Regional Glucose Metabolism Research Articles

78. Increased glucose metabolism during acute stress in emotional neural circuitry, assessed with FDG-PET, predicts airway inflammation and psychological symptoms in asthma

Although psychological stress contributes to frequency, severity, and burden of asthma symptoms, the role of the brain in the pathophysiology and treatment of this disease is unknown. To examine the neural mechanisms through which stress contributes to airway inflammation, asthmatic subjects high or low in chronic life stress underwent an acute stressor. [18F]Fluoro-deoxyglucose positron emission tomography (FDG-PET) was used to identify neural circuits active during performance of a social stress task or a matched control condition. Sputum was collected to assess markers of airway inflammation, including expression of genes in the IL-17 pathway, products of which can contribute to both inflammation and depression. Preliminary results indicate that, during an acute stressor, activation in the anterior and mid-cingulate cortex, as well as the inferior frontal gyrus is greater in those with high vs. low chronic stress. These increases in regional glucose metabolism also predicted increased gene expression in the IL-17 pathway, as well as symptoms of anxiety and depression. Moreover, those subjects high in chronic stress showed increased gene expression in the IL-17 pathway following an acute stressor, as well as increased symptoms of anxiety and depression, relative to those with low chronic stress levels. These data suggest potential neural pathways through which psychological stress may influence airway inflammation, thus leading to an increase in asthma symptoms, disease severity, and uncovering novel targets for future treatment.

Anesthetic effects of propofol in the healthy human brain: functional imaging evidence.

Functional imaging methods, including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), have become important tools for studying how anesthetic drugs act in the human brain to induce the state of general anesthesia. Recent imaging studies using fMRI and PET techniques have demonstrated the regional effects of propofol on the brain. However, the pharmacological mechanism of the action of propofol in the intact human central nervous system is unclear. To explore the possible action targets of propofol in the human brain, a systematic review of the literature was performed. The literature search was performed with limiting factors of "propofol," "functional imaging," "positron emission tomography", and "functional magnetic resonance imaging" from 1966 to July 2013 (using Medline, EMBASE, CINAHL and hand searches of references). Studies meeting the inclusion criteria were reviewed and critiqued for the purpose of this literature research. Eighteen researches meeting the inclusion criteria were reviewed in terms of the appropriateness of valuation technique. In the unconscious state, propofol sharply reduces the regional glucose metabolism rate (rGMR) and regional cerebral blood flow (rCBF) in all brain regions, particularly in the thalamus. However, GMR, such as in the occipital, temporal, and frontal lobes, was obviously decreased at a sedative dosage of propofol, whereas, changes in the thalamus were not obvious. Using fMRI, several studies observed a decrease of connectivity of the thalamus versus an increase of connectivity within the pons of the brainstem during propofol-induced mild sedation. During deep sedation, propofol preserves cortical sensory reactivity, the specific thalamocortical network is moderately affected, whereas the nonspecific thalamocortical network is severely suppressed. In contrast, several recent fMRI studies are consistent on the systemic decreased effects of propofol in the frontoparietal network. Accumulating evidence suggest that propofol-induced unconsciousness is associated with a global metabolic and vascular depression in the human brain and especially with a significant reduction in the thalamocortical network and the frontoparietal network.

Regional cerebral glucose metabolism and gait speed in healthy community-dwelling older women.

