Multi-Modal Imaging in Down's Syndrome: Maximizing Utility Through Innovative Neuroimaging Approaches.

In recent decades, the field of neuroimaging has experienced a surge of popularity and innovation which has led to significant advancements in the understanding of neurological disease, if not immediate clinical translation. In the case of Down's syndrome, a complex interplay of neurodevelopmental and neurodegenerative processes occur as a result of the trisomy of chromosome 21. The substantial potential impact of improved clinical intervention and the limited research under-taken to date make it a prime candidate for longitudinal neuroimaging-based study. However, as with a multitude of other multifaceted brain-based disorders, singular utilization of lone modality imaging has limited interpretability and applicability. Indeed, a present challenge facing the neuroimaging community as a whole is the methodological integration of multi-modal imaging to enhance clinical understanding. This review therefore aims to assess the current literature in Down's syndrome utilizing a multi-modal approach with regards to improvement upon consideration of a single modality. Additionally, we discuss potential avenues of future research that may effectively combine structural, functional and molecular-based imaging techniques for the significant benefit of the understanding of Down's syndrome pathology

Dissociated Accumbens and Hippocampal Structural Abnormalities across Obesity and Alcohol Dependence.

BACKGROUND: Processing of food and drug rewards involves specific neurocircuitry, and emerging evidence implicates subcortical abnormalities, particularly the nucleus accumbens and hippocampus. We specifically hypothesized that these 2 established regions in addiction neurocircuitry are associated with distinctive in vivo structural abnormalities in obesity and alcohol dependence. METHODS: To specifically investigate anatomically discrete volumetric changes associated with overconsumption of different rewards, we acquired T1 MRI data from 118 subjects in 3 groups comprising obesity (n=42), alcohol dependence (n=32), and healthy volunteer controls (n=44). To exploit novel methods of automated hippocampal subfield segmentation, we used Freesurfer software to generate volumetric data in subject groups for the hippocampal subiculum and its major striatal efferent target, the nucleus accumbens. Hypothesis-led, selective group difference comparisons were analyzed. RESULTS: We found markedly greater accumbens volumes (P=.002) and relatively preserved hippocampal subfield volumes in obesity. Conversely, in alcohol dependence, we found preserved accumbens volumes but atrophy of specific ventral hippocampal subfields, the subiculum and presubiculum. Smaller global subcortical gray-matter volume was found in the alcohol dependence group only. CONCLUSIONS: Reward neurocircuitry including the accumbens and ventral hippocampus may show key structural abnormalities in disorders involving processing of both food and drug rewards, although the foci of disruption may vary as a function of reward modality. Structural differences may subserve altered reward and motivational processes in obesity and alcohol dependence and represent a potential biomarker for therapeutic targeting in key public health disorders.Research was supported by a Wellcome Trust Intermediate Clinical Fellowship awarded to VV. 093705/Z/10/Z. VV is affiliated with the NIHR Biomedical Research Council University of Cambridge. TM is a NIHR Academic Clinical Fellow in The Department of Psychiatry. Elijah Mak was in receipt of the Gates Cambridge scholarship.This is final version. It was originally published by Oxford University Press via http://dx.doi.org/10.1093/ijnp/pyw03

The segregated connectome of late-life depression: a combined cortical thickness and structural covariance analysis.

