeans with Type 2 diabetes and 14 healthy volunteers underwent clinical and neurophysiological assessments. People with Type 2 diabetes were then divided into three groups (17 with painful diabetic peripheral neuropathy, 14 with painless diabetic peripheral neuropathy and 14 with no diabetic peripheral neuropathy). All had seasonal sunlight exposure and daily activity measured, underwent a lower limb skin biopsy and had 25-hydroxyvitamin D measured during the summer months, July to September. Results: After adjusting for age, BMI, activity score and sunlight exposure, 25-hydroxyvitamin D levels (nmol/l) (se) were significantly lower in people with painful diabetic peripheral neuropathy [painful diabetic peripheral neuropathy 34.9 (5.8), healthy volunteers 62.05 (6.7), no diabetic peripheral neuropathy 49.6 (6.1), painless diabetic peripheral neuropathy 53.1 (6.2); ANCOVAP = 0.03]. Direct logistic regression was used to assess the impact of seven independent variables on painful diabetic peripheral neuropathy. Vitamin D was the only independent variable to make a statistically significant contribution to the model with an inverted odds ratio of 1.11. Lower 25-hydroxyvitamin D levels also correlated with lower cold detection thresholds (r = 0.39, P = 0.02) and subepidermal nerve fibre densities (r = 0.42, P = 0.01). Conclusions: We have demonstrated a significant difference in 25-hydroxyvitamin D levels in well-characterized people with painful diabetic peripheral neuropathy, while accounting for the main confounding factors. This suggests a possible role for vitamin D in the pathogenesis of painful diabetic peripheral neuropathy. Further prospective and intervention trials are required to prove causality between low vitamin D levels and painful diabetic peripheral neuropathy.

Purpose Detection of endogenous metabolites using multiplexed editing substantially improves the efficiency of edited magnetic resonance spectroscopy. Multiplexed editing (i.e., performing more than one edited experiment in a single acquisition) requires a tailored, robust approach for correction of frequency and phase offsets. Here, a novel method for frequency and phase correction (FPC) based on spectral registration is presented and compared against previously presented approaches. Methods One simulated dataset and 40 γ-aminobutyric acid-/glutathione-edited HERMES datasets acquired in vivo at three imaging centers were used to test four FPC approaches: no correction; spectral registration; spectral registration with post hoc choline-creatine alignment; and multistep FPC. The performance of each routine for the simulated dataset was assessed by comparing the estimated frequency/phase offsets against the known values, whereas the performance for the in vivo data was assessed quantitatively by calculation of an alignment quality metric based on choline subtraction artifacts. Results The multistep FPC approach returned corrections that were closest to the true values for the simulated dataset. Alignment quality scores were on average worst for no correction, and best for multistep FPC in both the γ-aminobutyric acid- and glutathione-edited spectra in the in vivo data. Conclusions Multistep FPC results in improved correction of frequency/phase errors in multiplexed γ-aminobutyric acid-/glutathione-edited magnetic resonance spectroscopy experiments. The optimal FPC strategy is experiment-specific, and may even be dataset-specific. Magn Reson Med 80:21-28, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

ObjectiveTo assess clinical, electrophysiological and whole-body muscle MRI measurements of progression in patients with motor neuron disease (MND), as tools for future clinical trials, and to probe pathophysiological mechanisms in vivo.MethodsA prospective, longitudinal, observational, clinicoelectrophysiological and radiological cohort study was performed. Twenty-nine patients with MND and 22 age-matched and gender-matched healthy controls were assessed with clinical measures, electrophysiological motor unit number index (MUNIX) and T2-weighted whole-body muscle MRI, at first clinical presentation and 4 months later. Between-group differences and associations were assessed using age-adjusted and gender-adjusted multivariable regression models. Within-subject longitudinal changes were assessed using paired t-tests. Patterns of disease spread were modelled using mixed-effects multivariable regression, assessing associations between muscle relative T2 signal and anatomical adjacency to site of clinical onset.ResultsPatients with MND had 30% higher relative T2 muscle signal than controls at baseline (all regions mean, 95% CI 15% to 45%, pConclusionsWhole-body muscle MRI offers a new approach to objective assessment of denervation over short timescales in MND and enables investigation of patterns of disease spread in vivo. Muscles inaccessible to conventional clinical and electrophysiological assessment may be investigated using this methodology.