The objective of this study was to investigate the relationship between normalized regional cerebral metabolic rates of glucose (normalized-rCMRglc) and gait function in physically and mentally high-functioning older women. One hundred eighty-two community-dwelling older women (mean age [SD], 69.4 [6.6] years) without disability in instrumental activities of daily living and without mobility limitations underwent positron emission tomography with 18F-fluorodeoxyglucose at rest to assess brain activity associated with gait function. We measured normalized-rCMRglc in 16 regions of interest. Within 6 months of the positron emission tomography with 18F-fluorodeoxyglucose scan, gait speed, step length, and step frequency both at comfortable and maximum paces were measured as indices of gait function. Associations between normalized-rCMRglc and gait indices were examined with multiple linear regression analyses adjusted for demographic characteristics, including age, height, body weight, blood pressure, past illness, and education. Slower maximum gait speed even in the range of individual difference was associated with lower normalized-rCMRglc in the prefrontal, posterior cingulate, and parietal cortices. Lower step frequency at the maximum pace was also associated with lower normalized-rCMRglc in these regions. However, there was no significant association between step length at the maximum pace and normalized-rCMRglc or between all gait variables at a comfortable pace and normalized-rCMRglc. The normalized-rCMRglc values in specific regions were associated with individual differences in gait function, even in healthy older women. These regions of the cerebrum could play an important role in gait control. Understanding the cerebral glucose metabolism in these brain regions may enable early detection of mobility limitation.

An evaluation of MSDC-0160, a prototype mTOT modulating insulin sensitizer, in patients with mild Alzheimer's disease.

Alzheimer’s disease (AD) is associated with insulin resistance and specific regional declines in cerebral metabolism. The effects of a novel mTOT modulating insulin sensitizer (MSDC-0160) were explored in non-diabetic patients with mild AD to determine whether treatment would impact glucose metabolism measured by FDG-PET in regions that decline in AD. MSDC-0160 (150 mg once daily; N=16) compared to placebo (N=13) for 12 weeks did not result in a significant difference in glucose metabolism in pre-defined regions when referenced to the pons or whole brain. However, glucose metabolism referenced to cerebellum was maintained in MSDC-0160 treated participants while it significantly declined for placebo patients in anterior and posterior cingulate, and parietal, lateral temporal, medial temporal cortices. Voxel-based analyses showed additional differences in FDG-PET related to MSDC-0160 treatment. These exploratory results suggest central effects of MSDC-0160 and provide a basis for further investigation of mTOT modulating insulin sensitizers in AD patients.

NEURONAL AND BEHAVIORAL SUBSTRATES OF ORIENTATION IN MILD COGNITIVE IMPAIRMENT AND ALZHEIMER'S DISEASE

We sought to examine neurocognitive, structural MRI, and PET glucose metabolism correlates of orientation in the context of Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD), the functional consequences of disorientation longitudinally, and the impact of orientation on conversion from MCI to AD. 473 MCI and AD participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) with yearly follow-ups were included. Regression analyses at baseline were conducted to find significant predictors of orientation (as measured through MMSE) among cognitive measures (memory, executive function, and speed of processing), brain morphometry measures, and regional glucose metabolism measures. Mixed model longitudinal analysis were performed to examine consequences of disorientation on functional decline, and Cox hazard models examined risk of conversion to AD in the MCI group according to orientation status over a four year period. Orientation was predicted by neurocognitive performance on memory measures (r 2 =0.21). Orientation was also predicted by entorhinal cortex thickness, hippocampal volume, and inferior temporal cortex thickness (r 2 =0.22). Glucose metabolism in middle-inferior temporal cortex and hippocampus was also found to be predictive of orientation (r 2 =0.21). Functional capacity systematically declined over four years of follow-up in disoriented individuals (p< 0.0001), while rate of conversion from MCI to AD was increased (hazard ratio =1.77, p= 0.001). Our findings provide convergent evidence that the neural substrate of orientation in MCI and AD include medial temporal lobe areas associated with episodic memory. Additionally, disorientation was associated with worse prognosis. These results also suggest that orientation is a useful surrogate for medial temporal function and episodic memory in clinical examinations.

