Search

Symptomatic brainstem compression from vertebral artery dolichoectasia is rare. There are no recognised diagnostic or treatment criteria to guide management of this disease. We report a case of medullary compression and cerebral ischaemia from an enlarged and tortuous vertebral artery. Our patient developed progressive dysphonia and dysphagia. Cerebral MRI revealed compression of the medulla oblongata by a right ectatic vertebral artery and a right occipital lobe infarct. Other causes of bulbar dysfunction were ruled out. He was treated with anticoagulation and underwent percutaneous endoscopic gastrostomy. We review selected literature on the presentation, diagnosis and management of this rare neurologic condition., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Clearance of amyloid-β (Aβ) from the brain is hypothesized to be mediated by the glymphatic system through aquaporin-4 (AQP4) water channels. Genetic variation of AQP4 may impact water channel function, Aβ clearance, and clinical outcomes. We examined whether single-nucleotide polymorphisms (SNPs) of the AQP4 gene were related to Aβ neuropathology on [ 18 F]Florbetapir PET in 100 Aβ positive late mild cognitive impairment (LMCI) or Alzheimer's disease (AD) patients and were predictive of clinical outcome in prodromal AD patients. AQP4 SNP rs72878794 was associated with decreased Aβ uptake, whereas rs151244 was associated with increased Aβ uptake, increased risk of conversion from MCI and LMCI to AD, and an increased 4-year rate of cognitive decline in LMCI. AQP4 genetic variation was associated with Aβ accumulation, disease stage progression, and cognitive decline. This variation may correspond to changes in glymphatic system functioning and brain Aβ clearance and could be a useful biomarker in predicting disease burden for those on the dementia spectrum., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: We evaluated myelin changes throughout the central nervous system in Multiple Sclerosis (MS) patients by using hybrid [ 18 F]florbetapir PET-MR imaging., Methods: We included 18 relapsing-remitting MS patients and 12 healthy controls. Each subject performed a hybrid [ 18 F]florbetapir PET-MR and both a clinical and cognitive assessment. [ 18 F]florbetapir binding was measured as distribution volume ratio (DVR), through the Logan graphical reference method and the supervised cluster analysis to extract a reference region, and standard uptake value (SUV) in the 70-90 min interval after injection. The two quantification approaches were compared. We also evaluated changes in the measures derived from diffusion tensor imaging and arterial spin labeling., Results: [ 18 F]florbetapir DVRs decreased from normal-appearing white matter to the centre of T2 lesion (P < 0.001), correlated with fractional anisotropy and with mean, axial and radial diffusivity within T2 lesions (coeff. = -0.15, P < 0.001, coeff. = -0.12, P < 0.001 and coeff. = -0.16, P < 0.001, respectively). Cerebral blood flow was reduced in white matter damaged areas compared to white matter in healthy controls (-10.9%, P = 0.005). SUV 70-90 and DVR are equally able to discriminate between intact and damaged myelin (area under the curve 0.76 and 0.66, respectively; P = 0.26)., Conclusion: Our findings demonstrate that [ 18 F]florbetapir PET imaging can measure in-vivo myelin damage in patients with MS. Demyelination in MS is not restricted to lesions detected through conventional MRI but also involves the normal appearing white matter. Although longitudinal studies are needed, [ 18 F]florbetapir PET imaging may have a role in clinical settings in the management of MS patients.

Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disease for which there is no cure. Mild cognitive impairment (MCI) is considered a prodromal stage of the disease. Molecular imaging with positron emission tomography (PET) allows for the in vivo visualisation and tracking of pathophysiological changes in AD and MCI. PET is a very promising methodology for differential diagnosis and novel targets of PET imaging might also serve as biomarkers for disease-modifying therapeutic interventions. This review provides an overview of the current status and applications of in vivo molecular imaging of AD pathology, specifically amyloid, tau, and microglial activation. PET imaging studies were included and evaluated as potential biomarkers and for monitoring disease progression. Although the majority of radiotracers showed the ability to discriminate AD and MCI patients from healthy controls, they had various limitations that prevent the recommendation of a single technique or tracer as an optimal biomarker. Newer research examining amyloid, tau, and microglial PET imaging in combination suggest an alternative approach in studying the disease process., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Astroglia are multifunctional cells that regulate neuroinflammation and maintain homeostasis within the brain. Astroglial α-synuclein-positive cytoplasmic accumulations have been shown post-mortem in patients with Parkinson's disease and therefore astroglia may play an important role in the initiation and progression of Parkinson's disease. Imidazoline 2 binding sites are expressed on activated astroglia in the cortex, hippocampus, basal ganglia and brainstem; therefore, by measuring imidazoline 2 binding site levels we can indirectly evaluate astrogliosis in patients with Parkinson's disease. Here, we aimed to evaluate the role of astroglia activation in vivo in patients with Parkinson's disease using 11C-BU99008 PET, a novel radioligand with high specificity and selectivity for imidazoline 2 binding sites. Twenty-two patients with Parkinson's disease and 14 healthy control subjects underwent 3 T MRI and a 120-min 11C-BU99008 PET scan with volume of distribution (VT) estimated using a two-tissue compartmental model with a metabolite corrected arterial plasma input function. Parkinson's disease patients were stratified into early (n = 8) and moderate/advanced (n = 14) groups according to disease stage. In early Parkinson's disease, increased 11C-BU99008 VT uptake was observed in frontal (P = 0.022), temporal (P = 0.02), parietal (P = 0.026) and occipital (P = 0.047) cortical regions compared with healthy controls. The greatest 11C-BU99008 VT increase in patients with early Parkinson's disease was observed in the brainstem (52%; P = 0.018). In patients with moderate/advanced Parkinson's disease, loss of 11C-BU99008 VT was observed across frontal (P = 0.002), temporal (P < 0.001), parietal (P = 0.039), occipital (P = 0.024), and insula (P < 0.001) cortices; and in the subcortical regions of caudate (P < 0.001), putamen (P < 0.001) and thalamus (P < 0.001); and in the brainstem (P = 0.018) compared with healthy controls. In patients with Parkinson's disease, loss of 11C-BU99008 VT in cortical regions, striatum, thalamus and brainstem correlated with longer disease duration (P < 0.05) and higher disease burden scores, measured with Movement Disorder Society Unified Parkinson's Disease Rating Scale (P < 0.05). In the subgroup of patients with moderate/advanced Parkinson's disease, loss of 11C-BU99008 VT in the frontal (r = 0.79; P = 0.001), temporal (r = 0.74; P = 0.002) and parietal (r = 0.89; P < 0.001) cortex correlated with global cognitive impairment. This study demonstrates in vivo the role of astroglia in the initiation and progression of Parkinson's disease. Reactive astroglia observed early in Parkinson's disease could reflect a neuroprotective compensatory mechanisms and pro-inflammatory upregulation in response to α-synuclein accumulation. However, as the disease progresses and significant neurodegeneration occurs, astroglia lose their reactive function and such loss in the cortex has clinical relevance in the development of cognitive impairment., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Because of the highly penetrant gene mutation and clinical features consistent with idiopathic Parkinson's disease, carriers of the autosomal dominant Ala53Thr (A53T; 209G→A) point mutation in the α-synuclein (SNCA) gene are an ideal population to study the premotor phase and evolution of Parkinson's pathology. Given the known neurochemical changes