Using advanced MR neuroimaging we have demonstrated altered brain structure and functional connectivity that could serve as a potential Central Pain Signature (CPS) for painful diabetic neuropathy (DN). However, the key challenge is how to apply this potential biomarker for routine diagnostic purposes. The aim of this study was to examine if the CPS can accurately classify painful DN patients based on a patient’s pain severity. Methods: 53 painful DN patients underwent detailed clinical and neurophysiological assessments. The NTSS-6, a validated questionnaire that measures both the frequency and the intensity of neuropathic pain was used to assess pain severity. Patients were divided into high pain (NTSS-6 score >7) and low pain ( Results: There was no age or gender difference (p > 0.05) between the high and low pain groups. The CPS classified painful DN patients based on their pain intensity with 94% accuracy (AUC 0.98). The positive and negative predictive values were 0.80 and 1.00 respectively. The F1 scores for predicting high pain and low pain were 0.89 and 0.96 respectively. Brain regions identified as the best classifier were the left and right postcentral gyri, thalami, and anterior and posterior cingulate cortices. Conclusions: This novel study demonstrates that a simple, 15-minute MR brain scan can accurately classify painful DN patients according to pain intensities with high accuracy. This assessment tool has a great potential as a biomarker of diabetic neuropathic pain and may serve as a target for future trials of analgesic compounds for painful DN. Disclosure D. Selvarajah: None. K. Teh: None. G.P. Sloan: None. P. Shillo: None. I.D. Wilkinson: None. S. Tesfaye: Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation, WÖRWAG Pharma. Speaker's Bureau; Self; AstraZeneca, Merck & Co., Inc., NAPP Pharmaceuticals Limited, Neurometrix, Novo Nordisk Inc., Pfizer Inc. Other Relationship; Self; Impeto Medical. Funding European Foundation for the Study of Diabetes

Background\ud \ud A common symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is post-exertional malaise (PEM). Various brain abnormalities have been observed in patients with ME/CFS, especially in insular and limbic areas, but their link with ME/CFS symptoms is still unclear. This pilot study aimed at investigating the association between PEM in ME/CFS and changes in functional connectivity (FC) of two main networks: the salience network (SN) and the default-mode network (DMN).\ud \ud \ud Methods\ud \ud A total of 16 women, 6 with and 10 without ME/CFS, underwent clinical and MRI assessment before and after cognitive exertion. Resting-state FC maps of 7 seeds (3 for the SN and 4 for the DMN) and clinical measures of fatigue, pain and cognition were analysed with repeated-measure models. FC-symptom change associations were also investigated.\ud \ud \ud Results\ud \ud Exertion induced increases in fatigue and pain in patients with ME/CFS compared to the control group, while no changes were found in cognitive performance. At baseline, patients showed altered FC between some DMN seeds and frontal areas and stronger FC between all SN seeds and left temporal areas and the medulla. Significantly higher FC increases in patients than in controls were found only between the right insular seed and frontal and subcortical areas; these increases correlated with worsening of symptoms.\ud \ud \ud Conclusions\ud \ud Cognitive exertion can induce worsening of ME/CFS-related symptoms. These changes were here associated with strengthening of FC of the right insula with areas involved in reward processing and cognitive control.

Purpose MR elastography (MRE) of the brain is being explored as a biomarker of neurodegenerative disease such as dementia. However, MRE measures for healthy brain have varied widely. Differing wave delivery methodologies may have influenced this, hence finite element-based simulations were performed to explore this possibility. Methods The natural frequencies of a series of cranial models were calculated, and MRE-associated vibration was simulated for different wave delivery methods at varying frequency, using simple isotropic viscoelastic material models for the brain. Displacement fields and the corresponding brain constitutive properties estimated by standard inversion techniques were compared across delivery methods and frequencies. Results The delivery methods produced widely different MRE displacement fields and inversions. Furthermore, resonances at natural frequencies influenced the displacement patterns. Consequently, some delivery methods led to lower inversion errors than others, and the error on the storage modulus varied by up to 11% between methods. Conclusion Wave delivery has a considerable impact on brain MRE reliability. Assuming small variations in brain biomechanics, as recently reported to accompany neurodegenerative disease (e.g., 7% for Alzheimer's disease), the effect of wave delivery is important. Hence, a consensus should be established on a consistent methodology to ensure diagnostic and prognostic consistency.