Longitudinal Effects of Metabolic Syndrome on Alzheimer and Vascular Related Brain Pathology

Background/Aims: This study examines the longitudinal effect of metabolic syndrome (MetS) on brain-aging indices among cognitively normal (CN) and amnestic mild cognitive impairment (aMCI) groups [single-domain aMCI (saMCI) and multiple-domain aMCI (maMCI)]. Methods: The study population included 739 participants (CN = 226, saMCI = 275, and maMCI = 238) from the Alzheimer's Disease Neuroimaging Initiative, a clinic-based, multi-center prospective cohort. Confirmatory factor analysis was employed to determine a MetS latent composite score using baseline data of vascular risk factors. We examined the changes of two Alzheimer's disease (AD) biomarkers, namely [¹⁸F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) regions of interest and medial temporal lobe volume over 5 years. A cerebrovascular aging index, cerebral white matter (cWM) volume, was examined as a comparison. Results: The vascular risk was similar in all groups. Applying generalized estimating equation modeling, all brain-aging indices declined significantly over time. Higher MetS scores were associated with a faster decline of cWM in the CN and maMCI groups but with a slower decrement of regional glucose metabolism in FDG-PET in the saMCI and maMCI groups. Conclusion: At the very early stage of cognitive decline, the vascular burden such as MetS may be in parallel with or independent of AD pathology in contributing to cognitive impairment in terms of accelerating the disclosure of AD pathology.

Changes in behavior and in brain glucose metabolism in rats after nine weeks on a high fat diet: a randomized controlled trial.

BackgroundA high-fat diet (HFD) is a well-known risk factor for cardio-cerebrovascular disease but the relationship between a HFD and depressive symptoms remains unknown.ObjectiveCompare changes in behavioral and measures of brain glucose metabolism in rats fed a HFD to those of rats fed a standard diet.MethodsTwenty male Sprague-Dawley rats were randomly assigned to a study group (n=10) that received a high fat diet for 9 weeks or a control group (n=10) that received a standard diet for 9 weeks. At baseline and at the end of the 9-week trial assessments included body weight, serum lipids (total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), the sucrose preference test, and the open field test. The rate of brain glucose metabolism in different brain regions (assessed using micro-positron emission tomography) at the end of the trial was also compared between the two groups of rats.ResultsNine weeks of a HFD in rats resulted in the expected increase in weight and changes in serum lipid levels, but it was also associated with a decreased preference for sucrose (which may be due to a loss of interest in pleasurable activities), increased weight-adjusted water intake, and a significant deactivation of the right thalamus and right striatum (based on decreased rates of glucose metabolism). In the HFD group the magnitude of the drop in the sucrose preference was strongly correlated to the magnitude of the deactivation of the right thalamus (r=0.78) and the right striatum (r=0.81).ConclusionsThese findings support hypotheses about the role of a HFD in the causal pathway for depressive symptoms. Further work is needed to clarify the underling mechanism, but it appears that the interaction between the content of the diet and the limbic system-striatum-thalamus circuit plays a role in both eating behavior and depressive symptoms.

Limited agreement between biomarkers of neuronal injury at different stages of Alzheimer's disease

New diagnostic criteria for Alzheimer's disease (AD) treat different biomarkers of neuronal injury as equivalent. Here, we quantified the degree of agreement between hippocampal volume on structural magnetic resonance imaging, regional glucose metabolism on positron emission tomography, and levels of phosphorylated tau in cerebrospinal fluid (CSF) in 585 subjects from all phases of the AD Neuroimaging Initiative. The overall chance-corrected agreement was poor (Cohen κ, 0.24–0.34), in accord with a high rate of conflicting findings (26%–41%). Neither diagnosis nor APOE ε4 status significantly influenced the distribution of agreement between the biomarkers. The degree of agreement tended to be higher in individuals with abnormal versus normal CSF β-amyloid (Aβ1-42) levels. Prospective diagnostic criteria for AD should address the relative importance of markers of neuronal injury and elaborate a way of dealing with conflicting biomarker findings.

Long-term lithium treatment reduces glucose metabolism in the cerebellum and hippocampus of nondemented older adults: an [¹⁸F]FDG-PET study.