in the serotonergic system and their association with symptoms of Parkinson's disease, we hypothesised that carriers of the A53T SNCA mutation might show abnormalities in the serotonergic neurotransmitter system before the diagnosis of Parkinson's disease, and that this pathology might be associated with measures of Parkinson's burden., Methods: In this cross-sectional study, we recruited carriers of the A53T SNCA mutation from specialist Movement Disorders clinics in Athens, Greece, and Salerno, Italy, and a cohort of healthy controls with no personal or family history of neurological or psychiatric disorders from London, UK (recruited via public advertisement) who were age matched to the A53T SNCA carriers. We also recruited one cohort of patients with idiopathic Parkinson's disease (cohort 1) from Movement Disorders clinics in London, UK, and retrieved data on a second cohort of such patients (cohort 2; n=40) who had been scanned with a different scanner. 7-day continuous recording of motor function was used to determine the Parkinson's disease status of the A53T carriers. To assess whether serotonergic abnormalities were present, we used [ 11 C]DASB PET non-displaceable binding to quantify serotonin transporter density. We constructed brain topographic maps reflecting Braak stages 1-6 and used these as seed maps to calculate [ 11 C]DASB non-displaceable binding potential in our cohort of A53T SNCA carriers. Additionally, all participants underwent a battery of clinical assessments to determine motor and non-motor symptoms and cognitive status, and [ 123 I]FP-CIT single-photon emission CT (SPECT) to assess striatal dopamine transporter binding and MRI for volumetric analyses to assess whether pathology is associated with measures of Parkinson's disease burden., Findings: Between Sept 1, 2016, and Sept 30, 2018, we recruited 14 A53T SNCA carriers, 25 healthy controls, and 25 patients with idiopathic Parkinson's disease. Seven (50%) of 14 A53T SCNA carriers were confirmed to have motor symptoms and confirmed to have Parkinson's disease, and the absence of motor symptoms was confirmed in seven (50%) A53T SCNA carriers (ie, premotor), in whom [ 123 I]FP-CIT SPECT confirmed the absence of striatal dopaminergic deficits. Compared with healthy controls, premotor A53T SNCA carriers showed loss of [ 11 C]DASB non-displaceable binding potential in the ventral (p<0·0001) and dorsal (p=0·0002) raphe nuclei, caudate (p=0·00015), putamen (p=0·036), thalamus (p=0·00074), hypothalamus (p<0·0001), amygdala (p=0·0041), and brainstem (p=0·046); and in A53T SNCA carriers with Parkinson's disease this loss was extended to the hippocampus (p=0·0051), anterior (p=0·022) and posterior cingulate (p=0·036), insula (p=0·0051), frontal (p=0·0016), parietal (p=0·019), temporal (p<0·0001), and occipital (p=0·0053) cortices. A53T SNCA carriers with Parkinson's disease showed a loss of striatal [ 123 I]FP-CIT-specific binding ratio compared with healthy controls (p<0·0001). Premotor A53T SNCA carriers had loss of [ 11 C]DASB non-displaceable binding potential in brain areas corresponding to Braak stages 1-3, whereas [ 11 C]DASB non-displaceable binding potential was largely preserved in areas corresponding to Braak stages 4-6. Except for one participant who was diagnosed with Parkinson's disease in the past year, all A53T SNCA carriers with Parkinson's disease had decreases in [ 11 C]DASB non-displaceable binding potential in brain areas corresponding to Braak stages 1-6. Decreases in [ 11 C]DASB non-displaceable binding potential in the brainstem were associated with increased Movement Disorder Score-Unified Parkinson's Disease Rating Scale total scores in all A53T SNCA carriers (r -0·66, 95% CI -0·88 to -0·20; p=0·0099), idiopathic Parkinson's disease cohort 1 (r -0·66, -0·84 to -0·36; p=0·00031), and idiopathic Parkinson's disease cohort 2 (r -0·71, -0·84 to -0·52; p<0·0001)., Interpretation: The presence of serotonergic pathology in premotor A53T SNCA carriers preceded development of dopaminergic pathology and motor symptoms and was associated with disease burden, highlighting the potential early role of serotonergic pathology in the progression of Parkinson's disease. Our findings provide evidence that molecular imaging of serotonin transporters could be used to visualise premotor pathology of Parkinson's disease in vivo. Future work might establish whether serotonin transporter imaging is suitable as an adjunctive tool for screening and monitoring progression for individuals at risk or patients with Parkinson's disease to complement dopaminergic imaging, or as a