Objective: The aims of this study were (1) to examine cerebrovascular autoregulation in subjects with impaired glucose tolerance and type 2 diabetes and (2) to clarify whether cardiovascular autonomic nerve function is associated with abnormal cerebrovascular autoregulation. Research design and methods: Totally, 46 subjects were recruited (12 = impaired glucose tolerance, 17 = type 2 diabetes and 17 = healthy volunteers). Arterial blood flow was assessed within the internal carotid artery at baseline and 20 min after intravenous pharmacological stress (1 g acetazolamide), using quantitative magnetic resonance phase-contrast angiography. Internal carotid artery vascular reactivity and pulsatility index was determined. All subjects underwent baroreceptor reflex sensitivity assessment. Results: Subjects with impaired glucose tolerance and type 2 diabetes had significantly lower internal carotid artery vascular reactivity [40.2%(19.8) and 41.5%(18.7)], respectively, compared with healthy volunteers [57.0%(14.2); analysis of variance, p = 0.02]. There was no significant difference in internal carotid artery vascular reactivity between type 2 diabetes and impaired glucose tolerance groups ( p = 0.84). There was a significant positive correlation between baroreceptor reflex sensitivity (low frequency:high frequency) with cardiac rhythm variability (ρ = 0.47, p = 0.04) and PI (ρ = 0.46, p = 0.04). Conclusion: We have demonstrated significant cerebrovascular haemodynamic abnormalities in subjects with type 2 diabetes and impaired glucose tolerance. This was associated with greater sympathovagal imbalance. This may provide an important mechanistic explanation for increased risk of cerebrovascular disease in diabetes. It also highlights that these abnormalities may already be present in prediabetes.

Diabetic peripheral neuropathy (DPN) affects up to 50% of patients with diabetes and is a major cause of morbidity and increased mortality. Its clinical manifestations include distressing painful neuropathic symptoms and insensitivity to trauma that result in foot ulcerations and amputations. Several recent studies have implicated poor glycemic control, duration of diabetes, hyperlipidemia (particularly hypertryglyceridaemia), elevated albumin excretion rates, and obesity as risk factors for the development of DPN. However, similar data are not available for painful DPN. Moreover, although there is now strong evidence for the importance of peripheral nerve microvascular disease in the pathogenesis of DPN, peripheral structural biomarkers of painful DPN are lacking. However, there is now emerging evidence for the involvement of the central nervous system in both painful and painless DPN afforded by magnetic resonance imaging. This review will focus on this emerging evidence for central changes in DPN, hitherto considered a peripheral nerve disease only.

Aim: The risk of developing mild cognitive impairment (MCI) increases with type 2 diabetes (T2DM). Brain morphometric changes associated with MCI have been described. However Cerebral Blood Flow (CBF) changes in relation to MCI has not been fully investigated. This study aims to investigate regional CBF changes in subjects with T2DM and MCI. Method: Seventy-four age and gender matched subjects [28, T2DM (T2DM); 17, T2DM+MCI (T2DM/MCI) and 29, healthy volunteers (HV)] were recruited. All subjects underwent clinical and questionnaire (Addenbrooke’s Cognitive Assessment [ACE-R]) assessment along with Arterial Spin Labelling (ASL) perfusion Magnetic Resonance Imaging (MRI) of the brain. The ASL data was modelled to yield quantitative arterial CBF maps in neuroanatomical regions involved with cognitive function. Results: Demographic data revealed aged-matched participants between all three groups (mean age 69.3-71.5 years, ANOVA, p = 0.164). Mean age of last education was significantly lower in the T2DM/MCI group (mean±SD;15.1 ±0.9 when compared to the other groups (HV 19.3±5.6, T2DM 17.1±2.9) Kruskal-Wallis, p=0.003. T2DM/MCI ACE-R score (mean±SD; 83±4) was significantly lower compared to other groups (HV=96±2, T2DM=94±3; ANOVA p. Pearson’s correlation revealed significant correlations between ACE-R score and regional CBF measurements in the medial temporal lobes, (p Conclusion: This study demonstrates significantly lower CBF in T2DM MCI subjects in neuroanatomical regions responsible for cognitive function. This may be essential to help understand the pathological mechanisms that occur behind the increased risk of developing cognitive impairment in T2DM. Disclosure L. Hunt: None. D. Selvarajah: None. S. Tesfaye: Speaker's Bureau; Self; Pfizer Inc.. Other Relationship; Self; Janssen Pharmaceuticals, Inc., Takeda Development Centre Europe Ltd.. Advisory Panel; Self; Wörwag Pharma GmbH & Co. KG. I.D. Wilkinson: None.