Lithium modulates several intracellular pathways related to neuroplasticity and resilience against neuronal injury. These properties have been consistently reported in experimental models, and involve the up-regulation of neurotrophic response and autophagy, and down-regulation of apoptosis, oxidative stress, and inflammation. Clinical and epidemiological studies in bipolar disorder show that acute treatment with lithium increases plasma concentrations of brain-derived neurotrophic factor, and long-term treatment lowers the risk of dementia. Neuroimaging studies indicate that lithium use is further associated with increased cortical thickness and larger hippocampal volumes. The objective of the present study was to evaluate whether these neurobiological properties of lithium reflect in increased regional brain glucose metabolism, as shown by [(18)F]FDG-PET. Participants (n = 19) were nondemented older adults recruited at the end point of a controlled trial addressing clinical and biological effects of lithium in a sample of patients with amnestic mild cognitive impairment. Twelve patients who had received low-dose lithium carbonate for 4 years were compared to seven matched controls. Chronic lithium treatment was not associated with any significant increase in brain glucose metabolism in the studied areas. Conversely, we found a significant reduction in glucose uptake in several clusters of the cerebellum and in both hippocampi. These findings were not associated with any clinical evidence of toxicity. The clinical implications of the present findings need to be clarified by future controlled studies, particularly in the light of the potential use of lithium as a disease-modifying treatment approach for certain neurodegenerative disorders, namely, Alzheimer's disease and amyotrophic lateral sclerosis.

PET imaging reveals brain functional changes in internet gaming disorder.

Internet gaming disorder is an increasing problem worldwide, resulting in critical academic, social, and occupational impairment. However, the neurobiological mechanism of internet gaming disorder remains unknown. The aim of this study is to assess brain dopamine D2 (D2)/Serotonin 2A (5-HT2A) receptor function and glucose metabolism in the same subjects by positron emission tomography (PET) imaging approach, and investigate whether the correlation exists between D2 receptor and glucose metabolism. Twelve drug-naive adult males who met criteria for internet gaming disorder and 14 matched controls were studied with PET and (11)C-N-methylspiperone ((11)C-NMSP) to assess the availability of D2/5-HT2A receptors and with (18)F-fluoro-D-glucose ((18)F-FDG) to assess regional brain glucose metabolism, a marker of brain function. (11)C-NMSP and (18)F-FDG PET imaging data were acquired in the same individuals under both resting and internet gaming task states. In internet gaming disorder subjects, a significant decrease in glucose metabolism was observed in the prefrontal, temporal, and limbic systems. Dysregulation of D2 receptors was observed in the striatum, and was correlated to years of overuse. A low level of D2 receptors in the striatum was significantly associated with decreased glucose metabolism in the orbitofrontal cortex. For the first time, we report the evidence that D2 receptor level is significantly associated with glucose metabolism in the same individuals with internet gaming disorder, which indicates that D2/5-HT2A receptor-mediated dysregulation of the orbitofrontal cortex could underlie a mechanism for loss of control and compulsive behavior in internet gaming disorder subjects.

Device for simultaneous positron emission tomography, laser speckle imaging and RGB reflectometry: Validation and application to cortical spreading depression and brain ischemia in rats

