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1.  Neuroimaging of Inflammation in Memory and Related Other Disorders (NIMROD) study protocol: a deep phenotyping cohort study of the role of brain inflammation in dementia, depression and other neurological illnesses 
BMJ Open  2017;7(1):e013187.
Introduction
Inflammation of the central nervous system is increasingly regarded as having a role in cognitive disorders such as dementia and depression, but it is not clear how such inflammation relates to other aspects of neuropathology, structural and functional changes in the brain and symptoms (as assessed via clinical and neuropsychological assessment and MRI). This study will explore these pathophysiological mechanisms using positron emission tomography (PET) which allows in vivo imaging of inflammation, amyloid and τ deposition, together with neuropsychological profiling, MRI and peripheral biomarker analysis.
Methods and analysis
Using PET imaging of the ligand [11C]PK11195, we will test for increased neuroinflammation in vivo in patients with Alzheimer's disease, Lewy body dementia, frontotemporal dementia, progressive supranuclear palsy, late-onset depression and mild cognitive impairment, when compared to healthy controls. We will assess whether areas of inflammatory change are associated with amyloid and τ deposition (assessed using 11C-labelled Pittsburgh Compound B ([11C]PiB) and 18F-labelled AV-1451, respectively), as well as structural and connectivity markers found on MRI. Inflammatory biomarker analysis and immune-phenotyping of peripheral blood monocytes will determine the correlation between central inflammation and peripheral inflammation. Finally, we will examine whether central inflammatory markers seen on PET imaging are associated with global and domain specific cognitive impairments or predict cognitive decline over 12 months.
Ethics and dissemination
The study protocol was approved by the local ethics committee, East of England—Cambridge Central Research Ethics Committee (reference: 13/EE/0104). The study is also Administration of Radioactive Substances Advisory Committee (ARSAC) approved as part of this process. Data will be disseminated by presentation at national and international conferences and by publication, predominantly in journals of clinical neuroscience, neurology and psychiatry.
doi:10.1136/bmjopen-2016-013187
PMCID: PMC5223666  PMID: 28064175
Tau; Neuroinflammation; [18F]AV-1451; [11C]PK11195; Positron emission tomography
2.  The segregated connectome of late-life depression: a combined cortical thickness and structural covariance analysis 
Neurobiology of Aging  2016;48:212-221.
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.
doi:10.1016/j.neurobiolaging.2016.08.013
PMCID: PMC5096887  PMID: 27721203
Imaging; Depression; Dementia; Graph theory; Brain network; Late-life depression; Psychiatry
3.  Peripheral Inflammatory Parameters in Late-Life Depression: A Systematic Review 
Depressive disorders appear relatively frequently in older patients, and therefore represent an important disease burden worldwide. Given the high levels of inflammatory parameters found in depressed elderly patients, the “inflammaging” hypothesis is gaining strength. In this systematic review, we summarize current evidence regarding the relationship between inflammatory parameters and late-life depression, with a unique focus on longitudinal studies to guarantee temporality. According to the data summarized in this review, the levels of some proinflammatory parameters—especially interleukin (IL)-8, IL-6, and tumor necrosis factor (TNF)-α—could serve as biomarkers for the future development of depressive symptoms in elderly patients. Proinflammatory cytokines seem to be associated with the future development of clinically significant depression, irrespective of baseline scores, thus indicating that inflammation temporally precedes and increases depression risk. As insufficient research has been conducted in this field, further prospective studies are clearly warranted.
doi:10.3390/ijms17122022
PMCID: PMC5187822  PMID: 27918465
inflammation; aging; depression; late-life
4.  A spatial covariance 123I-5IA-85380 SPECT study of α4β2 nicotinic receptors in Alzheimer's disease 
Neurobiology of Aging  2016;47:83-90.
Alzheimer's disease (AD) is characterized by widespread degeneration of cholinergic neurons, particularly in the basal forebrain. However, the pattern of these deficits and relationship with known brain networks is unknown. In this study, we sought to clarify this and used 123I-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (1235IA-85380) single photon emission computed tomography to investigate spatial covariance of α4β2 nicotinic acetylcholine receptors in AD and healthy controls. Thirteen AD and 16 controls underwent 1235IA-85380 and regional cerebral blood flow (99mTc-exametazime) single photon emission computed tomography scanning. We applied voxel principal component (PC) analysis, generating series of principal component images representing common intercorrelated voxels across subjects. Linear regression generated specific α4β2 and regional cerebral blood flow covariance patterns that differentiated AD from controls. The α4β2 pattern showed relative decreased uptake in numerous brain regions implicating several networks including default mode, salience, and Papez hubs. Thus, as well as basal forebrain and brainstem cholinergic system dysfunction, cholinergic deficits mediated through nicotinic acetylcholine receptors could be evident within key networks in AD. These findings may be important for the pathophysiology of AD and its associated cognitive and behavioral phenotypes.