Late-life depression (LLD) has been associated with both generalized and focal neuroanatomical changes including gray matter atrophy and white matter abnormalities. However, previous literature has not been consistent and, in particular, its impact on the topology organization of brain networks remains to be established. In this multimodal study, we first examined cortical thickness, and applied graph theory to investigate structural covariance networks in LLD. Thirty-three subjects with LLD and 25 controls underwent T1-weighted, fluid-attenuated inversion recovery and clinical assessments. Freesurfer was used to perform vertex-wise comparisons of cortical thickness, whereas the Graph Analysis Toolbox (GAT) was implemented to construct and analyze the structural covariance networks. LLD showed a trend of lower thickness in the left insular region (p < 0.001 uncorrected). In addition, the structural network of LLD was characterized by greater segregation, particularly showing higher transitivity (i.e., measure of clustering) and modularity (i.e., tendency for a network to be organized into subnetworks). It was also less robust against random failure and targeted attacks. Despite relative cortical preservation, the topology of the LLD network showed significant changes particularly in segregation. These findings demonstrate the potential for graph theoretical approaches to complement conventional structural imaging analyses and provide novel insights into the heterogeneous etiology and pathogenesis of LLD.This work was supported by the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, and the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Newcastle upon Tyne Hospitals NHS Foundation Trust and the Newcastle University. Elijah Mak was in receipt of a Gates Cambridge, PhD studentship.This is the author accepted manuscript. It first appeared from Elsevier at http://dx.doi.org/10.1016/j.neurobiolaging.2016.08.013

Neuroimaging correlates of cognitive impairment and dementia in Parkinson's disease.

There has been a gradual shift in the definition of Parkinson's disease, from a movement disorder to a neurodegenerative condition affecting multiple cognitive domains. Mild cognitive impairment (PD-MCI) is a frequent comorbidity in PD that is associated with progression to dementia (PDD) and debilitating consequences for patients and caregivers. At present, the pathophysiology underpinning cognitive impairment in PD is not established, although emerging evidence has suggested that multi-modal imaging biomarkers could be useful in the early diagnosis of PD-MCI and PDD, thereby identifying at-risk patients to enable treatment at the earliest stage possible. Structural MRI studies have revealed prominent grey matter atrophy and disruptions of white matter tracts in PDD, although findings in non-demented PD have been more variable. There is a need for further longitudinal studies to clarify the spatial and temporal progression of morphological changes in PD, as well as to assess their underlying involvement in the evolution of cognitive deficits. In this review, we discuss the aetiology and neuropsychological profiles of PD-MCI and PDD, summarize the putative imaging substrates in light of evidence from multi-modal neuroimaging studies, highlight limitations in the present literature, and suggest recommendations for future research.This work was supported by the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, and the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Newcastle upon Tyne Hospitals NHS Foundation Trust and the Newcastle University. Elijah Mak was in receipt of a Gates Cambridge PhD studentship.This is the accepted manuscript. The final version is available at http://www.sciencedirect.com/science/article/pii/S1353802015002151

11 C-PK11195 PET imaging and white matter changes in Parkinson's disease dementia.

There is evidence of increased microglial activation in Parkinson's disease (PD) as shown by in vivo PET ligand such as 11 C-PK11195. In addition, diffusion tensor imaging (DTI) imaging reveals widespread changes in PD, especially when the associated dementia develops. In the present case series, we studied five subjects with Parkinson's disease dementia (PDD). Our findings suggest that while DTI metrics mirror cognitive severity, higher 11 C-PK11195 binding seems to be associated with a relative preservation of both white matter tracts and cognition. Longitudinal studies are warranted to tackle the complex relationship between microglial activation and structural abnormalities in neurodegenerative conditions.We are grateful to our volunteers for their participation in the study. We thank the radiographers at Wolfson Brain Imaging Centre and the PET/CT unit, Addenbrooke's Hospital for their technical expertise and support in data acquisition. We thank Alzheimer Research UK, the National Institute for Health Research Cambridge Biomedical Research Centre (NIHR, RG64473) and the Wellcome Trust (JBR: 103838) for funding and support