Brain function critically relies on the supply with energy substrates (oxygen and glucose) via blood flow. Alterations in energy demand as during neuronal activation induce dynamic changes in substrate fluxes and blood flow. To study the complex system that regulates cerebral metabolism requires the combination of methods for the simultaneous assessment of multiple parameters. We developed a multimodal imaging device to combine positron emission tomography (PET) with laser speckle imaging (LSI) and RGB reflectometry (RGBR). Depending on the radiotracer, PET provides 3-dimensional quantitative information of specific molecular processes, while LSI and RGBR measure cerebral blood flow (CBF) and hemoglobin oxygenation at high temporal and spatial resolution. We first tested the functional capability of each modality within our system and showed that interference between the modalities is negligible. We then cross-calibrated the system by simultaneously measuring absolute CBF using 15O-H2O PET (CBFPET) and the inverse correlation time (ICT), the LSI surrogate for CBF. ICT and CBFPET correlated in multiple measurements in individuals as well as across different animals (R2=0.87, n=44 measurements) indicating that ICT can be used for absolute quantitative assessment of CBF. To demonstrate the potential of the combined system, we applied it to cortical spreading depression (CSD), a wave of transient cellular depolarization that served here as a model system for neurovascular and neurometabolic coupling. We analyzed time courses of hemoglobin oxygenation and CBF alterations coupled to CSD, and simultaneously measured regional uptake of 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) used as a radiotracer for regional glucose metabolism, in response to a single CSD and to a cluster of CSD waves. With this unique combination, we characterized the changes in cerebral metabolic rate of oxygen (CMRO2) in real-time and showed a correlation between 18F-FDG uptake and the number of CSD waves that passed the local tissue. Finally, we examined CSD spontaneously occurring during focal ischemia also referred to as peri-infarct depolarization (PID). In the vicinity of the ischemic territory, we observed PIDs that were characterized by reduced CMRO2 and increased oxygen extraction fraction (OEF), indicating a limitation of oxygen supply. Simultaneously measured PET showed an increased 18F-FDG uptake in these regions. Our combined system proved to be a novel tool for the simultaneous study of dynamic spatiotemporal alterations of cortical blood flow, oxygen metabolism and glucose consumption under normal and pathologic conditions.

Differential Diagnosis of Neurodegenerative Dementias Using Metabolic Phenotypes on F-18 FDG PET/CT

Positron emission tomography (PET) imaging with F-18 fluorodeoxyglucose (FDG) can be used as a downstream marker of neuronal injury, a hallmark of neurodegenerative dementias. Characteristic patterns of regional glucose metabolism have been used to classify the dementia subtypes, namely Alzheimer's dementia (AD), frontotemporal dementia (FTD), diffuse Lewy body (DLBD) and vascular dementia (VD). We undertook this study to assess the utility of FDG-PET in the differential diagnosis of dementia subtypes. One hundred and twenty-five patients diagnosed with dementia were referred from cognitive disorders and memory clinics of speciality neurology centres for the FDG-PET study. Imaging-based diagnosis of dementia type was established in 101 patients by visual assessment of individual scans by a PET physician blinded to the clinical diagnosis. The results were compared with an 18-month follow-up clinical assessment made by the specialist neurologist. Concordance of visual evaluation of FDG-PET scans with clinical diagnosis of the dementia type was achieved in 90% of patients scanned. This concordance was 93.4% for AD, 88.8% for FTD, 66.6% for DLBD and 92.3% for the other dementia syndromes. FDG-PET performed after the initial work-up of dementias is useful for supporting the clinical diagnosis of dementia subtype.

A Rat Model of Photothrombotic Capsular Infarct with a Marked Motor Deficit: A Behavioral, Histologic, and microPET Study

We present a new method for inducing a circumscribed subcortical capsular infarct (SCI), which imposes a persistent motor impairment in rats. Photothrombotic destruction of the internal capsule (IC) was conducted in Sprague Dawley rats (male; n=38). The motor performance of all animals was assessed using forelimb placing, forelimb use asymmetry, and the single pellet reaching test. On the basis of the degree of motor recovery, rats were subdivided into either the poor recovery group (PRG) or the moderate recovery group (MRG). Imaging assessment of the impact of SCI on brain metabolism was performed using 2-deoxy-2-[(18)F]-fluoro-D-glucose ([(18)F]-FDG) microPET (positron emission tomography). Photothrombotic lesioning using low light energy selectively disrupted circumscribed capsular fibers. The MRG showed recovery of motor performance after 1 week, but the PRG showed a persistent motor impairment for >3 weeks. Damage to the posterior limb of the IC (PLIC) is more effective for producing a severe motor deficit. Analysis of PET data revealed decreased regional glucose metabolism in the ipsilesional motor and bilateral sensory cortex and increased metabolism in the contralesional motor cortex and bilateral hippocampus during the early recovery period after SCI. Behavioral, histologic, and functional imaging findings support the usefulness of this novel SCI rat model for investigating motor recovery.