doi:10.1016/j.neurobiolaging.2016.07.017
PMCID: PMC5082764  PMID: 27565302
Alzheimer's disease; Cholinergic; Acetylcholine; Nicotinic; Spatial covariance; SPECT
5.  [18F]AV‐1451 PET in behavioral variant frontotemporal dementia due to MAPT mutation 
Abstract
The validation of tau radioligands could improve the diagnosis of frontotemporal lobar degeneration and the assessment of disease‐modifying therapies. Here, we demonstrate that binding of the tau radioligand [18F]AV‐1451 was significantly abnormal in both magnitude and distribution in a patient with familial frontotemporal dementia due to a MAPT 10 + 16C>T gene mutation, recapitulating the pattern of neuropathology seen in her father. Given the genetic diagnosis and the non‐Alzheimer's pathology, these findings suggest that [18F]AV‐1451 might be a useful biomarker in primary tauopathies. Largerscale in vivo and post‐mortem studies will be needed to assess the technique's specificity.
doi:10.1002/acn3.366
PMCID: PMC5224822  PMID: 28097206
6.  Predictors of poor outcome among children with heterotaxy syndrome: a retrospective review 
Open Heart  2016;3(2):e000328.
Objective
To determine predictors of poor outcome in patients with heterotaxy syndrome.
Methods
A retrospective review of children with heterotaxy syndrome, in a single tertiary paediatric cardiology centre, was conducted between 1 January 1997 and 1 January 2014 to determine predictors of poor outcome. Poor outcome was defined as death, cardiac transplantation or New York Heart Association (NYHA) functional class III or IV.
Results
There were 35 patients diagnosed with heterotaxy syndrome, 17 of whom were diagnosed antenatally. 22 patients had right atrial isomerism and 13 had left atrial isomerism. The median age of postnatal diagnosis was 2.5 days old (1 day to 19 months). 12 patients had a poor outcome; 6 patients died, 1 underwent cardiac transplantation and 5 had an NYHA functional class of >III. 5 patients had a biventricular repair and the remaining 30 had a univentricular repair. Type of atrial isomerism, univentricular or biventricular anatomy, severity of atrioventricular valve regurgitation or ventricular dysfunction, obstructed pulmonary venous return, occurrence of arrhythmia and presence of pulmonary atresia did not predict poor outcome. Fetal diagnosis also did not confer a survival advantage. The median duration of follow-up in this cohort was 65 months (2 days to 16.8 years).
Conclusions
Survival for patients with heterotaxy syndrome was 83% over a median follow-up of 65 months. 34% of patients had a poor outcome. None of the variables studied were predictive of death, transplantation or NYHA classification III or IV.
doi:10.1136/openhrt-2015-000328
PMCID: PMC5073560  PMID: 27843561
CONGENITAL HEART DISEASE; Heterotaxy; Right atrial isomerism; Left atrial isomerism; Survival
7.  Approaches to estimating inbreeding coefficients in clinical isolates of Plasmodium falciparum from genomic sequence data 
Malaria Journal  2016;15:473.
Background
The advent of whole-genome sequencing has generated increased interest in modelling the structure of strain mixture within clinical infections of Plasmodium falciparum The life cycle of the parasite implies that the mixture of multiple strains within an infected individual is related to the out-crossing rate across populations, making methods for measuring this process in situ central to understanding the genetic epidemiology of the disease.
Results
This paper derives a set of new estimators for inferring inbreeding coefficients using whole genome sequence read count data from P. falciparum clinical samples, which provides resources to assess within-sample mixture that connect to extensive literatures in population genetics and conservation ecology. Features of the P. falciparum genome mean that standard methods for inbreeding coefficients and related F-statistics cannot be used directly. After reviewing an initial effort to estimate the inbreeding coefficient within clinical isolates of P. falciparum, several generalizations using both frequentist and Bayesian approaches are provided. A simpler, more intuitive frequentist estimator is shown to have nearly identical properties to the initial estimator both in simulation and in real data sets. The Bayesian approach connects these estimates to the Balding–Nichols model, a mainstay within genetic epidemiology, and a possible framework for more complex modelling. A simulation study shows strong performance for all estimators with as few as ten variants. Application to samples from the PF3K data set indicate significant across-country variation in within-sample mixture. Finally, a comparison with results from a recent mixture model for within-sample strain mixture show that inbreeding coefficients provide a strong proxy for these more complex models.
Conclusions
This paper provides a set of methods for estimating inbreeding coefficients within P. falciparum samples from whole-genome sequence data, supported by simulation studies and empirical examples. It includes a substantially simple estimator with similar statistical properties to the estimator in current use. These methods will also be applicable to other species with similar life-cycles. Implementations of the methods described are available in an open-source R package pfmix. Estimates for the PF3K public data release are provide as part of this resource.
doi:10.1186/s12936-016-1531-z
PMCID: PMC5025560  PMID: 27634595
Inbreeding coefficient; MOI; COI; F-statistics; Balding–Nichols model
8.  Grey matter atrophy in prodromal stage of dementia with Lewy bodies and Alzheimer’s disease 
Background
Little is known about the patterns of brain atrophy in prodromal dementia with Lewy bodies (pro-DLB).
