Regional Hypometabolism Research Articles

The Brain's Structural Connectome Mediates the Relationship between Regional Neuroimaging Biomarkers inAlzheimer's Disease.

Alzheimer's disease (AD), one of the most common causes of dementia in adults, is a progressive neurodegenerative disorder exhibiting well-defined neuropathological hallmarks. It is known that disease pathology involves misfolded amyloid-β (Aβ) and tau proteins, and exhibits a relatively stereotyped progression over decades. The relationship between AD neuropathological hallmarks (Aβ, hypometabolism, and tau proteins) and imaging biomarkers (MRI, AV-45/FDG-PET) is not fully understood. In addition, biomarker pathologies are oftentimes discordant, wherein it may show varying levels of abnormality across brain regions. Evidence based on recent elucidation of trans-neuronal "prion-like" transmission and other available data already suggests that disease spread follows the brain's fiber connectivity network. Thereby, the brain's connectome information can be used to predict the process of disease spread in AD. A recently established mathematical model of AD pathology spread using a connectome-based network diffusion model was successful in encapsulating neurodegenerative progression. Motivated by these network-based findings, the current study explores whether and how network connectivity mediates the interactions between various AD biomarkers. We hypothesized that the structural connectivity matrix will mediate the cross-sectional association between regional AD-associated hypometabolism and Aβ deposition. Given recent reports of inherent or lifetime activity of brain regions as strong predictors of Aβ deposition in patients, we also tested whether healthy metabolism exerts a network-mediated effect on Aβ deposition and hypometabolism in AD patients. We found that regional Aβ deposition is best predicted by a linear combination of both regional healthy local metabolism and connectome-mediated regional healthy metabolism.

18F-FDG PET in Posterior Cortical Atrophy and Dementia with Lewy Bodies.

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) have both been associated with occipital lobe hypometabolism on 18F-FDG PET, whereas relative sparing of posterior cingulate metabolism compared with precuneus/cuneus (i.e., cingulate island sign) is a feature of DLB. We aimed to determine whether patterns of hypometabolism or the cingulate island sign differed between PCA and DLB. Methods: Sixteen clinically diagnosed PCA and 13 probable DLB subjects underwent 18F-FDG PET. All PCA subjects showed β-amyloid deposition on PET scanning. Regional hypometabolism was assessed compared with a control cohort (n = 29) using voxel- and region-level analyses in statistical parametric mapping. A ratio of metabolism in the posterior cingulate to precuneus plus cuneus was calculated to assess the cingulate island sign. In addition, the 18F-FDG PET scans were visually assessed to determine whether the cingulate island sign was present in each subject. Results: PCA and DLB showed overlapping patterns of hypometabolism involving the lateral occipital lobe, lingual gyrus, cuneus, precuneus, posterior cingulate, inferior parietal lobe, supramarginal gyrus, striatum, and thalamus. However, DLB showed greater hypometabolism in the medial occipital lobe, orbitofrontal cortex, anterior temporal lobe, and caudate nucleus than PCA, and PCA showed more asymmetric patterns of hypometabolism than DLB. The cingulate island sign was present in both DLB and PCA, although it was more asymmetric in PCA. Conclusion: Regional hypometabolism overlaps to a large degree between PCA and DLB, although the degree of involvement of the frontal and anterior temporal lobes and the presence of asymmetry could be useful in differential diagnosis.

Differential patterns of regional cerebral hypometabolism according to the level of cerebral amyloid deposition in patients with amnestic mild cognitive impairment

Although amnestic mild cognitive impairment (aMCI) with high cerebral deposition of amyloid-beta proteins (Aβ) could be classified as a prodromal state of Alzheimer’s disease (AD) dementia, aMCI with the absence of or very little cerebral Aβ deposition is likely related to other pathophysiological processes. Thus, the present study aimed to investigate the differential patterns of regional cerebral glucose metabolism (rCMglu) according to the level of Aβ burden in the brains of patients with aMCI. This study included 25 patients with aMCI and 33 cognitively normal (CN) elderly individuals who underwent a comprehensive clinical examination, 11C-labelled Pittsburgh Compound B (PiB) positron emission tomography (PET) scans, and 18F-fluorodeoxyglucose (FDG) PET scans. Based on cerebral PiB retention, the aMCI subjects were divided into low Aβ (aMCI−, n=10) and high Aβ (aMCI+, n=15) subgroups, and differences in rCMglu among the CN group and aMCI subgroups were estimated on a voxel-by-voxel basis. Compared with the CN group, rCMglu was decreased in the bilateral medial temporal regions of the aMCI− subgroup and in the medial temporal cortices as well as the right precuneus of the aMCI+ subgroup. Additionally, rCMglu was lower in the right precuneus of the aMCI+ subgroup compared with the aMCI− subgroup. The present findings indicate that, even though both aMCI subgroups were phenomenologically very similar, the patients with aMCI− exhibited a markedly different regional pattern of functional neurodegeneration compared with the aMCI+ patients.

