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Alzheimer’s disease (AD) is the most common major neurocognitive disorder of ageing. Although largely ignored until about a decade ago, accumulating evidence suggests that deteriorating brain energy metabolism plays a key role in the development and/or progression of AD-associated cognitive decline. Brain glucose hypometabolism is a well-established biomarker in AD but was mostly assumed to be a consequence of neuronal dysfunction and death. However, its presence in cognitively asymptomatic populations at higher risk of AD strongly suggests that it is actually a pre-symptomatic component in the development of AD. The question then arises as to whether progressive AD-related cognitive decline could be prevented or slowed down by correcting or bypassing this progressive ‘brain energy gap’. In this review, we provide an overview of research on brain glucose and ketone metabolism in AD and its prodromal condition – mild cognitive impairment (MCI) – to provide a clearer basis for proposing keto-therapeutics as a strategy for brain energy rescue in AD. We also discuss studies using ketogenic interventions and their impact on plasma ketone levels, brain energetics and cognitive performance in MCI and AD. Given that exercise has several overlapping metabolic effects with ketones, we propose that in combination these two approaches might be synergistic for brain health during ageing. As cause-and-effect relationships between the different hallmarks of AD are emerging, further research efforts should focus on optimising the efficacy, acceptability and accessibility of keto-therapeutics in AD and populations at risk of AD.
Autism spectrum disorder (ASD) remains a behaviourally defined condition. Its molecular basis is unknown; however, its prevalence has been increasing significantly. There have been several abnormalities in neurotransmitter systems reported in ASD. In our review, we described studies involving positron emission tomography (PET) and single-photon emission computed tomography (SPECT) that can provide useful and corroborative data.
We conducted a literature review by comprehensive database searching on EMBASE, Scopus, PubMed, and PsychINFO looking for articles published since January 2009. Thirty-one studies were carefully selected – 22 PET studies and 9 SPECT studies – and reviewed by 2 independent researchers. References of the articles were also cross-checked.
Results of the studies, which mainly involve small groups of participants, are frequently inconclusive and often controversial due to the nature of ASD and its wide spectrum. Studies are conducted under different conditions and with poor control for confounding factors which creates difficulties in comparing the data.
There is ongoing need to improve methodology of the studies involving molecular imaging in ASD. Lack of consistent findings causes difficulties in evaluation, diagnosis, and treatment of the condition.
Much of the extant work in the cognitive neurosciences of aging has focused on identifying the neural correlates of age-related declines in episodic memory and working memory. This chapter reviews evidence from human studies that speaks to the hypothesis that age-related dysfunctions in specific neurotransmitter systems play a critical role in cognitive decline. Based in large part on results from functional neuroimaging studies including positron emission tomography (PET) and pharmacological functional magnetic resonance imaging (fMRI), we conclude that there is emerging evidence that dysfunctions in the dopamine, noradrenaline, and cholinergic systems play a critical role in age-related cognitive decline of working memory and episodic memory. These conclusions are important and encourage further study in order to tailor interventions that preserve cognitive functions in older age via augmentation of neurotransmitter functions.
Neuroreceptor imaging has been used to examine dopamine function in schizophrenia. The evidence from PET and SPECT studies suggests that there is excess dopamine release subcortically, in the striatum, and that dopaminergic transmission may be abnormal in the cortex also, because of an upregulation in D1 receptors. We have found that patients with schizophrenia have higher subcortical levels of intrasynaptic dopamine (and have a greater proportion of D2 receptors occupied by dopamine) at baseline than controls. Those patients who had the highest levels of dopamine were the ones whose positive symptoms responded best to six weeks of treatment with an antipsychotic. Recent studies have also produced new evidence of dopaminergic disturbance in the cortex. When controls were compared with patients with schizophrenia, we found a significant increase in D1 receptors in patients, but only in the dorsolateral prefrontal cortex. Patients were also studied while they undertook a test of working memory. While there was no relationship between test performance and D1 binding potential for controls, those patients with the highest densities (most pathological levels) of D1 receptors performed the worst on the test. Both the D1 upregulation and the poor working memory may be secondary to a chronic, possibly neurodevelopmental deficit in dopamine innervation of the dorsolateral prefrontal cortex in schizophrenia. The D1 binding potential may prove to be a good biomarker with which to identify those patients suffering from schizophrenia who are most likely to benefit from treatment with a D1 agonist. A D1 receptor radiotracer that is sensitive to endogenous dopamine competition would be very valuable in the further exploration of this area.