Gender Differences of Brain Glucose Metabolic Networks Revealed by FDG-PET: Evidence from a Large Cohort of 400 Young Adults

BackgroundGender differences of the human brain are an important issue in neuroscience research. In recent years, an increasing amount of evidence has been gathered from noninvasive neuroimaging studies supporting a sexual dimorphism of the human brain. However, there is a lack of imaging studies on gender differences of brain metabolic networks based on a large population sample.Materials and MethodsFDG PET data of 400 right-handed, healthy subjects, including 200 females (age: 25∼45 years, mean age±SD: 40.9±3.9 years) and 200 age-matched males were obtained and analyzed in the present study. We first investigated the regional differences of brain glucose metabolism between genders using a voxel-based two-sample t-test analysis. Subsequently, we investigated the gender differences of the metabolic networks. Sixteen metabolic covariance networks using seed-based correlation were analyzed. Seven regions showing significant regional metabolic differences between genders, and nine regions conventionally used in the resting-state network studies were selected as regions-of-interest. Permutation tests were used for comparing within- and between-network connectivity between genders.ResultsCompared with the males, females showed higher metabolism in the posterior part and lower metabolism in the anterior part of the brain. Moreover, there were widely distributed patterns of the metabolic networks in the human brain. In addition, significant gender differences within and between brain glucose metabolic networks were revealed in the present study.ConclusionThis study provides solid data that reveal gender differences in regional brain glucose metabolism and brain glucose metabolic networks. These observations might contribute to the better understanding of the gender differences in human brain functions, and suggest that gender should be included as a covariate when designing experiments and explaining results of brain glucose metabolic networks in the control and experimental individuals or patients.

Central correlation of muscle sympathetic nerve activation during baroreflex unloading – a microneurography–positron emission tomography study

The baroreceptor reflex controls spontaneous fluctuations in blood pressure. One major control variable of the baroreflex is the sympathetic vasoconstrictor activity to muscles [MSNA; burst frequency (BF) and burst incidence (BI)], which can be quantitatively assessed by microneurography. We aimed to investigate the central regions involved in baroreflex regulation of MSNA. Healthy men (mean age 25 years) participated in three experimental sessions. (i) Microneurography recordings of MSNA from the left peroneal nerve during rest and baroreflex unloading, induced by lower body negative pressure (LBNP; -40 mmHg). If MSNA could be reliably recorded throughout this procedure (n = 15), the subjects entered the positron emission tomography (PET) experiments. The two PET sessions took place in a randomised order. Cerebral glucose metabolism (18-fluorodeoxyglucose) was analysed after: (ii) baroreflex unloading (LBNP); and (iii) control condition (lying in the LBNP chamber without suction). The PET data were analysed employing SPM8. LBNP elicited a significant increase in MSNA in all successfully recorded subjects (BI: P = 0.001; F = 5.54; BF: P < 0.001; F = 36.59). As compared with the control condition, LBNP was associated with increased PET regional glucose metabolism bilaterally in the orbitofrontal cortex (OFC; BA 11, 47). Related to the rise of BF, there was increased activation of the left OFC (BA 11); related to the rise of BI there was increased activation of the brainstem corresponding to the rostral ventrolateral medulla. Our data support a role for the ventrolateral medulla and the OFC in baroreflex-mediated control of MSNA in humans.