RELATIONSHIPS BETWEEN TAU BURDEN MEASURED USING AV1451 PET, REGIONAL CEREBRAL GLUCOSE METABOLISM, AND COGNITIVE STATUS

In amyloid positive (Am+) subjects at all stages of the AD pathway, the expression of an AD-like pattern of hypometabolism detected using a multivariate FDG classifier correlates with the rate of subsequent cognitive decline (Figure 1), supporting clinical trial enrichment. However, the pathology underlying Am+ subjects negative for an AD-like pattern is unknown. Using AV1451 PET scans, we studied the temporal and spatial relationship between FDG AD-like pattern expression and tau burden with the goal of understanding these differences. The AV1451 scans of 36 ADNI2 subjects (Table 1) were downloaded with their closest MRI, AV45, FDG, CSF Abeta, tau, and ptau, demographic, and cognitive data. Regions of interest were measured in structures aligned with Braak stages I–VI (Scholl, 2016). SUVRs were calculated using cerebellar cortex (AV1451) and pons (FDG), and Z-scores generated using Normal Am- references. FDG scans were scored for expression of an AD-like pattern using a multivariate AD Progression classifier (FDG CV1). AV1451 and FDG PET scores and patterns were compared across diagnostic and amyloid classes, and between subjects who expressed an AD like FDG pattern vs. those who did not. Using a threshold of z-score ≥2, only NL and SMC subjects with Am+ PET were Tau PET+ with Braak stage-like progression. Most Tau- subjects were negative for a FDG CV1 pattern. Compared to Am-Tau- subjects, Tau+ subjects expressed a tau pattern highly similar to AD hypometabolism (FDG CV1 pattern), differing in sensorimotor cortex (Figure 2). In Tau+ subjects, greater FDG CV1+ pattern expression was associated with greater deposition in FDG CV1 regions (Figure 3). Two of three Am+Tau+ subjects who were FDG CV1- had atypical, asymmetric tau patterns or relatively minimal tau burden and showed corresponding atypical hypometabolism (Figure 4). Regional glucose metabolism decline is associated with tau deposition in this preliminary data set, consistent with other findings (Ossenkoppele, 2016). Typical vs. atypical tau patterns and their extent may help to explain the correlation between FDG CV1 and subsequent rate of clinical decline, and to understand whether cognitive decline arises from tau or the extent of neurodegenerative response to burden. a) FDG CV1 pattern: Blue = hypometabolism, Red = hypermetabolism (preservation), relative to whole brain. Higher CV1 score corresponds to greater pattern expression. b) 36 month MMSE scores for Late MCI subjects stratified by baseline CV1. Subjects negative for AD-like pattern at baseline typically remain stable in contrast to higher scoring subjects who decline at greater rates. SPM-t comparison of Am+ Tau+ subjects with AD-like FDG CV1 vs. Am- Tau- subjects (p<0.005 uncorrected, N=5 Tau+,9 Tau-). Comparison of Am+ Tau+ subjects who exhibit AD-like hypometabolism vs. those who do not. AV1451 scan of Am+ Tau+ EMCI subject with atypical deposition pattern superimposed on MRI reference (with two different axial slices). Subject was negative for a typical AD-like pattern, but had hypometabolism in regions overlapping those with tau, including amygdala, lingual gyrus, fusiform gyrus, parahippocampus, and additionally in cerebellum and subcortical white matter relative to pons. Brightest color intensity corresponds with greater tau z-score (z = 4 to 5).