Objective: Painful diabetic peripheral neuropathy (painful-DPN) causes distressing neuropathic pain that is only partially responsive to treatment. A better understanding of CNS correlates of painful-DPN is vital to develop more effective therapeutics. The aim of this study was to measure cerebral perfusion of the pain processing areas of the brain using MR-Dynamic Susceptibility Contrast (MR-DSC) imaging at rest and under experimental pain condition. Methods: 55 T1DM subjects (20 painful-DPN, 23 painless-DPN, 13 no-DPN) and 19 Healthy Volunteers (HV); underwent detailed clinical and neurophysiological assessment (NISLL+7 tests of nerve function; DN4 questionnaire). MR images were obtained at 3T using a MR-DSC, T2*-weighted technique (TR/TE=1250/35ms; 72 dynamics) to assess the passage of a bolus of intravenous gadolinium-chelate through cerebral vascular bed. Subjects were scanned at baseline and during 90s of heat-pain applied to the right lateral thigh (non-neuropathic area). The time-to-peak (TTP) concentration of gadolinium in regions of interest (ROI): right and left thalamus, right and left sensory cortices (RSC and LSC), was measured. Results: At baseline, although the mean TTP (s) in the ROIs was shorter in the painful-DPN group [e.g., RT: M (SD): 9.22 (1.13) vs. HV 9.83 (0.99), no-DPN 9.59 (0.90), painless-DPN 9.94 (0.97)] this was not statistically significant (p=0.058). However the ΔTTP in response to thermal pain was significantly different between the groups LT (p=0.021), RT (p=0.003), LSC (p=0.009), RSC (p=0.008). Whilst HV respond to thermal pain by shortening the TTP in ROI the painful-DPN group do the reverse (p Conclusion: Subjects with painful-DPN have a paradoxical increase in TTP, indicating that chronic neuropathic pain state may result in a failure to mount a hemodynamic response to external pain and descending inhibition. This novel finding may serve as an objective marker of painful-DPN, and in the future may facilitate the development of novel treatments. Disclosure M. Greig: None. I.D. Wilkinson: None. D. Selvarajah: None. P. Shillo: None. R. Gandhi: None. S. Tesfaye: Speaker's Bureau; Self; Pfizer Inc.. Other Relationship; Self; Janssen Pharmaceuticals, Inc., Takeda Development Centre Europe Ltd.. Advisory Panel; Self; Wörwag Pharma GmbH & Co. KG.

Aims: Diabetic neuropathy (DN) is a serious complication which was hitherto considered a disease of the peripheral nervous system. In this study we sought to investigate in detail changes in brain morphometry in DN. The aim of this study was to identify regional brain volume changes that were specific to DN (painful and painless DN) Methods: 102 patients with diabetes (34 No-DN, 34 Painless DN and 34 Painful DN) and 34 healthy volunteers underwent detailed clinical and neurophysiological assessments. All subjects underwent 3-dimensional T1-weighted brain MRI (3.0T, Philips). Brain volume analysis was performed using SIENAX (www.fmrib.ox.ac.uk/fsl) and Freesurfer (http://surfer.nmr.mgh.harvard.edu/). Results: Groups were matched for age and gender. Total brain volume was significantly lower painful DN [1401.7 (10.7)ml] and painless DN [1393.5 (69.6)ml]) compared to HV [1457.2(79.2)ml] and No DN [1437.2(60.9)ml]; ANOVA p= Conclusion: This is the largest cohort study of brain volume changes in subjects with DN examined to date. We have demonstrated significant reduction in grey matter volume in painful and painless DN subjects. In painful DN this is localised within the somatomotor cortex and insula. These findings highlight significant CNS involvement in DN that provides clues to the pathogenesis of this condition. Disclosure D. Selvarajah: None. F. Heiberg-Gibbons: None. I.D. Wilkinson: None. R. Gandhi: None. S. Tesfaye: Speaker's Bureau; Self; Pfizer Inc.. Other Relationship; Self; Janssen Pharmaceuticals, Inc., Takeda Development Centre Europe Ltd.. Advisory Panel; Self; Wörwag Pharma GmbH & Co. KG.