Methods
In this study, we used SPM8 with diffeomorphic anatomical registration through exponentiated lie algebra to measure grey matter (GM) volume and investigate patterns of GM atrophy in pro-DLB (n = 28) and prodromal Alzheimer’s disease (pro-AD) (n = 27) and compared and contrasted them with those in elderly control subjects (n = 33) (P ≤ 0.05 corrected for family-wise error).
Results
Patients with pro-DLB showed diminished GM volumes of bilateral insulae and right anterior cingulate cortex compared with control subjects. Comparison of GM volume between patients with pro-AD and control subjects showed a more extensive pattern, with volume reductions in temporal (hippocampi and superior and middle gyri), parietal and frontal structures in the former. Direct comparison of prodromal groups suggested that more atrophy was evident in the parietal lobes of patients with pro-AD than patients with pro-DLB. In patients with pro-DLB, we found that visual hallucinations were associated with relative atrophy of the left cuneus.
Conclusions
Atrophy in pro-DLB involves the insulae and anterior cingulate cortex, regions rich in von Economo neurons, which we speculate may contribute to the early clinical phenotype of pro-DLB.
doi:10.1186/s13195-016-0198-6
PMCID: PMC4970221  PMID: 27484179
Prodromal dementia with Lewy bodies; Dementia with Lewy bodies; Alzheimer’s disease; Alzheimer’s dementia; Prodromal Alzheimer’s disease; Lewy body disease; Mild cognitive impairment; MRI; Insula
9.  Depressive symptoms are associated with daytime sleepiness and subjective sleep quality in dementia with Lewy bodies 
Objective
Sleep problems and depression are common symptoms in dementia with Lewy bodies (DLB), where patients typically experience subjectively poor sleep quality, fatigue and excessive daytime sleepiness. However, whilst sleep disturbances have been linked to depression, this relationship has not received much attention in DLB. The present cross‐sectional study addresses this by examining whether depressive symptoms are specifically associated with subjective sleep quality and daytime sleepiness in DLB, and by examining other contributory factors.
Methods
DLB patients (n = 32) completed the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and the 15‐item Geriatric Depression Scale (GDS‐15). Motor and cognitive functioning was also assessed. Pearson correlations were used to assess the relationship between GDS‐15, ESS and PSQI scores.
Results
GDS‐15 scores were positively associated with both ESS (r = 0.51, p < 0.01) and PSQI (r = 0.59, p < 0.001) scores.
Conclusions
Subjective poor sleep and daytime sleepiness were associated with depressive symptoms in DLB. Given the cross‐sectional nature of the present study, the directionality of this relationship cannot be determined, although this association did not appear to be mediated by sleep quality or daytime sleepiness. Nevertheless, these findings have clinical relevance; daytime sleepiness or poor sleep quality might indicate depression in DLB, and subsequent work should examine whether the treatment of depression can reduce excessive daytime sleepiness and improve sleep quality in DLB patients. Alternatively, more rigorous screening for sleep problems in DLB might assist the treatment of depression. © 2015 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd.
doi:10.1002/gps.4389
PMCID: PMC4949673  PMID: 26560190
dementia with Lewy bodies; sleep quality; daytime sleepiness; depression; depressive symptoms
10.  Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia 
Nature Communications  2016;7:12086.
Sphingosine-1-phosphate (S1P) is a bioactive signalling lipid highly enriched in mature erythrocytes, with unknown functions pertaining to erythrocyte physiology. Here by employing nonbiased high-throughput metabolomic profiling, we show that erythrocyte S1P levels rapidly increase in 21 healthy lowland volunteers at 5,260 m altitude on day 1 and continue increasing to 16 days with concurrently elevated erythrocyte sphingonisne kinase 1 (Sphk1) activity and haemoglobin (Hb) oxygen (O2) release capacity. Mouse genetic studies show that elevated erythrocyte Sphk1-induced S1P protects against tissue hypoxia by inducing O2 release. Mechanistically, we show that intracellular S1P promotes deoxygenated Hb anchoring to the membrane, enhances the release of membrane-bound glycolytic enzymes to the cytosol, induces glycolysis and thus the production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific glycolytic intermediate, which facilitates O2 release. Altogether, we reveal S1P as an intracellular hypoxia-responsive biolipid promoting erythrocyte glycolysis, O2 delivery and thus new therapeutic opportunities to counteract tissue hypoxia.
The presence of the signalling lipid Sphingosine 1-phosphate (S1P) in erythrocytes has unclear physiological implications. Here the authors show that the S1P-generating enzyme Sphingosine kinase type 1 and its product S1P play an important role in the red blood cell adaptation to hypoxic environments in mice and humans.
doi:10.1038/ncomms12086
PMCID: PMC4947158  PMID: 27417539
11.  Cholinergic and perfusion brain networks in Parkinson disease dementia 
Neurology  2016;87(2):178-185.
Objective:
To investigate muscarinic M1/M4 cholinergic networks in Parkinson disease dementia (PDD) and their association with changes in Mini-Mental State Examination (MMSE) after 12 weeks of treatment with donepezil.