18FDG-PET (2-DEOXY-2-(18F)FLUORO-D-GLUCOSE POSITRON EMISSION TOMOGRAPHY)PATTERN CAN FACILITATE NMDAR- ENCEPHALITIS DIAGNOSIS: A SERIES OF CASES AT THE NATIONAL INSTITUTE OF NEUROLOGY AND NEUROSURGERY OF MEXICO

N-methyl-D-aspartate glutamate receptor (NMDA-R) encephalitis requires early diagnosis and prompt treatment. The under- diagnosed disorder has been recognized in patients of all ages, including elderly and presents with a variety of neuropsychiatric symptoms. As in dementia patients, age-related increase in NMDA-R antibodies have been found in the general population. In this descriptive, observational and retrospective study, patients diagnosed with NMDAR- encephalitis from the National Institute of Neurology and Neurosurgery of Mexico were included. 18FDG-PET findings were categorized in patterns. Demographic, clinical and other diagnostic features were also discussed. 8 patients were studied, adults 28 ± 12 years, 6 (75%) were female and 2 (25%) male. The result of their PET studies were:5 (63%) patients showed a combined pattern of frontotemporal hypermetabolism and occipital hypometabolism (group A), and 3 (37%) patients had hypometabolism in several regions (group B). From group A: 3 (60%) patients were in a prodromal phase, 4(80%) had multiple neuropsychiatric symptoms, 2(40%) presented catatonia, 2(40%) reported epileptic seizures, 5(100%) showed EEG dysfunction, 2(40%) had pathological findings in MRI, and 5(100%) were within first 10 weeks from onset of the disease when the18FDG-PET was acquired. From group B: 1(33%) was in a prodromal phase, 3(100%) had multiple neuropsychiatric symptoms, 3(100%) presented catatonia, 2(67%) had epileptic seizures, 2(67%) EEG dysfunction and 1(37) with epileptic activity, 2(67%) presented pathological findings in MRI, and 2(67%) had the 18FDG-PET study within first 10 weeks from onset of the disease and 1(33%) within 10-30 weeks from onset of the disease. All values had p>0.001. Fronto-temporal hypermetabolism with occipital hypometabolism was the pattern most commonly presented. Variability of these findings should be correlated with clinical severity, timeline and other diagnostic tools in future studies. We can speculate same findings in elderly population. Antibodies could be related to the pathogenesis of neurodegenerative disorders, psychotic symptoms in dementia patients or a brain-blood barrier (BBB) dependent phenomenon.

COGNITIVE DECLINE IS DRIVEN BY THE REGIONAL SYNERGISM BETWEEN AMYLOID LOAD AND HYPOMETABOLISM IN MILD COGNITIVE IMPAIRMENT

COGNITIVE DECLINE IS DRIVEN BY THE REGIONAL SYNERGISM BETWEEN AMYLOID LOAD AND HYPOMETABOLISM IN MILD COGNITIVE IMPAIRMENT

COGNITIVE DECLINE IS DRIVEN BY THE REGIONAL SYNERGISM BETWEEN AMYLOID LOAD AND HYPOMETABOLISM IN MILD COGNITIVE IMPAIRMENT

COGNITIVE DECLINE IS DRIVEN BY THE REGIONAL SYNERGISM BETWEEN AMYLOID LOAD AND HYPOMETABOLISM IN MILD COGNITIVE IMPAIRMENT

Functional neuroimaging and clinical features of drug naive patients with de novo Parkinson’s disease and probable RBD

IntroductionThe association between Parkinson Disease (PD) and REM sleep behavior disorder (RBD) has been related to a specific, malignant clinical phenotype. Definite RBD diagnosis requires video-polysomnography that is often unfeasible. A malignant clinical PD-RBD phenotype could be expected also in PD patients with probable RBD. Aim of this cross-sectional study was to evaluate whether a more severe neuropsychological and functional neuroimaging phenotype can be identified in PD patients with probable RBD. MethodsThirty-eight de novo, drug naïve PD patients underwent a first-line clinical assessment and a second-line multimodal assessment, including neuropsychological evaluation, 123I-FP-CIT-SPECT and 18F-FDG-PET, which were compared between PD patients with (PD + RBD+) and without (PD + RBD-) probable RBD. ResultsOn first-line assessment, PD + RBD + patients had significantly more constipation (p = 0.02) and showed worse olfaction (p = 0.01) compared with PD + RBD-while the two groups were similar as for age, presence of orthostatic hypotension, UPDRS-III and MMSE scores. On second-line assessment, PD + RBD + patients showed a worse neuropsychological test profile, more severe nigro-striatal dopaminergic impairment, mainly at caudate level in the less affected hemisphere (p = 0.004) and impaired brain glucose metabolism, with relative hypometabolism in posterior cortical regions and relative hypermetabolism mainly in anterior regions of the more affected hemisphere (p = 0.015). ConclusionsPD patients with probable RBD are likely to have a more severe neuropsychological and functional brain-imaging phenotype already at the time of diagnosis.