Cerebral Blood Flow and Glucose Metabolism in Appetite-Related Brain Regions in Type 1 Diabetic Patients After Treatment With Insulin Detemir and NPH Insulin

OBJECTIVETo test the hypothesis that insulin detemir, which is associated with less weight gain than other basal insulin formulations, exerts its weight-modulating effects by acting on brain regions involved in appetite regulation, as represented by altered cerebral blood flow (CBF) or cerebral glucose metabolism (CMRglu).RESEARCH DESIGN AND METHODSTwenty-eight male type 1 diabetic patients (age 36.9 ± 9.7 years, BMI 24.9 ± 2.7 kg/m2, A1C 7.5 ± 0.6%) successfully completed a randomized crossover study, consisting of two periods of 12-week treatment with either insulin detemir or NPH insulin, both in combination with prandial insulin aspart. After each treatment period, patients underwent positron emission tomography scans to measure regional CBF and CMRglu.RESULTSAfter 12 weeks, A1C, daily insulin doses, fasting insulin, and blood glucose levels were similar between treatments. Insulin detemir resulted in body weight loss, whereas NPH insulin induced weight gain (between-treatment difference 1.3 kg; P = 0.02). After treatment with insulin detemir relative to NPH insulin, CBF was higher in brain regions involved in appetite regulation, whereas no significant difference in CMRglu was observed.CONCLUSIONSTreatment with insulin detemir versus NPH insulin resulted in weight loss, paralleled by increased CBF in appetite-related brain regions in the resting state, in men with well-controlled type 1 diabetes. These findings lend support to the hypothesis that a differential effect on the brain may contribute to the consistently observed weight-sparing effect of insulin detemir.

Neural correlates of cognitive dysfunction in Lewy body diseases and tauopathies: Combined assessment with FDG-PET and the CERAD test battery

We investigated disease-specific cognitive profiles and their neural correlates in Lewy-body diseases (LBD) and tauopathies by CERAD assessment and FDG-PET. Analyses revealed a significant interaction between reduced semantic fluency in tauopathies and impaired verbal learning in LBD. Semantic fluency discriminated between groups with high accuracy (83%). Compared to LBD, tauopathy patients showed bilateral hypometabolism of midbrain, thalamus, middle cingulate gyrus and supplementary motor/premotor cortex. In the reverse contrast, LBD patients exhibited bilateral hypometabolism in posterior parietal cortex, precuneus and inferior temporal gyrus extending into occipital and frontal cortices. In diagnosis-independent voxel-based analyses, verbal learning/memory correlated with left temporal and right parietal metabolism, while fluency was coupled to bilateral striatal and frontal metabolism. Naming correlated with left frontal metabolism and drawing with metabolism in bilateral temporal and left frontal regions. In line with disease-specific patterns of regional glucose metabolism, tauopathies and LBD show distinct cognitive profiles, which may assist clinical differentiation.

Amyloid-β Load Predicts Medial Temporal Lobe Dysfunction in Alzheimer Dementia

Amyloid-β (Aβ) deposition is a pathologic hallmark of Alzheimer disease (AD). Although the typical spatial distribution pattern of Aβ deposition in early AD mainly involves regions distant from the hippocampus, the predominant clinical feature is impairment of hippocampus-dependent memory. We aimed at elucidating the relationship between neocortical Aβ load, regional neuronal function, and memory impairment. Thirty patients with early AD underwent combined (11)C-Pittsburgh compound B ((11)C-PIB) and (18)F-FDG PET and memory assessments. Composite measures of hemispheric Aβ load were calculated by volume-weighted mean values of neocortical (11)C-PIB binding. Voxelwise (18)F-FDG uptake was used as a measure of regional glucose metabolism reflecting neuronal activity. We investigated the relationship between left- and right-hemispheric Aβ load and regional glucose metabolism (voxelwise analyses). In addition, we assessed the correlations of hemispheric Aβ load (region-of-interest-based analyses) and regional glucose metabolism (voxelwise analysis) with memory performance. Analyses were corrected for age and sex. Higher Aβ load in the left hemisphere was associated with reduced glucose metabolism of the left medial temporal lobe (MTL; r(2) = 0.38) and correlated with worse wordlist recall (r = -0.37; partial correlation controlled for sex and age). Furthermore, wordlist recall correlated with regional glucose metabolism in the bilateral MTL and precuneus-posterior cingulate cortex and right lingual gyrus (r(2) = 0.24). We demonstrated an association between the left-hemispheric Aβ load and impairment of the left MTL in AD at 2 different levels: regional hypometabolism and verbal memory. This correlation suggests that neocortical amyloid deposition is connected to or even drives neuronal dysfunction and neurodegeneration of the MTL, which is associated with impaired episodic memory processing as a clinical core symptom of AD.