Methods:
Forty-nine participants (25 PDD and 24 elderly controls) underwent 123I-QNB and 99mTc-exametazime SPECT scanning. We implemented voxel principal components (PC) analysis, producing a series of PC images of patterns of interrelated voxels across individuals. Linear regression analyses derived specific M1/M4 and perfusion spatial covariance patterns (SCPs).
Results:
We found an M1/M4 SCP of relative decreased binding in basal forebrain, temporal, striatum, insula, and anterior cingulate (F1,47 = 31.9, p < 0.001) in cholinesterase inhibitor–naive patients with PDD, implicating limbic-paralimbic and salience cholinergic networks. The corresponding regional cerebral blood flow SCP showed relative decreased uptake in temporoparietal and prefrontal areas (F1,47 = 177.5, p < 0.001) and nodes of the frontoparietal and default mode networks (DMN). The M1/M4 pattern that correlated with an improvement in MMSE (r = 0.58, p = 0.005) revealed relatively preserved/increased pre/medial/orbitofrontal, parietal, and posterior cingulate areas coinciding with the DMN and frontoparietal networks.
Conclusion:
Dysfunctional limbic-paralimbic and salience cholinergic networks were associated with PDD. Established cholinergic maintenance of the DMN and frontoparietal networks may be prerequisite for cognitive remediation following cholinergic treatment in this condition.
doi:10.1212/WNL.0000000000002839
PMCID: PMC4940066  PMID: 27306636
12.  Extracellular zinc induces phosphoethanolamine addition to Pseudomonas aeruginosa lipid A via the ColRS two-component system 
Molecular microbiology  2015;97(1):166-178.
Summary
Gram-negative bacteria survive harmful environmental stressors by modifying their outer membrane. Much of this protection is afforded upon remodeling of the lipid A region of the major surface molecule lipopolysaccharide (LPS). For example, the addition of cationic substituents, such as 4-amino-4-deoxy-L-arabinose (L-Ara4N) and phosphoehthanolamine (pEtN) at the lipid A phosphate groups is often induced in response to specific environmental flux stabilizing the outer membrane. The work herein represents the first report of pEtN addition to P. aeruginosa lipid A. We have identified the key pEtN transferase which we named EptAPa and characterized its strict activity on only one position of lipid A, contrasting from previously studied EptA enzymes. We further show that transcription of eptAPa is regulated by zinc via the ColRS two-component system instead of the PmrAB system responsible for eptA regulation in E. coli and S. enterica. Further, although L-Ara4N is readily added to the same position of lipid A as pEtN under certain environmental conditions, ColR specifically induces pEtN addition to lipid A in lieu of L-Ara4N when Zn2+ is present. The unique, specific regulation of eptAPa transcription and enzymatic activity described in this work demonstrates the tight yet inducible control over LPS modification in P. aeruginosa.
doi:10.1111/mmi.13018
PMCID: PMC4715879  PMID: 25846400
lipid A; EptA; phosphoethanolamine; ColRS; Pseudomonas; outer membrane; lipopolysaccharide; LPS
13.  Multimodal EEG-MRI in the differential diagnosis of Alzheimer's disease and dementia with Lewy bodies 
Differential diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) remains challenging; currently the best discriminator is striatal dopaminergic imaging. However this modality fails to identify 15–20% of DLB cases and thus other biomarkers may be useful. It is recognised electroencephalography (EEG) slowing and relative medial temporal lobe preservation are supportive features of DLB, although individually they lack diagnostic accuracy. Therefore, we investigated whether combined EEG and MRI indices could assist in the differential diagnosis of AD and DLB.
Seventy two participants (21 Controls, 30 AD, 21 DLB) underwent resting EEG and 3 T MR imaging. Six EEG classifiers previously generated using support vector machine algorithms were applied to the present dataset. MRI index was derived from medial temporal atrophy (MTA) ratings. Logistic regression analysis identified EEG predictors of AD and DLB. A combined EEG-MRI model was then generated to examine whether there was an improvement in classification compared to individual modalities.
For EEG, two classifiers predicted AD and DLB (model: χ2 = 22.1, df = 2, p < 0.001, Nagelkerke R2 = 0.47, classification = 77% (AD 87%, DLB 62%)). For MRI, MTA also predicted AD and DLB (model: χ2 = 6.5, df = 1, p = 0.01, Nagelkerke R2 = 0.16, classification = 67% (77% AD, 52% DLB). However, a combined EEG-MRI model showed greater prediction in AD and DLB (model: χ2 = 31.1, df = 3, p < 0.001, Nagelkerke R2 = 0.62, classification = 90% (93% AD, 86% DLB)).