The Effect of Endogenous Adenosine on Neuronal Activity in Rats: An FDG PET Study

ABSTRACT2–18F‐fluorodeoxy‐D‐glucose (FDG) is a glucose analog that is taken up by cells and phosphorylated. The amount of FDG accumulated by cells is a measure of the rate of glycolysis, which reflects cellular activity. As the levels and actions of the neuromodulator adenosine are dynamically regulated by neuronal activity, this study was designed to test whether endogenous adenosine affects tissue accumulation of FDG as assessed by positron emission tomography (PET) or by postmortem analysis of tissue radioactivity. Rats were given an intraperitoneal injection of the adenosine A1 receptor antagonist 8‐cyclopentyl‐1,3‐dipropyl‐xanthine (DPCPX, 3 mg/kg), the adenosine kinase inhibitor ABT‐702 (3 mg/kg), or vehicle 10 minutes prior to an intravenous injection of FDG (15.4 ± 0.7 MBq per rat). Rats were then subjected to a 15 minute static PET scan. Reconstructed images were normalized to FDG PET template for rats and standard uptake values (SUVs) were calculated. To examine the regional effect of active treatment compared to vehicle, statistical parametric mapping analysis was performed. Whole‐brain FDG uptake was not affected by drug treatment. Significant regional hypometabolism was detected, particularly in cerebellum, of DPCPX‐ and ABT‐702 treated rats, relative to vehicle‐treated rats. Thus, endogenous adenosine can affect FDG accumulation although this effect is modest in quiescent rats.

First PET Imaging Studies With 63Zn-Zinc Citrate in Healthy Human Participants and Patients With Alzheimer Disease.

Abnormalities in zinc homeostasis are indicated in many human diseases, including Alzheimer disease (AD). 63Zn-zinc citrate was developed as a positron emission tomography (PET) imaging probe of zinc transport and used in a first-in-human study in 6 healthy elderly individuals and 6 patients with clinically confirmed AD. Dynamic PET imaging of the brain was performed for 30 minutes following intravenous administration of 63Zn-zinc citrate (∼330 MBq). Subsequently, body PET images were acquired. Urine and venous blood were analyzed to give information on urinary excretion and pharmacokinetics. Regional cerebral 63Zn clearances were compared with 11C-Pittsburgh Compound B (11C-PiB) and 18F-fluorodeoxyglucose (18F-FDG) imaging data. 63Zn-zinc citrate was well tolerated in human participants with no adverse events monitored. Tissues of highest uptake were liver, pancreas, and kidney, with moderate uptake being seen in intestines, prostate (in males), thyroid, spleen, stomach, pituitary, and salivary glands. Moderate brain uptake was observed, and regional dependencies were observed in 63Zn clearance kinetics in relationship with regions of high amyloid-β plaque burden (11C-PiB) and 18F-FDG hypometabolism. In conclusion, zinc transport was successfully imaged in human participants using the PET probe 63Zn-zinc citrate. Primary sites of uptake in the digestive system accent the role of zinc in gastrointestinal function. Preliminary information on zinc kinetics in patients with AD evidenced regional differences in clearance rates in correspondence with regional amyloid-β pathology, warranting further imaging studies of zinc homeostasis in patients with AD.

Chapter 51 - Neuroimaging of epilepsy

Imaging is pivotal in the evaluation and management of patients with seizure disorders. Elegant structural neuroimaging with magnetic resonance imaging (MRI) may assist in determining the etiology of focal epilepsy and demonstrating the anatomical changes associated with seizure activity. The high diagnostic yield of MRI to identify the common pathological findings in individuals with focal seizures including mesial temporal sclerosis, vascular anomalies, low-grade glial neoplasms and malformations of cortical development has been demonstrated. Positron emission tomography (PET) is the most commonly performed interictal functional neuroimaging technique that may reveal a focal hypometabolic region concordant with seizure onset. Single photon emission computed tomography (SPECT) studies may assist performance of ictal neuroimaging in patients with pharmacoresistant focal epilepsy being considered for neurosurgical treatment. This chapter highlights neuroimaging developments and innovations, and provides a comprehensive overview of the imaging strategies used to improve the care and management of people with epilepsy.