Personality has been correlated with differences in cytokine expression, an indicator of peripheral inflammation; however, the associations between personality and central markers of inflammation have never been investigated in vivo in humans. Microglia are the resident macrophages of the central nervous system, and the first responders to tissue damage and brain insult. Microglial activation is associated with elevated expression of translocator protein 18kDa (TSPO), which can be imaged with positron emission tomography (PET) to quantify immune activation in the human brain. This study aimed to investigate the association between personality and TSPO expression across the psychosis spectrum. A total of 61 high-resolution [18F]FEPPA PET scans were conducted in 28 individuals at clinical high risk (CHR) for psychosis, 19 First-Episode Psychosis (FEP), and 14 healthy volunteers (HVs), and analyzed using a two-tissue compartment model and plasma input function to obtain a total volume of distribution (VT) as an index of brain TSPO expression (controlling for the rs6971 TSPO polymorphism). Personality was assessed using the Revised NEO Personality Inventory (NEO-PI-R). We found TSPO expression to be specifically associated with neuroticism. A positive association between TSPO expression and neuroticism was found in HVs, in contrast to a nonsignificant, negative association in CHR and significant negative association in FEP. The TSPO-associated neuroticism trait indicates an unexplored connection between neuroimmune activation and personality that varies across the psychosis spectrum.
We present the first results of the MINDVIEW project. An innovative imaging system for the human brain examination, allowing simultaneous acquisition of PET/MRI images, has been designed and constructed. It consists of a high sensitivity and high resolution PET scanner integrated in a novel, head-dedicated, radio frequency coil for a 3T MRI scanner. Preliminary measurements from the PET scanner show sensitivity 3 times higher than state-of-the-art PET systems that will allow safe repeated studies on the same patient. The achieved spatial resolution, close to 1 mm, will enable differentiation of relevant brain structures for schizophrenia. A cost-effective and simple method of radiopharmaceutical production from 11C-carbon monoxide and a mini-clean room has been demonstrated. It has been shown that 11C-raclopride has higher binding potential in a new VAAT null mutant mouse model of schizophrenia compared to wild type control animals. A significant reduction in TSPO binding has been found in gray matter in a small sample of drug-naïve, first episode psychosis patients, suggesting a reduced number or an altered function of immune cells in brain at early stage schizophrenia.
In this chapter, the rare yet critical pediatric surgical procedure of pancreatectomy for hyperinsulinism is reviewed. The pathophysiology and diagnostic approach for congenital hyperinsulinism is discussed. The author covers the surgical interventions and their related complex anesthetic management in these patients, particularly with regards to maintenance of glucose homeostasis. The preoperative evaluation, anesthetic implications and regional anesthetic considerations are presented for this complex disease process.
The past decade has seen a surge of reports and investigations into cases of autoimmune-mediated encephalitis. The increasing recognition of these disorders is especially of relevance to the fields of neurology and psychiatry. Autoimmune encephalitis involves antibodies against synaptic receptors, neuronal cell surface proteins and intracellular targets. These disorders feature prominent symptoms of cognitive impairment and behavioural changes, often associated with the presence of seizures. Early in the clinical course, autoimmune encephalitis may manifest as psychiatric symptoms of psychosis and involve psychiatry as an initial point of contact. Although commonly associated with malignancy, these disorders can present in the absence of an inciting neoplasm. The identification of autoimmune encephalitis is of clinical importance as a large proportion of individuals experience a response to immunotherapy. This review focuses on the current state of knowledge on n-methyl-d-aspartate (NMDA) receptor-associated encephalitis and limbic encephalitis, the latter predominantly involving antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, the γ-aminobutyric acid (GABA)B receptor and leucine-rich glioma-inactivated 1 (LGI1) protein. In addition, we briefly describe anti-dopamine D2 receptor encephalitis. A summary of the literature will focus on common clinical presentations and course, diagnostic approaches and response to treatment. Since a substantial proportion of patients with autoimmune encephalitis exhibit symptoms of psychosis, the relevance of this disorder to theories of psychosis and schizophrenia will also be discussed.