marker of Parkinson's burden in clinical trials., Funding: Lily Safra Hope Foundation and National Institute for Health Research (NIHR) Biomedical Research Centre at King's College London., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The underlying pathophysiology of dysphagia is multifactorial and evidence clarifying the precise mechanisms are scarce. Dysfunction in dopamine-related and non-dopamine-related pathways, changes in cortical networks related with swallowing and peripheral mechanisms have been implicated in the pathogenesis of dysphagia. We aimed at investigating whether dysphagia is associated with presynaptic dopaminergic deficits, faster motor symptom progression and cognitive decline in a population of early drug-naïve patients with Parkinson's disease., Methods: By exploring the database of Parkinson's Progression Markers Initiative we identified forty-nine early drug-naïve Parkinson's disease patients with dysphagia. Dysphagia was identified with SCOPA-AUT question 1 (answer regularly) and was assessed with MDS-UPDRS Part-II, Item 2.3 (Chewing and Swallowing). We compared Parkinson's disease patients with dysphagia to Parkinson's disease patients without dysphagia, and investigated differences in striatal [123I]FP-CIT single photon emission computed tomography levels. Using Cox proportional hazards analyses, we also evaluated whether dysphagia can predict motor deterioration and cognitive dysfunction., Results: Parkinson's disease patients with dysphagia, harbored a greater deterioration regarding motor and non-motor symptoms and decreased [123I]FP-CIT binding when compared with patients without dysphagia. Higher burden of dysphagia (MDS-UPDRS-II, item 2.3) was correlated with lower [123I]FP-CIT uptakes within the striatum (rs = -0.157; P = 0.002) and the caudate (rs = -0.156; P = 0.002). The presence of dysphagia was not a predictor of motor progression (Hazard ratio [HR]: 1.143, 95% confidence interval [CI]: 0.848-1.541; P = 0.379) or cognitive decline (HR: 1.294, 95% CI: 0.616-2.719; P = 0.496)., Conclusions: Dysphagia is associated with decreased presynaptic dopaminergic integrity within caudate and greater motor and non-motor symptoms burden in early drug-naïve PD., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: GP is a paid employee of F. Hoffmann-La Roche Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Research utilizing magnetic resonance imaging (MRI) has been crucial to the understanding of the neuropathological mechanisms behind and clinical identification of Alzheimer's disease (AD) and mild cognitive impairment (MCI). MRI modalities show patterns of brain damage that discriminate AD from other brain illnesses and brain abnormalities that are associated with risk of conversion to AD from MCI and other behavioural outcomes. This review discusses the application of various MRI techniques to and their clinical usefulness in AD and MCI. MRI modalities covered include structural MRI, diffusion tensor imaging (DTI), arterial spin labelling (ASL), magnetic resonance spectroscopy (MRS), and functional MRI (fMRI). There is much evidence supporting the validity of MRI as a biomarker for these disorders; however, only traditional structural imaging is currently recommended for routine use in clinical settings. Future research is needed to warrant the inclusion for more advanced MRI methodology in forthcoming revisions to diagnostic criteria for AD and MCI.

Lewy body dementia (DLB) is a common form of cognitive impairment, accounting for 30% of dementia cases in ages over 65 years. Early diagnosis of DLB has been challenging; particularly in the context of differentiation with Parkinson's disease dementia and other forms of dementias, such as Alzheimer's disease and rapidly progressive dementias. Current practice involves the use of [ 123 I]FP-CIT-SPECT, [ 18 F]FDG PET and [ 123 I]MIBG molecular imaging to support diagnostic procedures. Structural imaging techniques have an essential role for excluding structural causes, which could lead to a DLB-like phenotype, as well as aiding differential diagnosis through illustrating disease-specific patterns of atrophy. Novel PET molecular imaging modalities, such as amyloid and tau imaging, may provide further insights into DLB pathophysiology and may aid in early diagnosis. A multimodal approach, through combining various established techniques and possibly using novel radioligands, might further aid towards an in-depth understanding of this highly disabling disease. In this review, we will provide an overview of neuroimaging applications in patients with DLB.