Detecting Small Vessel Pathology in Cocaine Use Disorder

BackgroundCocaine use is associated with an increased risk of cerebrovascular accidents. Small vessel pathology has been linked to the risk of stroke in cocaine users, but can be challenging to detect on conventional magnetic resonance (MR) scans. Fluid-attenuated inversion recovery (FLAIR) scans permit better resolution of small vessel lesions.ObjectivesFLAIR scans are currently only acquired based on the subjective judgement of abnormalities on MR scans at face value. We sought to evaluate this practice and the added value of FLAIR scans for patients with cocaine use disorder (CUD), by comparing microbleeds detected by MR and FLAIR scans. We hypothesised that microbleeds are more pronounced in CUD patients, particularly so in participants who had been selected for a FLAIR scan by radiographers.MethodsSixty-four patients with CUD and 60 control participants underwent a brain scan. The MR of 20 CUD patients and 16 control participants showed indicators of cerebral infarction at face value and were followed up by a FLAIR scan. We determined the volume of microbleeds in both MR and FLAIR scans and examined associations with various risk factors.ResultsWhile MR lesion volumes were significantly increased in CUD patients, no significant differences in lesion volume were found in the subgroup of individuals who received a FLAIR.ConclusionThe current practice of subjectively evaluating MR scans as a basis for the follow-up FLAIR scans to detect vascular pathology may miss vulnerable individuals. Hence, FLAIR scans should be included as a routine part of research studies.</jats:sec

Longitudinal assessment of global and regional atrophy rates in Alzheimer's disease and dementia with Lewy bodies.

BACKGROUND & OBJECTIVE: Percent whole brain volume change (PBVC) measured from serial MRI scans is widely accepted as a sensitive marker of disease progression in Alzheimer's disease (AD). However, the utility of PBVC in the differential diagnosis of dementia remains to be established. We compared PBVC in AD and dementia with Lewy bodies (DLB), and investigated associations with clinical measures. METHODS: 72 participants (14 DLBs, 25 ADs, and 33 healthy controls (HCs)) underwent clinical assessment and 3 Tesla T1-weighted MRI at baseline and repeated at 12 months. We used FSL-SIENA to estimate PBVC for each subject. Voxelwise analyses and ANCOVA compared PBVC between DLB and AD, while correlational tests examined associations of PBVC with clinical measures. RESULTS: AD had significantly greater atrophy over 1 year (1.8%) compared to DLB (1.0%; p = 0.01) and HC (0.9%; p < 0.01) in widespread regions of the brain including periventricular areas. PBVC was not significantly different between DLB and HC (p = 0.95). There were no differences in cognitive decline between DLB and AD. In the combined dementia group (AD and DLB), younger age was associated with higher atrophy rates (r = 0.49, p < 0.01). CONCLUSIONS: AD showed a faster rate of global brain atrophy compared to DLB, which had similar rates of atrophy to HC. Among dementia subjects, younger age was associated with accelerated atrophy, reflecting more aggressive disease in younger people. PBVC could aid in differentiating between DLB and AD, however its utility as an outcome marker in DLB is limited.This work was supported by the Sir Jules Thorn Charitable Trust (grant number 05/JTA), the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, and the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Newcastle upon Tyne Hospitals NHS Foundation Trust and the Newcastle University. Elijah Mak was in receipt of a Gates Cambridge, PhD studentship.This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S2213158215000182#

Progressive cortical thinning and subcortical atrophy in dementia with Lewy bodies and Alzheimer's disease.