Age-Related Sex-Specific Changes in Brain Metabolism and Morphology.

With a large database, we aimed to evaluate sex-specific distinctive changes in brain glucose metabolism and morphology during normal aging using MRI and (18)F-FDG PET. A total of 963 cognitively healthy adults were included in this study. All subjects completed a medical questionnaire, took the mini-mental state examination, and underwent brain MRI and whole-body (18)F-FDG PET. The MR and PET images were statistically analyzed using 3-dimensional stereotactic surface projection. All images were corrected for whole-brain pixel value to identify the brain regions with significant changes, and regions of interest were set up with reference to Brodmann areas. We evaluated morphologic and glucose metabolic changes by cross-sectional analysis. The baseline database consisted of subjects from 30 to 40 y old, and the age-step for comparison was 5-y ranges. We also compared sex-specific differences in MR and PET images in each age group. Regarding age-related changes, in both sexes brain atrophy was observed in the lateral frontal and parietal regions and glucose hypometabolism in the medial frontal regions. There were significant differences in these parameters between the sexes; parallel changes in volume and metabolism were manifested in the medial frontal cortex in men and in the lateral and medial temporal cortex in women. By contrast, metabolism-dominant reductions were manifested in the lateral and medial parietal cortex in men and in the ventrolateral prefrontal cortex, including the Broca area, in women. These differences became insignificant in individuals 66 y or older. Our brain mapping study with a large number of reference human brain data demonstrated age-related parallel changes between morphology and metabolism in the medial frontal regions and sex-specific hypometabolism in the parietal (male) and ventrolateral prefrontal (female) cortices. These findings may suggest an aging vulnerability in sex-specific brain regions: the parietal cortex for visuospatial ability in men and the Broca area for speech processing in women.

18F-FDG-PET correlates of cognitive impairment in ALS.

To identify the metabolic signature of the various levels of cognitive deficits in amyotrophic lateral sclerosis (ALS) using 18F-2-fluoro-2-deoxy-d-glucose-PET (18F-FDG-PET). A total of 170 ALS cases consecutively enrolled at the ALS Center of Turin underwent brain 18F-FDG-PET and were classified as displaying normal cognition (ALS-Cn; n = 94), full-blown frontotemporal dementia (ALS-FTD; n = 20), executive or nonexecutive cognitive impairment not fulfilling FTD criteria (ALS-Ci; n = 37), prevalent behavioral changes (n = 9), or nonclassifiable impairment (n = 10) according to neuropsychological testing. Group comparisons of 18F-FDG-PET pattern were carried out among the cognitive subgroups. We found a significantly reduced frontal and prefrontal metabolism in ALS-FTD as compared to ALS-Cn, while ALS-Ci showed an intermediate metabolic behavior in frontal cortex, being hypometabolic as compared to ALS-Cn, and relatively hypermetabolic as compared to ALS-FTD. Hypometabolism in frontal regions was associated in all comparisons to hypermetabolism in cerebellum, midbrain, and corticospinal tracts: the more severe the cognitive decline, the larger the size of the cluster and the statistical significance of 18F-FDG uptake differences. This study demonstrated in a large cohort of patients with ALS a continuum of frontal lobe metabolic impairment reflecting the clinical and anatomic continuum ranging from pure ALS, through ALS with intermediate cognitive deficits, to ALS-FTD, and showing that patients with intermediate cognitive impairment display a characteristic metabolic pattern. Since 18F-FDG-PET allows us to estimate the cerebral lesion load in vivo in neurodegenerative diseases, it might be helpful to investigate in ALS its association with neuropsychological testing along the disease course to disclose the early metabolic signature of possible cognitive impairment.