While suggestive and requiring validation, diagnostic performance could be improved by combining EEG and MRI, and may represent an alternative to dopaminergic imaging.
doi:10.1016/j.jpsychires.2016.03.010
PMCID: PMC4866554  PMID: 27060340
MRI; EEG; Alzheimer's disease; Dementia with Lewy bodies; Differential diagnosis; Dopaminergic imaging
14.  Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations 
Dementia with Lewy bodies (DLB) patients frequently experience well formed recurrent complex visual hallucinations (RCVH). This is associated with reduced blood flow or hypometabolism on imaging of the primary visual cortex. To understand these associations in DLB we used pathological and biochemical analysis of the primary visual cortex to identify changes that could underpin RCVH. Alpha-synuclein or neurofibrillary tangle pathology in primary visual cortex was essentially absent. Neurone density or volume within the primary visual cortex in DLB was also unchanged using unbiased stereology. Microarray analysis, however, demonstrated changes in neuropeptide gene expression and other markers, indicating altered GABAergic neuronal function. Calcium binding protein and GAD65/67 immunohistochemistry showed preserved interneurone populations indicating possible interneurone dysfunction. This was demonstrated by loss of post synaptic GABA receptor markers including gephyrin, GABARAP, and Kif5A, indicating reduced GABAergic synaptic activity. Glutamatergic neuronal signalling was also altered with vesicular glutamate transporter protein and PSD-95 expression being reduced. Changes to the primary visual cortex in DLB indicate that reduced GABAergic transmission may contribute to RCVH in DLB and treatment using targeted GABAergic modulation or similar approaches using glutamatergic modification may be beneficial.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-016-0334-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s40478-016-0334-3
PMCID: PMC4928325  PMID: 27357212
Dementia with Lewy bodies; α-synuclein; Primary visual cortex; Hallucinations; Alzheimer’s disease
15.  Inferring Strain Mixture within Clinical Plasmodium falciparum Isolates from Genomic Sequence Data 
PLoS Computational Biology  2016;12(6):e1004824.
We present a rigorous statistical model that infers the structure of P. falciparum mixtures—including the number of strains present, their proportion within the samples, and the amount of unexplained mixture—using whole genome sequence (WGS) data. Applied to simulation data, artificial laboratory mixtures, and field samples, the model provides reasonable inference with as few as 10 reads or 50 SNPs and works efficiently even with much larger data sets. Source code and example data for the model are provided in an open source fashion. We discuss the possible uses of this model as a window into within-host selection for clinical and epidemiological studies.
Author Summary
Since the 1960’s researchers have observed that Plasmodium falciparum infections, the cause of most severe malaria, are frequently composed of several different strains of the parasite. In this work, the authors use Bayesian methods on whole genome sequence data to model the structure of these mixtures. Results from this method are consistent with previous approaches but provide finer resolution of these mixtures. As whole genome data in malaria research becomes increasingly common, this work will allow researchers to delve further into the within-host dynamics of the parasite, a much-discussed but previously difficult-to-access aspect of this disease.
doi:10.1371/journal.pcbi.1004824
PMCID: PMC4928962  PMID: 27362949
16.  Changes to the lateral geniculate nucleus in Alzheimer's disease but not dementia with Lewy bodies 
Aims
Complex visual hallucinations occur in 70% of dementia with Lewy bodies (DLB) cases and significantly affect patient well‐being. Visuo‐cortical and retinal abnormalities have been recorded in DLB and may play a role in visual hallucinations. The present study aimed to investigate the lateral geniculate nucleus (LGN), a visual relay centre between the retina and visual cortex, to see if changes to this structure underlie visual hallucinations in DLB.
Methods
Fifty‐one [17 probable DLB, 19 control and 15 probable Alzheimer's disease (AD)] cases were recruited for a functional magnetic resonance imaging study, in which patients' response to a flashing checkerboard stimulus was detected and measured in the LGN, before comparison across experimental groups. Additionally, post mortem  LGN tissue was acquired for a cross‐sectional study using 20 (six DLB, seven control and seven AD) cases and analysed using stereology. α‐Synuclein, phosphorylated tau and amyloid‐β pathology was also assessed in all cases.
Results
DLB cases did not significantly differ from controls on neuroimaging, morphometry or pathology. However, a significant increase in amyloid‐β pathology, a reduction in number of parvocellular neurones and magnocellular gliosis was found in AD cases compared with control and DLB cases.
Conclusions
These findings suggest that the early visual system is relatively spared in DLB, which implies that upstream visual structures may be largely responsible for the generation of hallucinatory percepts. The significance of the degeneration of the LGN in AD cases is uncertain.
doi:10.1111/nan.12249
PMCID: PMC4913748  PMID: 25967384
dementia with Lewy bodies; fMRI; lateral geniculate nucleus; neuropathology; stereology
17.  Frontal White Matter Hyperintensities, Clasmatodendrosis and Gliovascular Abnormalities in Ageing and Post-stroke Dementia 
Brain : a journal of neurology  2015;139(Pt 1):242-258.