Neural correlates of free T3 alteration after catecholamine depletion in subjects with remitted major depressive disorder and in controls

Thyroid hormones and their interactions with catecholamines play a potentially important role in alterations of mood and cognition. This study aimed to examine the neurobiological effects of catecholamine depletion on thyroid hormones by measuring endocrine and cerebral metabolic function in unmedicated subjects with remitted major depressive disorder (RMDD) and in healthy controls. This was a randomized, placebo-controlled, and double-blind crossover trial that included 15 unmedicated RMDD subjects and 13 healthy control subjects. The participants underwent two 3-day-long sessions at 1-week intervals; each participant was randomly administered oral α-methyl-para-tyrosine in one session (catecholamine depletion) and an identical capsule containing hydrous lactose (sham depletion) in the other session prior to a [(18)F]-fluorodeoxyglucose positron emission tomography scan. Serum concentrations of free T3 (FT3), free T4 (FT4), and TSH were obtained and assessed with respect to their relationship to regional cerebral glucose metabolism. Both serum FT3 (P = 0.002) and FT4 (P = 0.0009) levels were less suppressed after catecholamine depletion compared with placebo treatment in the entire study sample. There was a positive association between both FT3 (P = 0.0005) and FT4 (P = 0.002) and depressive symptoms measured using the Montgomery-Åsberg Depression Rating Scale. The relative elevation in FT3 level was correlated with a decrease in regional glucose metabolism in the right dorsolateral prefrontal cortex (rDLPFC; P < 0.05, corrected). This study provided evidence of an association between a thyroid-catecholamine interaction and mood regulation in the rDLPFC.

Dissociable Effects of Alzheimer Disease and White Matter Hyperintensities on Brain Metabolism

Cerebrovascular disease and Alzheimer disease (AD) frequently co-occur and seem to act through different pathways in producing dementia. To examine cerebrovascular disease and AD markers in relation to brain glucose metabolism in patients with mild cognitive impairment. Cohort study among the Alzheimer Disease Neuroimaging Initiative clinical sites in the United States and Canada. Two hundred three patients having amnestic mild cognitive impairment (74 of whom converted to AD) with serial imaging during a 3-year follow-up period. Quantified white matter hyperintensities (WMHs) represented cerebrovascular disease, and cerebrospinal fluid β-amyloid represented AD pathology. Brain glucose metabolism in temporoparietal and frontal brain regions was measured using positron emission tomography with fluorodeoxyglucose F18. In converters, greater WMHs were associated with decreased frontal metabolism (-0.048; 95% CI, -0.067 to -0.029) but not temporoparietal metabolism (0.010; 95% CI, -0.010 to 0.030). Greater cerebrospinal fluid β-amyloid (per 10-pg/mL increase) was associated with increased temporoparietal metabolism (0.005; 95% CI, 0.000-0.010) but not frontal metabolism (0.002; 95% CI, -0.004 to 0.007) in the same patients. In nonconverters, similar relationships were observed except for a positive association of greater WMHs with increased temporoparietal metabolism (0.051; 95% CI, 0.027-0.076). The dissociation of WMHs and cerebrospinal fluid β-amyloid in relation to regional glucose metabolism suggests that these pathologic conditions operate through different and independent pathways in AD that reflect dysfunction in different brain systems. The positive association of greater WMHs with temporoparietal metabolism suggests that these pathologic processes do not co-occur in nonconverters.