Aim: Mild Cognitive Impairment (MCI) is thought to be a chronic sequelae of type 2 diabetes (T2DM). Cerebral atrophy is known to be associated with cognitive decline, particularly in dementia. Cerebral tissue volumes, in areas associated with cognitive function, were examined in matched patients with T2DM subjects and early cognitive decline. The aim of this study was to compare T2DM patients with and without MCI to identify regional brain volume changes that were specific to MCI. Method: Seventy-six age and gender matched subjects [30, T2DM+normal cognition (T2DM); 17, T2DM+MCI (T2DM/MCI) and 29, healthy volunteers (HV)] were recruited. All subjects underwent clinical and questionnaire (Addenbrooke’s Cognitive Assessment [ACE-R]) assessments and high-resolution, 3D T1-weighted Magnetic Resonance Imaging (MRI, 3T Philips Ingenia). Cerebral volumes were analysed using voxel based morphometry (VBM, FSL, Oxford). Results: Demographic data revealed aged-matched participants between all three groups (mean age 69.3-71.5 years, ANOVA, p = 0.164). Mean age of last education was significantly lower in the T2DM/MCI group (mean±SD;15.1 ±0.9 when compared to the other groups (HV 19.3±5.6, T2DM 17.1±2.9) Kruskal-Wallis, p = 0.003. T2DM/MCI ACE-R score (mean±SD; 83±4) was significantly lower compared to other groups (HV=96±2, T2DM=94±3; ANOVA, p Conclusion: This study demonstrates significantly lower cortical differences in areas associated with cognition in patients with T2DM and early cognitive impairment. Further investigation of both anatomical and functional cerebral involvement is required to examine the pathological mechanisms underlying the increased cognitive impairment risk associated with T2DM. Disclosure L. Hunt: None. D. Selvarajah: None. S. Tesfaye: Speaker's Bureau; Self; Pfizer Inc.. Other Relationship; Self; Janssen Pharmaceuticals, Inc., Takeda Development Centre Europe Ltd.. Advisory Panel; Self; Wörwag Pharma GmbH & Co. KG. I.D. Wilkinson: None.

PURPOSE: As Quantitative Susceptibility Mapping (QSM) is maturing, more clinical applications are being explored. With this comes the question whether QSM is sufficiently robust and reproducible to be directly used in a clinical setting where patients are possibly not cooperative and/or unable to suppress involuntary movements sufficiently. Subjects and Methods: Twenty-nine patients with Alzheimer's Disease (AD), 31 patients with Mild Cognitive Impairment (MCI) and 41 healthy controls (HC) were scanned on a 3T scanner, including a multi-echo gradient-echo sequence for QSM and an inversion-prepared segmented gradient-echo sequence (T1-TFE, MPRAGE). The severity of motion artifacts (excessive/strong /noticeable/invisible) was categorized via visual inspection by two independent raters. Quantitative susceptibility was reconstructed using "Joint background-field removal and segmentation-Enhanced Dipole Inversion" (JEDI), based on segmented subcortical gray-matter regions, as well as using "Morphology Enabled Dipole Inversion" (MEDI). Statistical analysis of the susceptibility maps was performed per region. Results: A large fraction of the data showed motion artifacts, visible in both magnitude images and susceptibility maps. No statistically significant susceptibility differences were found between groups including motion-affected data. Considering only subjects without visible motion, a significant susceptibility differences were observed in caudate nucleus as well as in putamen. Conclusion: Motion-effects can obscure statistically significant differences in QSM between patients and controls. Additional measures to restrict and/or compensate for subject motion should be taken for QSM in standard clinical settings to avoid risk of false findings.&#13.

Background Clinical phenotypic heterogeneity represents a major barrier to trials in motor neuron disease (MND) and objective surrogate outcome measures are required, especially for slowly progressive patients. We assessed responsiveness of clinical, electrophysiological and radiological muscle-based assessments to detect MND-related progression. Materials and methods A prospective, longitudinal cohort study of 29 MND patients and 22 healthy controls was performed. Clinical measures, electrophysiological motor unit number index/size (MUNIX/MUSIX) and relative T2- and diffusion-weighted whole-body muscle magnetic resonance (MR) were assessed three times over 12 months. Multi-variable regression models assessed between-group differences, clinico-electrophysiological associations, and longitudinal changes. Standardized response means (SRMs) assessed sensitivity to change over 12 months. Results MND patients exhibited 18% higher whole-body mean muscle relative T2-signal than controls (95% CI 7–29%, p