White matter hyperintensities (WMH) as seen on brain T2 weighted magnetic resonance imaging (MRI) are associated with varying degrees of cognitive dysfunction in stroke, cerebral small vessel disease (SVD) and dementia. The pathophysiological mechanisms within the white matter (WM) accounting for cognitive dysfunction remain unclear. With the hypothesis that gliovascular interactions are impaired in subjects with high burdens of WMH, we performed clinicopathological studies in post-stroke survivors, who had exhibited greater frontal WMH volumes that predicted shorter time to dementia onset. Histopathological methods were used to identify substrates in the WM that would distinguish post-stroke dementia (PSD) from post-stroke non-demented (PSND) subjects. We focused on the reactive cell marker glial fibrillary acidic protein (GFAP) to study the incidence and location of clasmatodendrosis, a morphological attribute of irreversibly injured astrocytes. In contrast to normal appearing GFAP immunopositive (GFAP+) astrocytes, clasmatodendrocytes were swollen and had vacuolated cell bodies. Other markers such as aldehyde dehydrogenase 1 family, member L1 (ADH1L1) showed cytoplasmic disintergration of the astrocytes. Total GFAP+ cells in both the frontal and temporal WM were not greater in PSD versus PSND subjects. However, the percentage of clasmatodendrocytes was increased by >2-fold in PSD compared to PSND subjects (p=0.026) and by 11-fold in older controls versus young controls (p<0.023) in the frontal WM. High ratios of clasmotodendrocytes to total astrocytes in the frontal WM were consistent with lower Mini-Mental State Examination and the revised Cambridge Cognition Examination scores in PSD. Double immunofluorescent staining showed aberrant co-localization of aquaporin-4 (AQP4) in retracted GFAP+ astrocytes with disrupted end-feet juxtaposed to microvessels. To explore whether this was associated with the disrupted gliovascular interactions or blood-brain barrier (BBB) damage, we assessed the co-localisation of GFAP and AQP4 immunoreactivities in post-mortem brains from adult baboons with cerebral hypoperfusive injury, induced by occlusion of 3-major vessels supplying blood to the brain. Analysis of the frontal WM in perfused brains from the animals surviving 1-28 days after occlusion revealed that the highest intensity of fibrinogen immunoreactivity was at 14 days. At this survival time point, we also noted strikingly similar redistribution of AQP4 and GFAP+ astrocytes transformed into clasmatodendrocytes. Our findings suggest novel associations between irreversible astrocyte injury and disruption of gliovascular interactions at the BBB in the frontal WM and cognitive impairment in elderly post-stroke survivors. We propose clasmatodendrosis is another pathological substrate, linked to WMH and frontal WM changes, which may contribute to post-stroke or SVD dementia.
doi:10.1093/brain/awv328
PMCID: PMC4905522  PMID: 26667280
Ageing; astrocytes; clasmatodendrocyte; blood brain barrier; cognitive impairment; post-stroke dementia; stroke; vascular dementia; white matter
18.  Regional functional synchronizations in dementia with Lewy bodies and Alzheimer's disease 
International Psychogeriatrics / Ipa  2016;28(7):1143-1151.
Background:
Dementia with Lewy bodies (DLB) is a common cause of dementia in the elderly population after Alzheimer's disease (AD), and at early stages differential diagnosis between DLB and AD might be difficult due to their symptomatic overlap, e.g. cognitive and memory impairments. We aimed to investigate functional brain differences between both diseases in patients recently diagnosed.
Methods:
We investigated regional functional synchronizations using regional homogeneity (ReHo) in patients clinically diagnosed with DLB (n = 19) and AD (n = 18), and for comparisons we also included healthy controls (HC, n = 16). Patient groups were matched by age, education, and by the level of cognitive impairment (MMSE p-value = 0.36). Additionally, correlations between ReHo values and clinical scores were investigated.
Results:
The DLB group showed lower ReHo in sensory-motor cortices and higher ReHo in left middle temporal gyrus when compared with HCs (p-value < 0.001 uncorrected). The AD group demonstrated lower ReHo in the cerebellum and higher ReHo in the left/right lingual gyri, precuneus cortex, and other occipital and parietal regions (p-value < 0.001 uncorrected).
Conclusions:
Our results agree with previous ReHo investigations in Parkinson's disease (PD), suggesting that functional alterations in motor-related regions might be a characteristic of the Lewy body disease spectrum. However, our results in AD contradict previously reported findings for this disease and ReHo, which we speculate are a reflection of compensatory brain responses at early disease stages. ReHo differences between patient groups were at regions related to the default mode and sensory-motor resting state networks which might reflect the aetiological divergences in the underlying disease processes between AD and DLB.
doi:10.1017/S1041610216000429
PMCID: PMC4894061  PMID: 26976496
Dementia with Lewy bodies (DLB); Alzheimer's disease (AD); magnetic resonance imaging (MRI); hallucinations; neuroimaging
19.  Esophageal Microperforation due to Calcified Mediastinal Lymph Node Leading to Tracheoesophageal Fistula 
A 42-year-old male presented with worsening gastroesophageal reflux disease symptoms and cough. The clinical symptoms during the early course of illness were striking for aspiration pneumonia. He was given a prescription of proton pump inhibitors and antibiotics. Rapid decline in the clinical condition with worsening respiratory status was noted. Worsening symptoms of fever, cough, and chest pain prompted further diagnostic work-up suggesting esophageal microperforation. Esophagogram was found to be suggestive of tracheoesophageal fistula. The tracheoesophageal fistula was due to subcarinal lymph node of nontuberculous origin.
doi:10.1155/2016/9747193
PMCID: PMC4913067  PMID: 27366334
20.  Characteristics and plasticity of electrical synaptic transmission 
BMC Cell Biology  2016;17(Suppl 1):13.