Even before the success of combined positron emission tomography and computed tomography (PET/CT), the neuroimaging community was conceiving the idea to integrate the positron emission tomography (PET), with very high molecular quantitative data but low spatial resolution, and magnetic resonance imaging (MRI), with high spatial resolution. Several technical limitations have delayed the use of a hybrid scanner in neuroimaging studies, including the full integration of the PET detector ring within the MRI system, the optimization of data acquisition, and the implementation of reliable methods for PET attenuation, motion correction, and joint image reconstruction. To be valid and useful in clinical and research settings, this instrument should be able to simultaneously acquire PET and MRI, and generate quantitative parametric PET images comparable to PET-CT. While post hoc co-registration of combined PET and MRI data acquired separately became the most reliable technique for the generation of "fused" PET-MRI images, only hybrid PET-MRI approach allows merging these measurements naturally and correlating them in a temporal manner. Furthermore, hybrid PET-MRI represents the most accurate tool to investigate in vivo the interplay between molecular and functional aspects of brain pathophysiology. Hybrid PET-MRI technology is still in the early stages in the movement disorders field, due to the limited availability of scanners with integrated optimized methodological models. This technology is ideally suited to investigate interactions between resting-state functional/arterial spin labeling MRI and [ 18 F]FDG PET glucose metabolism in the evaluation of the brain "hubs" particularly vulnerable to neurodegeneration, areas with a high degree of connectivity and associated with an efficient synaptic neurotransmission. In Parkinson's disease, hybrid PET-MRI is also the ideal instrument to deeper explore the relationship between resting-state functional MRI and dopamine release at [ 11 C]raclopride PET challenge, in the identification of early drug-naïve Parkinson's disease patients at higher risk of motor complications and in the evaluation of the efficacy of novel neuroprotective treatment able to restore at the same time the altered resting state and the release of dopamine. In this chapter, we discuss the key methodological aspects of hybrid PET-MRI; the evidence in movement disorders of the key resting-state functional and perfusion MRI; [ 18 F]FDG PET and [ 11 C]raclopride PET challenge studies; the potential advantages of using hybrid PET-MRI to investigate the pathophysiology of movement disorders and neurodegenerative diseases. Future directions of hybrid PET-MRI will be discussed alongside with up-to-date technological innovations on hybrid systems., (© 2019 Elsevier Inc. All rights reserved.)

Magnetic resonance imaging (MRI) is a non-invasive technique which can provide comprehensive, multi-parametric information on brain anatomy, function and metabolism. This chapter will give a brief introduction to the basic principles of MR and cover the evolution of image acquisition. Given the versatility of MR, a vast range of MR applications will be discussed, including structural, diffusion tensor, functional, perfusion and neuromelanin-sensitive imaging, as well as quantitative susceptibility mapping. This chapter will also cover methodological developments in MRI, including image analysis approaches that can be tailored according to experimental design or aims. The ultimate goal of this chapter is to equip readers with a fundamental understanding of the proficiencies and limitations of MR techniques and their corresponding analysis approaches., (© 2018 Elsevier Inc. All rights reserved.)

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, caused by expansion of the CAG repeat in the huntingtin gene. HD is characterized clinically by progressive motor, cognitive and neuropsychiatric symptoms. There are currently no disease modifying treatments available for HD, and there is a great need for biomarkers to monitor disease progression and identify new targets for therapeutic intervention. Neuroimaging techniques provide a powerful tool for assessing disease pathology and progression in premanifest stages, before the onset of overt motor symptoms. Structural magnetic resonance imaging (MRI) is non-invasive imaging techniques which have been employed to study structural and microstructural changes in premanifest and manifest HD gene carriers. This chapter described structural imaging techniques and analysis methods employed across HD MRI studies. Current evidence for structural MRI abnormalities in HD, and associations between atrophy, structural white matter changes, iron deposition and clinical performance are discussed; together with the use of structural MRI measures as a diagnostic tool, to assess longitudinal changes, and as potential biomarkers and endpoints for clinical trials., (© 2018 Elsevier Inc. All rights reserved.)

The detection of low density lipoprotein-4 (LRP4) antibodies in double seronegative (dSN) myasthenia gravis (MG) patients has provided new insights in the diagnosis and treatment of MG. However, there are limited data regarding the clinical presentation and treatment response in dSN MG patients with LRP4-antibodies. We present a case series of three Caucasian dSN MG patients with positive LRP4-antibodies sharing a common ethnic background that presented with isolated ocular symptoms (MGFA I). The demographic and clinical characteristics, the diagnostic work-up as well as the treatment response during a follow-up period of 12-24 months are described in detail. All patients were treated successfully with acetylcholinesterase inhibitors (AcheI) and prednisone with two exhibiting full remission of their symptoms, while the remaining exhibited mild residual diplopia. Notably, we documented no signs of generalized disease progression, while no patient required immunosuppressive treatment. In conclusion, the distinct clinical phenotype of our patients highlights the clinical relevance of screening for LRP4-antibodies in patients presenting with isolated ocular MG independent of age and gender, since it may lead to the timely diagnosis of MG and prompt initiation of effective therapy with ACheI and corticosteroids., (Copyright © 2014 Elsevier B.V. All rights reserved.)