Parkinsonism after climbing high amplitude mountain: a case report

Acute mountain sickness (AMS) is caused by climbing to a high altitude above 2,500 meters without acclimatization. Various clinical symptoms of AMS include headache, nausea, malaise, dizziness, and insomnia within 6 to 12 hours after reaching the high altitude. Neurological consequences like Parkinsonism following AMS without lesion of brain MRI have been reported rarely. A healthy 64-year-old man presented with gait disturbance. Neurological examination showed tremor of hands, limb rigidity, and bradykinesia. He had never climbed above 1,500 m before. Symptoms developed about 20 days after he had been climbing in the Baekdu Mountain up to 2,700 meters. Neurologic examination showed mental alertness and Unified Parkinson’s Disease Rating Scale (UPDRS) part III(Motor examination) was checked 10 points by rating resting tremor of his hands(2), limb rigidity(4), gait(2) and bradykinesia(finger tapping 1, toe tapping 1). Routine laboratory examinations were normal in blood tests. His electrocardiogram and echocardiography were normal, and there were no lesions detected in the brain MRI including T2-weighed and FLAIR image. He was almost improved after parkinsonism persisted for about five months. We presume that Parkinsonism occurred by transient regional hypometabolism due to hypoxia in both globus pallidus although we did not perform functional imaging. We suggest that Parkinsonism can develop after climbing to a high altitude but they can be transient symptoms in case of no abnormalities on brain MRI. Additionally, people who plan to climb high altitudes above 2,500 m need sufficient acclimatization before climbing and must pay attention to speed of ascent. Acute mountain sickness (AMS) is caused by climbing to a high altitude above 2,500 meters without acclimatization. Various clinical symptoms of AMS include headache, nausea, malaise, dizziness, and insomnia within 6 to 12 hours after reaching the high altitude. Neurological consequences like Parkinsonism following AMS without lesion of brain MRI have been reported rarely. A healthy 64-year-old man presented with gait disturbance. Neurological examination showed tremor of hands, limb rigidity, and bradykinesia. He had never climbed above 1,500 m before. Symptoms developed about 20 days after he had been climbing in the Baekdu Mountain up to 2,700 meters. Neurologic examination showed mental alertness and Unified Parkinson’s Disease Rating Scale (UPDRS) part III(Motor examination) was checked 10 points by rating resting tremor of his hands(2), limb rigidity(4), gait(2) and bradykinesia(finger tapping 1, toe tapping 1). Routine laboratory examinations were normal in blood tests. His electrocardiogram and echocardiography were normal, and there were no lesions detected in the brain MRI including T2-weighed and FLAIR image. He was almost improved after parkinsonism persisted for about five months. We presume that Parkinsonism occurred by transient regional hypometabolism due to hypoxia in both globus pallidus although we did not perform functional imaging. We suggest that Parkinsonism can develop after climbing to a high altitude but they can be transient symptoms in case of no abnormalities on brain MRI. Additionally, people who plan to climb high altitudes above 2,500 m need sufficient acclimatization before climbing and must pay attention to speed of ascent.

Regional brain hypometabolism is unrelated to regional amyloid plaque burden.

In its original form, the amyloid cascade hypothesis of Alzheimer's disease holds that fibrillar deposits of amyloid are an early, driving force in pathological events leading ultimately to neuronal death. Early clinicopathological investigations highlighted a number of inconsistencies leading to an updated hypothesis in which amyloid plaques give way to amyloid oligomers as the driving force in pathogenesis. Rather than focusing on the inconsistencies, amyloid imaging studies have tended to highlight the overlap between regions that show early amyloid plaque signal on positron emission tomography and that also happen to be affected early in Alzheimer's disease. Recent imaging studies investigating the regional dependency between metabolism and amyloid plaque deposition have arrived at conflicting results, with some showing regional associations and other not. We extracted multimodal neuroimaging data from the Alzheimer's disease neuroimaging database for 227 healthy controls and 434 subjects with mild cognitive impairment. We analysed regional patterns of amyloid deposition, regional glucose metabolism and regional atrophy using florbetapir ((18)F) positron emission tomography, (18)F-fluordeoxyglucose positron emission tomography and T1-weighted magnetic resonance imaging, respectively. Specifically, we derived grey matter density and standardized uptake value ratios for both positron emission tomography tracers in 404 functionally defined regions of interest. We examined the relation between regional glucose metabolism and amyloid plaques using linear models. For each region of interest, correcting for regional grey matter density, age, education and disease status, we tested the association of regional glucose metabolism with (i) cortex-wide florbetapir uptake; (ii) regional (i.e. in the same region of interest) florbetapir uptake; and (iii) regional florbetapir uptake while correcting in addition for cortex-wide florbetapir uptake. P-values for each setting were Bonferroni corrected for 404 tests. Regions showing significant hypometabolism with increasing cortex-wide amyloid burden were classic Alzheimer's disease-related regions: the medial and lateral parietal cortices. The associations between regional amyloid burden and regional metabolism were more heterogeneous: there were significant hypometabolic effects in posterior cingulate, precuneus, and parietal regions but also significant positive associations in bilateral hippocampus and entorhinal cortex. However, after correcting for global amyloid burden, few of the negative associations remained and the number of positive associations increased. Given the wide-spread distribution of amyloid plaques, if the canonical cascade hypothesis were true, we would expect wide-spread, cortical hypometabolism. Instead, cortical hypometabolism appears to be linked to global amyloid burden. Thus we conclude that regional fibrillar amyloid deposition has little to no association with regional hypometabolism.