The co-occurrence of hepatic cystic echinococcosis (CE) and alveolar echinococcosis (AE) is extremely rare. Here, we present the clinical manifestations and treatment outcomes of three cases with co-occurring CE and AE in the liver. Computed tomography (CT), magnetic resonance imaging and 18FFluorodeoxyglucose Positron Emission Tomography-CT were used for preoperative diagnosis. Specimens were taken intraoperatively and sent for pathological studies to confirm the coexistence of CE and AE by laminated membrane, daughter cysts or germinal layer and infiltration structure. Albendazole was prescribed after operation for 12 months. All patients were completely recovered and showed no recurrence at last follow-up. Therefore, surgical intervention and postoperative application of albendazole are recommended for patients with concurrence of hepatic AE and CE.
Rationale: Presurgical localization of the epileptogenic focus is critical to successful surgery. Traditionally, localization of the epileptogenic focus depends on seizure semiology, scalp video-electroencephalography (vEEG), magnetic resonance imaging (MRI), neuropsychological assessment, and, when needed, intracranial EEG (iEEG). We aimed to explore the role of positron emission tomography (PET) in the presurgical evaluation of patients with refractory epilepsy. Methods: A retrospective review was conducted on patients from London Health Sciences Centre (London, Ontario) with refractory epilepsy who underwent PET from September of 2011 to April of 2016. The accuracy of epileptogenic focus localization was compared between different investigative modalities (MRI, vEEG, iEEG, PET), and the outcomes were documented, including seizure freedom after surgical resection, improvement of seizure frequency, guidance for further investigations, and exclusion of patients from further evaluation. Patients who underwent surgery were followed up at 3 months and onward. Results: We identified 62 patients with refractory epilepsy who underwent PET. The mean age was 34 years (range=20-68). A total of 36 had concordant PET and vEEG findings: 6 had surgical resection and either became seizure-free (29.4%) or had improvement in seizure frequency (5.9%) at 3 months; 11 had surgical resection and either became seizure-free (29.4%) or had improvement in seizure frequency (35.3%) at 3 months, but required iEEG for final verification. Conclusions: PET has an important role in presurgical evaluation of patients with refractory epilepsy. It may allow resection of the epileptogenic focus without the need for iEEG, guiding intracranial electrode placement for further localization of the epileptogenic focus, or exclusion of patients from further evaluation.
Currently it is estimated that about 1 billion people globally have non-alcoholic fatty liver disease (NAFLD), a condition in which liver fat exceeds 5 % of liver weight in the absence of significant alcohol intake. Due to the central role of the liver in metabolism, the prevalence of NAFLD is increasing in parallel with the prevalence of obesity, insulin resistance and other risk factors of metabolic diseases. However, the contribution of liver fat to the risk of type 2 diabetes mellitus and CVD, relative to other ectopic fat depots and to other risk markers, is unclear. Various studies have suggested that the accumulation of liver fat can be reduced or prevented via dietary changes. However, the amount of liver fat reduction that would be physiologically relevant, and the timeframes and dose–effect relationships for achieving this through different diet-based approaches, are unclear. Also, it is still uncertain whether the changes in liver fat per se or the associated metabolic changes are relevant. Furthermore, the methods available to measure liver fat, or even individual fatty acids, differ in sensitivity and reliability. The present report summarises key messages of presentations from different experts and related discussions from a workshop intended to capture current views and research gaps relating to the points above.
Objectives: We examined florbetapir positron emission tomography (PET) amyloid scans across stages of preclinical Alzheimer’s disease (AD) in cortical, allocortical, and subcortical regions. Stages were characterized using empirically defined methods. Methods: A total of 312 cognitively normal Alzheimer’s Disease Neuroimaging Initiative participants completed a neuropsychological assessment and florbetapir PET scan. Participants were classified into stages of preclinical AD using (1) a novel approach based on the number of abnormal biomarkers/cognitive markers each individual possessed, and (2) National Institute on Aging and the Alzheimer’s Association (NIA-AA) criteria. Preclinical AD groups were compared to one another and to a mild cognitive impairment (MCI) sample on florbetapir standardized uptake value ratios (SUVRs) in cortical and allocortical/subcortical regions of interest (ROIs). Results: Amyloid deposition increased across stages of preclinical AD in all cortical ROIs, with SUVRs in the later stages reaching levels seen in MCI. Several subcortical areas showed a pattern of results similar to the cortical regions; however, SUVRs in the hippocampus, pallidum, and thalamus largely did not differ across stages of preclinical AD. Conclusions: Substantial amyloid accumulation in cortical areas has already occurred before one meets criteria for a clinical diagnosis. Potential explanations for the unexpected pattern of results in some allocortical/subcortical ROIs include lack of correspondence between (1) cerebrospinal fluid and florbetapir PET measures of amyloid, or between (2) subcortical florbetapir PET SUVRs and underlying neuropathology. Findings support the utility of our novel method for staging preclinical AD. By combining imaging biomarkers with detailed cognitive assessment to better characterize preclinical AD, we can advance our understanding of who is at risk for future progression. (JINS, 2016, 22, 978–990)
To review our experience of managing patients with a dual diagnosis of metastatic cutaneous squamous cell carcinoma in the head and neck region and low-grade non-Hodgkin lymphoma. The secondary aim was to evaluate the utility of 18F-fluorodeoxyglucose positron emission tomography during diagnosis.