Purpose Magnetic resonance elastography (MRE) of the brain has demonstrated potential as a biomarker of neurodegenerative disease such as dementia but requires further evaluation. Cranial anatomical features such as the falx cerebri and tentorium cerebelli membranes may influence MRE measurements through wave reflection and interference and tissue heterogeneity at their boundaries. We sought to determine the influence of these effects via simulation. Methods MRE-associated mechanical stimulation of the brain was simulated using steady state harmonic finite element analysis. Simulations of geometrical models and anthropomorphic brain models derived from anatomical MRI data of healthy individuals were compared. Constitutive parameters were taken from MRE measurements for healthy brain. Viscoelastic moduli were reconstructed from the simulated displacement fields and compared with ground truth. Results Interference patterns from reflections and heterogeneity resulted in artifacts in the reconstructions of viscoelastic moduli. Artifacts typically occurred in the vicinity of boundaries between different tissues within the cranium, with a magnitude of 10%–20%. Conclusion Given that MRE studies for neurodegenerative disease have reported only marginal variations in brain elasticity between controls and patients (e.g., 7% for Alzheimer's disease), the predicted errors are a potential confound to the development of MRE as a biomarker of dementia and other neurodegenerative diseases. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Self-deception and impression-management comprise two types of deceptive, but generally socially acceptable behaviours, which are common in everyday life as well as being present in a number of psychiatric disorders. We sought to establish and dissociate the 'normal' brain substrates of self-deception and impression-management. Twenty healthy participants underwent fMRI scanning at 3T whilst completing the 'Balanced Inventory of Desirable Responding' test under two conditions: 'fake good', giving the most desirable impression possible and 'fake bad' giving an undesirable impression. Impression-management scores were more malleable to manipulation via 'faking' than self-deception scores. Response times to self-deception questions and 'fake bad' instructions were significantly longer than to impression-management questions and 'fake good' instructions respectively. Self-deception and impression-management manipulation and 'faking bad' were associated with activation of medial prefrontal cortex (mPFC) and left ventrolateral prefrontal cortex (vlPFC). Impression-management manipulation was additionally associated with activation of left dorsolateral prefrontal cortex and left posterior middle temporal gyrus. 'Faking bad' was additionally associated with activation of right vlPFC, left temporo-parietal junction and right cerebellum. There were no supra-threshold activations associated with 'faking good'. Our neuroimaging data suggest that manipulating self-deception and impression-management and more specifically 'faking bad' engages a common network comprising mPFC and left vlPFC. Shorter response times and lack of dissociable neural activations suggests that 'faking good', particularly when it comes to impression-management, may be our most practiced 'default' mode.

Detection of endogenous metabolites using multiplexed editing substantially improves the efficiency of edited magnetic resonance spectroscopy. Multiplexed editing (i.e., performing more than one edited experiment in a single acquisition) requires a tailored, robust approach for correction of frequency and phase offsets. Here, a novel method for frequency and phase correction (FPC) based on spectral registration is presented and compared against previously presented approaches.One simulated dataset and 40 γ-aminobutyric acid-/glutathione-edited HERMES datasets acquired in vivo at three imaging centers were used to test four FPC approaches: no correction; spectral registration; spectral registration with post hoc choline-creatine alignment; and multistep FPC. The performance of each routine for the simulated dataset was assessed by comparing the estimated frequency/phase offsets against the known values, whereas the performance for the in vivo data was assessed quantitatively by calculation of an alignment quality metric based on choline subtraction artifacts.The multistep FPC approach returned corrections that were closest to the true values for the simulated dataset. Alignment quality scores were on average worst for no correction, and best for multistep FPC in both the γ-aminobutyric acid- and glutathione-edited spectra in the in vivo data.Multistep FPC results in improved correction of frequency/phase errors in multiplexed γ-aminobutyric acid-/glutathione-edited magnetic resonance spectroscopy experiments. The optimal FPC strategy is experiment-specific, and may even be dataset-specific. Magn Reson Med 80:21-28, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