Brain metabolic abnormalities during gait with freezing in Parkinson’s disease

Introduction: Freezing of gait (FoG) is a debilitating gait disorder in Parkinson’s disease (PD). In advanced PD patients with FoG, the supraspinal locomotor network may be dysregulated (relative to similar patients without FoG) during gait. Here, we sought to characterize the metabolism of locomotor networks involved in FoG. Methods: Twenty-two PD patients (11 with off-drug FoG and 11 without) each underwent two [18F]-fluorodeoxyglucose PET brain scans in the off-drug state: one at rest and another during radiotracer uptake while performing a standardized gait trajectory that incorporated the usual triggers for FoG. Results: For the 11 freezers, FoG was present for 39% (±23%) of the time during the gait trajectory. The FoG-associated abnormalities were characterized by (i) hypometabolism in frontal regions (the associative premotor, temporopolar and orbitofrontal areas, i.e. Brodmann areas 6 and 8), (ii) hypermetabolism in the paracentral lobule (Brodmann area 5), and (iii) deregulation of the basal ganglia output (the globus pallidus and the mesencephalic locomotor region). Conclusion: FoG during a real gait task was associated with impaired frontoparietal cortical activation, as characterized by abnormally low metabolic activity of the premotor area (involved in the indirect locomotor pathway) and abnormally high metabolic activity of the parietal area (reflecting the harmful effect of external cueing).

Asymmetries of amyloid-β burden and neuronal dysfunction are positively correlated in Alzheimer's disease.

Clinical Alzheimer's disease affects both cerebral hemispheres to a similar degree in clinically typical cases. However, in atypical variants like logopenic progressive aphasia, neurodegeneration often presents asymmetrically. Yet, no in vivo imaging study has investigated whether lateralized neurodegeneration corresponds to lateralized amyloid-β burden. Therefore, using combined (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography, we explored whether asymmetric amyloid-β deposition in Alzheimer's disease is associated with asymmetric hypometabolism and clinical symptoms. From our database of patients who underwent positron emission tomography with both (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose (n = 132), we included all amyloid-positive patients with prodromal or mild-to-moderate Alzheimer's disease (n = 69). The relationship between (11)C-Pittsburgh compound B binding potential and (18)F-fluorodeoxyglucose uptake was assessed in atlas-based regions of interest covering the entire cerebral cortex. Lateralizations of amyloid-β and hypometabolism were tested for associations with each other and with type and severity of cognitive symptoms. Positive correlations between asymmetries of Pittsburgh compound B binding potential and hypometabolism were detected in 6 of 25 regions (angular gyrus, middle frontal gyrus, middle occipital gyrus, superior parietal gyrus, inferior and middle temporal gyrus), i.e. hypometabolism was more pronounced on the side of greater amyloid-β deposition (range: r = 0.41 to 0.53, all P < 0.001). Stronger leftward asymmetry of amyloid-β deposition was associated with more severe language impairment (P < 0.05), and stronger rightward asymmetry with more severe visuospatial impairment (at trend level, P = 0.073). Similarly, patients with predominance of language deficits showed more left-lateralized amyloid-β burden and hypometabolism than patients with predominant visuospatial impairment and vice versa in several cortical regions. Associations between amyloid-β deposition and hypometabolism or cognitive impairment were predominantly observed in brain regions with high amyloid-β load. The relationship between asymmetries of amyloid-β deposition and hypometabolism in cortical regions with high amyloid-β load is in line with the detrimental effect of amyloid-β burden on neuronal function. Asymmetries were also concordant with lateralized cognitive symptoms, indicating their clinical relevance.