Patients diagnosed with metastatic cutaneous squamous cell carcinoma of the head and neck and low-grade non-Hodgkin lymphoma, in a five-year period, were identified. Patient, tumour and treatment characteristics were identified. 18F-fluorodeoxyglucose positron emission tomography imaging was reviewed and correlated with histopathology findings.
Eight patients were identified. There was a delay in diagnosis of metastatic squamous cell carcinoma in two patients. 18F-fluorodeoxyglucose positron emission tomography differentiated metastatic squamous cell carcinoma from low-grade non-Hodgkin lymphoma with a sensitivity of 88.2 per cent and a specificity of 94.7 per cent. In 38 per cent of patients, compromises in management had to be made.
The management of metastatic squamous cell carcinoma can be challenging in patients with low-grade non-Hodgkin lymphoma. 18F-fluorodeoxyglucose positron emission tomography can be useful in the diagnosis of metastatic squamous cell carcinoma in patients with low-grade non-Hodgkin lymphoma.
The role of fludeoxyglucose F 18 positron emission tomography (PET) in the presurgical evaluation of patients with medically intractable epilepsy continues to be refined. The purpose of this study was to systematically review the literature to assess the diagnostic accuracy and utility of PET in this setting. Thirty-nine studies were identified through MEDLINE and EMBASE databases that met the inclusion criteria. In adult patients, PET hypometabolism showed a 56 to 90% agreement with seizure onset localized by intracranial electroencephalogram (pediatric: 21 to 86%). In temporal lobe epilepsy patients with good surgical outcome, PET displayed moderate to high sensitivity in localizing the seizure focus (range: 71 to 89%). The sensitivity increased by 8 to 23% when PET results were combined with magnetic resonance imaging or electroencephalogram. PET has been shown to affect patient management by improving the guidance of intracranial electrodes placement, altering the decision to perform surgery, or excluding patients from further evaluation.
Anisotropy and compositional and structural heterogeneity in clays are causes of considerable deviations from homogeneous diffusion, in particular in terms of direction-dependent transport rates and preferred transport zones. Conventional diffusion experiments, in which the sample is treated as a homogeneous black box in a concentration gradient, are interminable and insensitive to spatial effects. In contrast, tomographic imaging methods are capable of both reducing the amount of observation time required and revealing space-dependent features of the diffusion process.
In the present study, positron-emission-tomography (PET) was applied as the most sensitive quantitative spatiotemporal tomographic modality for direct observation of positron-emitting radiotracers in opaque media at reasonable resolution (1 mm) on a laboratory scale (100 mm).
Geoscientific applications of PET, or GeoPET, have revealed anisotropic and heterogeneous effects in diffusion experiments that have been conducted on Opalinus clay samples of different sizes, as well as on other rock types. Applying the Comsol Optimization Module to 2D-image sections of the PET tomograms, effective parameter values were derived, thereby quantifying the anisotropic diffusion.