Electrical synapses are an omnipresent feature of nervous systems, from the simple nerve nets of cnidarians to complex brains of mammals. Formed by gap junction channels between neurons, electrical synapses allow direct transmission of voltage signals between coupled cells. The relative simplicity of this arrangement belies the sophistication of these synapses. Coupling via electrical synapses can be regulated by a variety of mechanisms on times scales ranging from milliseconds to days, and active properties of the coupled neurons can impart emergent properties such as signal amplification, phase shifts and frequency-selective transmission. This article reviews the biophysical characteristics of electrical synapses and some of the core mechanisms that control their plasticity in the vertebrate central nervous system.
doi:10.1186/s12860-016-0091-y
PMCID: PMC4896238  PMID: 27230893
Connexin 36; Mauthner cell; MesV neuron; Amacrine cell; Photoreceptor
21.  Visual cortical excitability in dementia with Lewy bodies 
The British Journal of Psychiatry  2016;208(5):497-498.
Alterations in the visual system may underlie visual hallucinations in dementia with Lewy bodies (DLB). However, cortical excitability as measured by transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) activation of lower visual areas (V1–3) to visual stimuli appear normal in DLB. We explored the relationship between TMS-determined phosphene threshold and fMRI-related visual activation and found a positive relationship between the two in controls but a negative one in DLB. This double dissociation suggests a loss of inhibition in the visual system in DLB, which may predispose individuals to visual dysfunction and visual hallucinations.
doi:10.1192/bjp.bp.114.152736
PMCID: PMC4853644  PMID: 26541688
22.  Neural correlates of attention‐executive dysfunction in lewy body dementia and Alzheimer's disease 
Human Brain Mapping  2015;37(3):1254-1270.
Abstract
Attentional and executive dysfunction contribute to cognitive impairment in both Lewy body dementia and Alzheimer's disease. Using functional MRI, we examined the neural correlates of three components of attention (alerting, orienting, and executive/conflict function) in 23 patients with Alzheimer's disease, 32 patients with Lewy body dementia (19 with dementia with Lewy bodies and 13 with Parkinson's disease with dementia), and 23 healthy controls using a modified Attention Network Test. Although the functional MRI demonstrated a similar fronto‐parieto‐occipital network activation in all groups, Alzheimer's disease and Lewy body dementia patients had greater activation of this network for incongruent and more difficult trials, which were also accompanied by slower reaction times. There was no recruitment of additional brain regions or, conversely, regional deficits in brain activation. The default mode network, however, displayed diverging activity patterns in the dementia groups. The Alzheimer's disease group had limited task related deactivations of the default mode network, whereas patients with Lewy body dementia showed heightened deactivation to all trials, which might be an attempt to allocate neural resources to impaired attentional networks. We posit that, despite a common endpoint of attention‐executive disturbances in both dementias, the pathophysiological basis of these is very different between these diseases. Hum Brain Mapp 37:1254–1270, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.
doi:10.1002/hbm.23100
PMCID: PMC4784171  PMID: 26705763
Alzheimer's disease; attention; attention network test; executive; functional MRI; Lewy body dementia
23.  MRI visual rating scales in the diagnosis of dementia: evaluation in 184 post-mortem confirmed cases 
Brain  2016;139(4):1211-1225.
Distinguishing between the degenerative dementias during life can be challenging. Using histopathologically confirmed cases for comparison, Harper et al. evaluate six visual rating scales for use with routinely acquired structural MRI. Automated classification based on all six scales provides a practical, fast and inexpensive means of improving diagnostic certainty.
Distinguishing between the degenerative dementias during life can be challenging. Using histopathologically confirmed cases for comparison, Harper et al. evaluate six visual rating scales for use with routinely acquired structural MRI. Automated classification based on all six scales provides a practical, fast and inexpensive means of improving diagnostic certainty.