BackgroundThe anatomical location of the earliest damage in amyotrophic lateral sclerosis (ALS) is still debated. Two main competing hypotheses have been proposed: the dying-forward hypothesis states the damage occurs in the precentral gyrus (PCG) and spreads caudally, which is in contrast with the dying-back hypothesis. This study aims to address this question of directionality of neurodegeneration in vivo using a multimodal neuroimaging approach to derive measures of damage of the motor pathway and analyse them in a common domain.MethodsMRI was performed on 78 ALS patients and 13 controls. PCG thickness was derived from using FreeSurfer, corticospinal tract (CST) fractional anisotropy (FA) from diffusion tensor imaging using FSL, and axial C3 cord area estimates using Philips online software. Comparisons between patients and controls were reported using unpaired t-tests. Parameter estimates were converted to z-scores, referenced to control data, plotted from PCG through CST to cord and directionality of damage assessed by fitting a mixed-effects linear regression model.ResultsZ-scores were not significantly different between PCG and FA (0.24,[95%CI -0.13,0.61], p=0.208) but were significantly lower in FA compared to cross-sectional cord area (-0.85,[95%CI -1.25,-0.46] pDiscussionThis novel multimodal imaging approach supports a dying-forward neurodegenerative process in ALS.

Calibration of medical imaging systems that provide quantitative measures relating to complex physiological flows is challenging. Physical test objects available for the purpose either offer a known simple flow far removed from the complexity of pathology (e.g. parabolic flow in a straight pipe) or complex\ud relevant flows in which the details of the flow behaviour are unknown. This paper presents the ring vortex as a candidate for a complex flow phantom, since it is marked by inherently complex flow features that are controllable, predictable, reproducible and stable. These characteristics are demonstrated by a combination of analytical, numerical (CFD) and experimental methods. Together they provide a consistent perspective on ring vortex behaviour and highlight qualities relevant to phantom design. Discussion of the results indicates that a liquid phantom based on the ring vortex may have merit as a complex flow phantom for multimodal imaging. Furthermore, availability of such a flow reference may also serve as a benchmark for quality assurance of simulation methodologies.

MR elastography (MRE) of the brain is being explored as a biomarker of neurodegenerative disease such as dementia. However, MRE measures for healthy brain have varied widely. Differing wave delivery methodologies may have influenced this, hence finite element-based simulations were performed to explore this possibility.The natural frequencies of a series of cranial models were calculated, and MRE-associated vibration was simulated for different wave delivery methods at varying frequency, using simple isotropic viscoelastic material models for the brain. Displacement fields and the corresponding brain constitutive properties estimated by standard inversion techniques were compared across delivery methods and frequencies.The delivery methods produced widely different MRE displacement fields and inversions. Furthermore, resonances at natural frequencies influenced the displacement patterns. Consequently, some delivery methods led to lower inversion errors than others, and the error on the storage modulus varied by up to 11% between methods.Wave delivery has a considerable impact on brain MRE reliability. Assuming small variations in brain biomechanics, as recently reported to accompany neurodegenerative disease (e.g., 7% for Alzheimer's disease), the effect of wave delivery is important. Hence, a consensus should be established on a consistent methodology to ensure diagnostic and prognostic consistency. Magn Reson Med 78:341-356, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

To examine the extent of brain abnormality in patients with coeliac disease referred for neurological opinion and evaluate MR imaging sequences as biomarkers for neurological dysfunction, given the lack of readily available serological markers of neurological disease in this cohort.Retrospective examination of a consecutive cohort of patients (n = 33, mean age = 44 ± 13 years (range 19-64)) with biopsy proven coeliac disease referred for neurological opinion. Patients were divided into subgroups based on their primary neurological complaint (balance disturbance, headache and sensory loss). 3T MR was used to evaluate differences in brain grey matter density, cerebellar volume, cerebellar neurochemistry and white matter abnormalities (WMAs) between subjects and controls.Cerebellar volume was significantly less in the patient group than in controls (6.9 ± 0.7% vs 7.4 ± 0.9% of total intracranial volume, p0.05). Significantly less grey matter density was found in multiple brain regions, both above and below the tentorium cerebelli, than in controls (p0.05). 12 (36%) patients demonstrated WMAs unexpected for the patient's age, with the highest incidence occurring in the headache subgroup. This subgroup averaged almost twice the number of WMAs per MR imaging than the subgroup with balance disturbance and six times more than the subgroup with sensory loss.Patients with established coeliac disease referred for neurological opinion show significant brain abnormality on MR imaging. MR imaging may provide valuable biomarkers of disease in this patient cohort.