Objective: The radiological and clinical significance of a dilated Virchow-Robin space (dVRS) in the striatum (STR) remains unclear. We investigated the role of dVRS in STR on parkinsonism and dopamine transporter positron emission tomography (DaT-PET) findings. Methods: Patients with parkinsonism who underwent both brain magnetic resonance imaging and DaT-PET were included. Clinical status was evaluated by Hoehn and Yahr (HY) stage, Korean-Mini Mental Status Examination (K-MMSE), Montreal Cognitive Assessment Korea (MoCA-K), and Frontal Assessment Battery (FAB). dVRS was assessed by semi-quantitative and quantitative scales in each of the three segments of STR (caudate nuclei, anterior and posterior putamen) and was expressed as a dVRS score. DaT-PET was qualitatively assessed as either normal or abnormal in each segment. The relationship between dVRS and DaT-PET abnormality (ab-DaT-PET) was designated in each segment as either concordant or discordant. A concordant segment was defined by the presence of dVRS with ab-DaT-PET [Concordance rate (CR)=number of concordant segments/number of concordant and discordant segments]. Results: Eleven patients were included. There was no significant correlation between the presence of dVRS and ab-DaT-PET. The mean CR was 0.39. CR was not significantly correlated with any clinical or neuroimaging scales. The dVRS score was significantly correlated with K-MMSE, MoCA-K, and FAB (r=−0.675, −0.847, and −0.868, respectively) but not with HY stage. Conclusion: dVRS in STR played no significant role on dopaminergic innervation revealed by DaT-PET and made little contribution to clinical parkinsonism; however, it was correlated with cognitive impairment.
Magnetic seizure therapy (MST), despite being in an early phase of clinical research, has been demonstrated to be associated with antidepressant efficacy. However, safety, tolerability and efficacy data in connection with functional brain activity from larger samples are lacking. The aim of this study was to determine clinical and cognitive effects of MST and the influence of MST on regional brain glucose metabolism.
Twenty-six patients suffering from treatment-resistant depression (TRD) underwent MST. Ten patients underwent a randomized trial and 16 patients an open-label study design. The primary outcome criterion was the severity of depressive symptoms assessed with the Hamilton Depression Rating Scale (HAMD). Depressive symptoms, tolerability and cognitive safety, along with social functioning and quality of life parameters, were assessed using various rating scales. A clinical follow-up visit 6 months following the completion of a course of MST and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans of 12 patients were analysed.
A significant response to MST was demonstrated by 69% of the patient sample, with 46% meeting remission criteria. Anxiety ratings were significantly reduced in responders and their quality of life was improved. Half of the responders relapsed within 6 months. No cognitive side-effects were observed. FDG-PET scans showed a metabolic increase in the frontal cortex bilaterally and a decrease in the left striatum.
Robust antidepressant and anti-anxiety efficacy of MST was demonstrated, and found to be associated with localized metabolic changes in brain areas that are strongly implicated in depression. Thus, MST presents an effective, well-tolerated and safe treatment option for patients unable to respond to other forms of therapy for depression.
Renal metastasis is relatively unusual in patients with differentiated thyroid carcinoma.
The clinicoradiological parameters of a series of patients with differentiated thyroid carcinoma and renal metastasis were assessed, together with follow-up data.
Results and conclusion:
The series comprised 4 male patients over the age of 45 years with extensive disease at the primary site. Retro-sternal extension of a large goitre was observed in three patients. The primary tumour was 4 cm or larger in all patients (range, 4–14 cm), and three patients had associated lymph node metastasis. None had any genito-urinary symptoms at presentation. Two patients had isolated renal metastases with no other distant metastases, while the others had extensive multi-organ involvement. The bilateral occurrence of lesions was a hallmark, being observed in all cases. Ultrasound-guided fine needle aspiration cytology and 131I scintigraphy were pivotal in confirming the diagnosis. Evidence of ‘flip-flop’ between 131I study and fluoro-deoxyglucose positron emission tomography was noted in one patient, while the other three demonstrated concordant lesions in both modalities. At a minimum follow-up period of four years after diagnosis, three patients demonstrated stable disease with radioiodine therapy, and one had expired due to a poorly differentiated lung carcinoma which developed subsequently.
Modafinil, a wake-promoting drug used to treat narcolepsy, is a dopamine transporter inhibitor and is said to have very low abuse liability; this, however, is still up for debate. We conducted a dopamine transporter (DAT) occupancy study with modafinil (200 or 300 mg) in ten healthy volunteers using positron emission tomography (PET) with [18F]FE-PE2I, a new PET radioligand with high affinity and selectivity for the dopamine transporter, to characterize its relation to abuse liability. Mean striatal DAT occupancies were 51.4% at 200 mg and 56.9% at 300 mg. There was a significant correlation between occupancy and plasma concentration, indicating dose dependency of DAT inhibition by modafinil in the striatum, and especially in the nucleus accumbens. This study showed that DAT occupancy by modafinil was close to that of methylphenidate, indicating that modafinil may be near the same level as methylphenidate in relation to abuse liability in terms of dopaminergic transmission.