Accurately distinguishing between different degenerative dementias during life is challenging but increasingly important with the prospect of disease-modifying therapies. Molecular biomarkers of dementia pathology are becoming available, but are not widely used in clinical practice. Conversely, structural neuroimaging is recommended in the evaluation of cognitive impairment. Visual assessment remains the primary method of scan interpretation, but in the absence of a structured approach, diagnostically relevant information may be under-utilized. This definitive, multi-centre study uses post-mortem confirmed cases as the gold standard to: (i) assess the reliability of six visual rating scales; (ii) determine their associated pattern of atrophy; (iii) compare their diagnostic value with expert scan assessment; and (iv) assess the accuracy of a machine learning approach based on multiple rating scales to predict underlying pathology. The study includes T1-weighted images acquired in three European centres from 184 individuals with histopathologically confirmed dementia (101 patients with Alzheimer’s disease, 28 patients with dementia with Lewy bodies, 55 patients with frontotemporal lobar degeneration), and scans from 73 healthy controls. Six visual rating scales (medial temporal, posterior, anterior temporal, orbito-frontal, anterior cingulate and fronto-insula) were applied to 257 scans (two raters), and to a subset of 80 scans (three raters). Six experts also provided a diagnosis based on unstructured assessment of the 80-scan subset. The reliability and time taken to apply each scale was evaluated. Voxel-based morphometry was used to explore the relationship between each rating scale and the pattern of grey matter volume loss. Additionally, the performance of each scale to predict dementia pathology both individually and in combination was evaluated using a support vector classifier, which was compared with expert scan assessment to estimate clinical value. Reliability of scan assessment was generally good (intraclass correlation coefficient > 0.7), and average time to apply all six scales was <3 min. There was a very close association between the pattern of grey matter loss and the regions of interest each scale was designed to assess. Using automated classification based on all six rating scales, the accuracy (estimated using the area under the receiver-operator curves) for distinguishing each pathological group from controls ranged from 0.86–0.97; and from one another, 0.75–0.92. These results were substantially better than the accuracy of any single scale, at least as good as expert reads, and comparable to previous studies using molecular biomarkers. Visual rating scores from magnetic resonance images routinely acquired as part of the investigation of dementias, offer a practical, inexpensive means of improving diagnostic accuracy.
doi:10.1093/brain/aww005
PMCID: PMC4806219  PMID: 26936938
brain atrophy; dementia; MRI; neuropathology; visual rating
24.  Circadian Clock Control of Connexin36 Phosphorylation in Retinal Photoreceptors of the CBA/CaJ Mouse Strain 
Visual neuroscience  2015;32:E009.
The gap-junction-forming protein connexin36 (Cx36) represents the anatomical substrate of photoreceptor electrical coupling in mammals. The strength of coupling is directly correlated to the phosphorylation of Cx36 at 2 regulatory sites: Ser110 and Ser293. Our previous work demonstrated that the extent of biotinylated tracer coupling between photoreceptor cells, which provides an index of the extent of electrical coupling, depends on the mouse strain. In the C57Bl/6J strain, light or dopamine reduces tracer coupling and Cx36 phosphorylation in photoreceptors. Conversely, darkness or a dopaminergic antagonist increases tracer coupling and Cx36 phosphorylation, regardless of the time of day. In the CBA/CaJ strain, photoreceptor tracer coupling is regulated by light and dopamine, but also by a circadian clock, a type of oscillator with a period close to 24 h and intrinsic to the retina, so that under prolonged dark-adapted conditions tracer coupling is broader at night compared to daytime. In the current study, we examined whether the modulation of photoreceptor coupling by a circadian clock in CBA/CaJ mouse photoreceptors reflected a change in Cx36 protein expression and/or phosphorylation. We found no significant change in Cx36 expression or in the number of Cx36 gap junction among the conditions examined. However, we found that Cx36 phosphorylation is higher under dark-adapted conditions at night than in the daytime, and is the lowest under prolonged illumination at any time of the day/night cycle. Our observations are consistent with the view that the circadian clock regulation of photoreceptor electrical coupling is mouse strain-dependent and highlight the critical position of Cx36 phosphorylation in the control of photoreceptor coupling.
doi:10.1017/S0952523815000061
PMCID: PMC4760741  PMID: 26241696
retina; gap junction; electrical coupling; photoreceptors; circadian clock
25.  Resting state in Parkinson's disease dementia and dementia with Lewy bodies: commonalities and differences 
Objective
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are two dementias with overlapping phenotypes. Clinically, these are differentiated by the one‐year precedence rule between the onset of dementia with respect to Parkinsonism. In this report we aimed to find differences between DLB and PDD in functional connectivity (FC) using resting state functional magnetic resonance imaging, which we hypothesised would reflect the underlying pathological differences between DLB and PDD.
Methods
The study cohort comprised of 18 patients with DLB, 12 with PDD and 17 healthy control (HC) groups. Eight cortical and four subcortical seeds were chosen, and time series extracted to estimate correlation maps. We also implemented a voxel‐based morphometry (VBM) analysis to assess regional grey matter differences. FC analysis was corrected for age, sex and regional grey matter differences.
Results
The FC analysis showed greater alterations in DLB than in PDD for seeds placed within the fronto‐parietal network (FPN), whilst in contrast, for the supplementary motor area seed FC alterations were more apparent in PDD than in DLB. However, when comparing DLB and PDD, no significant differences were found. In addition, VBM analysis revealed greater atrophy in PDD than HC and DLB in the bilateral motor cortices and precuneus respectively.
Conclusions
PDD and DLB demonstrate similar FC alterations in the brain. However, attention‐ and motor‐related seeds revealed subtle differences between both conditions when compared with HC, which may relate to the neuropathology and chronological precedence of core symptoms in the Lewy body dementias. © 2015 The Authors International Journal of Geriatric Psychiatry Published by John Wiley & Sons, Ltd.
doi:10.1002/gps.4342
PMCID: PMC4737212  PMID: 26270627
default mode; cognitive fluctuations; attention; networks; fMRI

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