Although there is evidence that exact calculation recruits left hemisphere perisylvian language systems, recent work has shown that exact calculation can be retained despite severe damage to these networks. In this study, we sought to identify a "core" network for calculation and hence to determine the extent to which left hemisphere language areas are part of this network. We examined performance on addition and subtraction problems in two modalities: one using conventional two-digit problems that can be easily encoded into language; the other using novel shape representations. With regard to numerical problems, our results revealed increased left fronto-temporal activity in addition, and increased parietal activity in subtraction, potentially reflecting retrieval of linguistically encoded information during addition. The shape problems elicited activations of occipital, parietal and dorsal temporal regions, reflecting visual reasoning processes. A core activation common to both calculation types involved the superior parietal lobule bilaterally, right temporal sub-gyral area, and left lateralized activations in inferior parietal (BA 40), frontal (BA 6/8/32) and occipital (BA 18) regions. The large bilateral parietal activation could be attributed to visuo-spatial processing in calculation. The inferior parietal region, and particularly the left angular gyrus, was part of the core calculation network. However, given its activation in both shape and number tasks, its role is unlikely to reflect linguistic processing per se. A possibility is that it serves to integrate right hemisphere visuo-spatial and left hemisphere linguistic and executive processing in calculation.

Hadjivassiliou M, Wallis LI, Hoggard N, Grunewald RA, Griffiths PD, Wilkinson ID. MR spectroscopy and atrophy in Gluten, Friedreich’s and SCA6 ataxias. Acta Neurol Scand: 2012: 126: 138–143. © 2011 John Wiley & Sons A/S. Background – Previous work using proton MR spectroscopy (1H-MRS) of the cerebellum in the ataxias suggested that 1H-MRS abnormalities and atrophy do not necessarily occur concurrently. Aims – To investigate the spectroscopic features of different types of ataxias. Methods – Using a clinical MR system operating at 1.5T, we performed 1H-MRS with a single voxel placed over the right dentate nucleus in 22 patients with gluten ataxia (GA), six patients with Friedreich’s ataxia (FA), six patients with spinocerebellar ataxia type 6 (SCA6) and 21 healthy volunteers. Atrophy of the vermis and hemispheres on standard MRI was rated by a neuroradiologist. Any interaction between atrophy and 1H-MRS was analysed for the three groups of patients and controls. Results – Patients with GA had significant atrophy of the vermis and hemispheres as well as abnormal 1H-MRS. Patients with SCA6 had more severe overall atrophy of the vermis and hemispheres, but relatively preserved N-acetyl-aspartate/creatine (NAA/Cr). The FA group showed significant atrophy of only the superior vermis with normal 1H-MRS. Conclusions – This study suggests that 1H-MRS of the cerebellum in patients with ataxia provides information in addition to the presence of atrophy. There are significant 1H-MRS differences amongst different types of ataxia with interesting correlations between atrophy and NAA/Cr.

Introduction\ud Current methods of identifying axillary node metastases in breast cancer patients are highly accurate, but are associated with several adverse events. This review evaluates the diagnostic accuracy of magnetic resonance imaging (MRI) techniques for identification of axillary metastases in early stage newly diagnosed breast cancer patients.\ud \ud Methods\ud Comprehensive searches were conducted in April 2009. Study quality was assessed. Sensitivity and specificity were meta-analysed using a bivariate random effects approach, utilising pathological diagnosis via node biopsy as the comparative gold standard.\ud \ud Results\ud Based on the highest sensitivity and specificity reported in each of the nine studies evaluating MRI (n = 307 patients), mean sensitivity was 90% (95% CI: 78–96%; range 65–100%) and mean specificity 90% (95% CI: 75–96%; range 54–100%). Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced MRI (n = 93), mean sensitivity was 98% (95% CI: 61–100%) and mean specificity 96% (95% CI: 72–100%). Across three studies of gadolinium-enhanced MRI (n = 187), mean sensitivity was 88% (95% CI: 78–94%) and mean specificity 73% (95% CI: 63–81%). In the single study of in-vivo proton MR spectroscopy (n = 27), sensitivity was 65% (95% CI: 38–86%) and specificity 100% (95% CI: 69–100%).\ud \ud Conclusions\ud USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity and may make a useful addition to the current diagnostic pathway. Additional larger studies with standardised methods and standardised criteria for classifying a node as positive are needed. Current estimates of sensitivity and specificity do not support replacement of SLNB with any current MRI technology in this patient group.