Quantitative μPET Imaging of Cerebral Glucose Metabolism and Amyloidosis in the TASTPM Double Transgenic Mouse Model of Alzheimer's Disease.

Positron emission tomography studies of cerebral glucose utilization and amyloid-β deposition with fluoro-deoxy-D-glucose ([(18)F]-FDG) and amyloid tracers have shown characteristic pathological changes in Alzheimer's Disease that can be used for disease diagnosis and monitoring. Application of this technology to preclinical research with transgenic animal models would greatly facilitate drug discovery and further understanding of disease processes. The results from preclinical studies with these imaging biomarkers have however been highly inconsistent, causing doubts over whether animal models can truly replicate an AD-like phenotype. In this study we performed in vivo imaging with [(18)F]-FDG and [(18)F]-AV45 in double transgenic TASTPM mice, a transgenic model that been previously demonstrated high levels of fibrillar amyloid-β and decreases in cerebral glucose utilization with ex vivo techniques. Our results show widespread and significant retention of [(18)F]-AV45 (p < 0.0001) in aged TASTPM mice in addition to significant regional decreases in [(18)F]-FDG uptake (p < 0.05). In vivo quantification of amyloid-β showed a strong (Pearson's r = 0.7078), but not significant (p = 0.1156), positive correlation with ex vivo measures suggesting some limitations on tracer sensitivity. In the case of [(18)F]-FDG, voxelwise analysis greatly enhanced detection of hypometabolic regions. We further evidenced modest neuronal loss (thalamus p = 0.0318) that could underlie the observed hypometabolism. This research was performed in conjunction with the European Community's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under the PharmaCog Grant Agreement no.115009.

Multimodal Discrimination of Alzheimer's Disease Based on Regional Cortical Atrophy and Hypometabolism.

Structural MR image (MRI) and 18F-Fluorodeoxyglucose-positron emission tomography (FDG-PET) have been widely employed in diagnosis of both Alzheimer’s disease (AD) and mild cognitive impairment (MCI) pathology, which has led to the development of methods to distinguish AD and MCI from normal controls (NC). Synaptic dysfunction leads to a reduction in the rate of metabolism of glucose in the brain and is thought to represent AD progression. FDG-PET has the unique ability to estimate glucose metabolism, providing information on the distribution of hypometabolism. In addition, patients with AD exhibit significant neuronal loss in cerebral regions, and previous AD research has shown that structural MRI can be used to sensitively measure cortical atrophy. In this paper, we introduced a new method to discriminate AD from NC based on complementary information obtained by FDG and MRI. For accurate classification, surface-based features were employed and 12 predefined regions were selected from previous studies based on both MRI and FDG-PET. Partial least square linear discriminant analysis was employed for making diagnoses. We obtained 93.6% classification accuracy, 90.1% sensitivity, and 96.5% specificity in discriminating AD from NC. The classification scheme had an accuracy of 76.5% and sensitivity and specificity of 46.5% and 89.6%, respectively, for discriminating MCI from AD. Our method exhibited a superior classification performance compared with single modal approaches and yielded parallel accuracy to previous multimodal classification studies using MRI and FDG-PET.

Amyloid in dementia associated with familial FTLD: not an innocent bystander

Patients with frontotemporal lobar degeneration (FTLD) can show superimposed amyloid pathology, though the impact of amyloid on the clinical presentation of FTLD is not well characterized. This cross-sectional case–control study compared clinical features, fluorodeoxyglucose-positron emission tomography metabolism and gray matter volume loss in 30 patients with familial FTLD in whom amyloid status was confirmed with autopsy or Pittsburgh compound B-PET. Compared to the amyloid-negative patients, the amyloid-positive patients performed significantly worse on several cognitive tests and showed hypometabolism and volume loss in more temporoparietal regions. Our results suggest that in FTLD amyloid positivity is associated with a more Alzheimer’s disease-like pattern of neurodegeneration.