Patterns of progressive cortical thinning in dementia with Lewy bodies (DLB) remain poorly understood. We examined spatiotemporal patterns of cortical thinning and subcortical atrophy over 12 months in DLB (n = 13), compared with Alzheimer's disease (AD) (n = 23) and healthy control subjects (HC) (n = 33). Rates of temporal thinning in DLB were relatively preserved compared with AD. Volumetric analyses subcortical changes revealed that the AD group demonstrated significantly increased hippocampal atrophy (-5.8%) relative to the HC (-1.7%; p < 0.001) and DLB groups (-2.5%, p = 0.006). Significant lateral ventricular expansion was also observed in AD (8.9%) compared with HC (4.3%; p < 0.001) and DLB (4.7%; p = 0.008) at trend level. There was no significant difference in subcortical atrophy and ventricular expansion between DLB and HC. In the DLB group, increased rates of cortical thinning in the frontal and parietal regions were significantly correlated with decline in global cognition (Mini-Mental State Examination) and motor deterioration (Unified Parkinson's Disease Rating Scale 3), respectively. Overall, AD and DLB are characterized by different spatiotemporal patterns of cortical thinning over time. Our findings warrant further consideration of longitudinal cortical thinning as a potential imaging marker to differentiate DLB from AD.This work was supported by the Sir Jules Thorn Charitable Trust (Grant number 05/JTA), the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, and the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Newcastle upon Tyne Hospitals NHS Foundation Trust and the Newcastle University. Elijah Mak was in receipt of a Gates Cambridge PhD studentship. Elijah Mak formulated the research question, performed the statistical analyses, interpreted the results, and wrote the article. Li Su and Guy Williams assisted with the interpretation of the results and provided comments and additional suggestions for revisions of the draft. Rosie Watson recruited and assessed study participants, assisted with the interpretation of the results, and reviewed the article. Michael Firbank designed the imaging protocol, assisted with the interpretation of the results, and reviewed the article. Andrew Blamire obtained funding for the project, designed the imaging protocol, undertook routine quality assurance on the MR system, assisted with the interpretation of the results, and reviewed the article. John O’Brien obtained funding for the project, designed the imaging protocol, assisted with recruitment of study participants, assisted with the interpretation of the results, and reviewed the article. All authors approved the final article.This is the accepted manuscript for a paper published in Neurobiology of Aging Volume 36, Issue 4, April 2015, Pages 1743–1750, DOI: 10.1016/j.neurobiolaging.2014.12.03

Associations of hippocampal subfields in the progression of cognitive decline related to Parkinson's disease.

OBJECTIVE: Hippocampal atrophy has been associated with mild cognitive impairment (MCI) in Parkinson's disease (PD). However, literature on how hippocampal atrophy affects the pathophysiology of cognitive impairment in PD has been limited. Previous studies assessed the hippocampus as an entire entity instead of their individual subregions. We studied the progression of cognitive status in PD subjects over 18 in relation to hippocampal subfields atrophy. METHODS: 65 PD subjects were included. Using the MDS task force criteria, PD subjects were classified as either having no cognitive impairment (PD-NCI) or PD-MCI. We extended the study by investigating the hippocampal subfields atrophy patterns in those who converted from PD-NCI to PD-MCI (PD-converters) compared to those who remained cognitively stable (PD-stable) over 18 months. Freesurfer 6.0 was used to perform the automated segmentation of the hippocampus into thirteen subregions. RESULTS: PD-MCI showed lower baseline volumes in the left fimbria, right CA1, and right HATA; and lower global cognition scores compared to PD-NCI. Baseline right CA1 was also correlated with baseline attention. Over 18 months, decline in volumes of CA2-3 and episodic memory were also seen in PD-converters compared to PD-stable. Baseline volumes of GC-DG, right CA4, left parasubiculum, and left HATA were predictive of the conversion from PD-NCI to PD-MCI. CONCLUSION: The findings from this study add to the anatomical knowledge of hippocampal subregions in PD, allowing us to understand the unique functional contribution of each subfield. Structural changes in the hippocampus subfields could be early biomarkers to detect cognitive impairment in PD

Longitudinal diffusion tensor imaging in dementia with Lewy bodies and Alzheimer's disease.

OBJECTIVE: Changes in the white matter of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) have been reported using diffusion weighted MRI, though few longitudinal studies have been done. METHODS: We performed diffusion weighted MRI twice, a year apart on 23 AD, 14 DLB, and 32 healthy control subjects. Mean diffusivity (MD) and fractional anisotropy (FA) were calculated. RESULTS: In AD, there were widespread regions where the longitudinal MD increase was greater than in controls, and small areas in the parietal and temporal lobes where it was greater in AD than DLB. In AD, decrease in brain volume correlated with increased MD. There were no significant differences in progression between DLB and controls. CONCLUSIONS: In AD the white matter continues to degenerate during the disease process, whereas in DLB, changes in the white matter structure are a relatively early feature. Different mechanisms are likely to underpin changes in diffusivity.The study was supported by the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, and the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. Elijah Mak was in receipt of a Gates Cambridge PhD studentship.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.parkreldis.2016.01.00