Background
Neuroinflammation, which receives ever increasing interest in neurodegenerative diseases, comprises a heterogeneous cascade of events that are thought to be related to the downstream ...neurodegeneration. The aim of this study was to evaluate the binding of 11C‐Deuterium‐L‐Deprenyl PET (DED) as a measure of reactive astrocytes in patients with different dementia disorders, and to assess its association with other disease biomarkers.
Method
Eleven patients with a clinical diagnosis of semantic variant of primary progressive aphasia (svPPA, n = 5) and behavioral variant of frontotemporal dementia (bvFTD, n = 6) were recruited. All patients had a cerebrospinal fluid biomarker profile that was inconsistent with Alzheimer’s disease (AD) or a negative amyloid‐β PET scan. The imaging protocol included 11C‐DED‐PET, 18F‐FDG‐PET, and a 3D T1 MRI. A group of amyloid‐beta positive patients with AD (n = 20) that underwent similar investigations were used for comparison. Z‐scores were created for 11C‐DED binding (Patlak slopes) and tracer relative delivery (R1 parameter) relative to that of healthy controls (HC; n = 20), for assessing the load of reactive astrocytes and cerebral perfusion, respectively.
Result
The patients with svPPA and bvFTD showed significantly higher 11C‐DED binding in frontotemporal areas, compared to HC. Patients with AD showed significantly higher 11C‐DED binding in temporo‐occipital areas, compared to HC. The regional distribution of 11C‐DED binding in the patients with svPPA and bvFTD was consistent with the expected underlying pattern of neurodegeneration in those disorders, although the load of binding was heterogeneous across patients with the same clinical diagnosis.
Conclusion
Reactive astrocytes appear to be a common feature of different dementia disorders, although the regional pattern of reactivity differs. Ongoing work evaluates the relationship between patterns of reactive astrocyte activation, cerebral perfusion, glucose metabolism, atrophy, and cognitive performance.
The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer's disease (AD) and other tauopathies. Eighteen ...patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with
FTHK5317 (tau deposition) and
FFDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with
CPIB (amyloid-β deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged
FTHK5317 retention over time, in contrast to significant decreases in
FFDG uptake in temporoparietal areas. The pattern of changes in
FTHK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High
FTHK5317 retention was significantly associated over time with low episodic memory encoding scores, while low
FFDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative
CPIB scan, high
FTHK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased
FTHK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.
For amyloid positron emission tomography tracers, the simplified reference tissue model derived ratio of influx rate in target relative to reference region (R1) has been shown to serve as a marker of ...brain perfusion, and, due to the strong coupling between perfusion and metabolism, as a proxy for glucose metabolism. In the present study, 11 prodromal Alzheimer’s disease and nine Alzheimer’s disease dementia patients underwent 18FTHK5317, carbon-11 Pittsburgh Compound-B (11CPIB), and 2-deoxy-2-18Ffluoro-D-glucose (18FFDG) positron emission tomography to assess the possible use of early-phase 18FTHK5317 and R1 as proxies for brain perfusion, and thus, for glucose metabolism. Discriminative performance (prodromal vs Alzheimer's disease dementia) of 18FTHK5317 (early-phase SUVr and R1) was compared with that of 11CPIB (early-phase SUVr and R1) and 18FFDG. Strong positive correlations were found between 18FTHK5317 (early-phase, R1) and 18FFDG, particularly in frontal and temporoparietal regions. Differences in correlations between early-phase and R1 (18FTHK5317 and 11CPIB) and 18FFDG, were not statistically significant, nor were differences in area under the curve values in the discriminative analysis. Our findings suggest that early-phase 18FTHK5317 and R1 provide information on brain perfusion, closely related to glucose metabolism. As such, a single positron emission tomography study with 18FTHK5317 may provide information about both tau pathology and brain perfusion in Alzheimer’s disease, with potential clinical applications.
OBJECTIVETo study the macrostructural and microstructural MRI correlates of brain astrocytosis, measured with C-deuterium-L-deprenyl (C-DED)–PET, in familial autosomal-dominant Alzheimer disease ...(ADAD).
METHODSThe total sample (n = 31) comprised ADAD mutation carriers (n = 10 presymptomatic, 39.2 ± 10.6 years old; n = 3 symptomatic, 55.5 ± 2.0 years old) and noncarriers (n = 18, 44.0 ± 13.7 years old) belonging to families with mutations in either the presenilin-1 or amyloid precursor protein genes. All participants underwent structural and diffusion MRI and neuropsychological assessment, and 20 participants (6 presymptomatic and 3 symptomatic mutation carriers and 11 noncarriers) also underwent C-DED-PET.
RESULTSVertex-wise interaction analyses revealed a differential relationship between carriers and noncarriers in the association between C-DED binding and estimated years to onset (EYO) and between cortical mean diffusivity (MD) and EYO. These differences were due to higher C-DED binding in presymptomatic carriers, with lower binding in symptomatic carriers compared to noncarriers, and to lower cortical MD in presymptomatic carriers, with higher MD in symptomatic carriers compared to noncarriers. Using a vertex-wise local correlation approach, C-DED binding was negatively correlated with cortical MD and positively correlated with cortical thickness.
CONCLUSIONSOur proof-of-concept study is the first to show that microstructural and macrostructural changes can reflect underlying neuroinflammatory mechanisms in early stages of Alzheimer disease (AD). The findings support a role for neuroinflammation in AD pathogenesis, with potential implications for the correct interpretation of neuroimaging biomarkers as surrogate endpoints in clinical trials.
Apoptosis is a fundamental biologic process. Molecular imaging of apoptosis in vivo may have important implications for clinical practice, assisting in early detection of disease, monitoring of ...disease course, assessment of treatment efficacy, or development of new therapies. Although a PET probe for clinical imaging of apoptosis would be highly desirable, this is yet an unachieved goal, mainly because of the required challenging integration of various features, including sensitive and selective detection of the apoptotic cells, clinical aspects such as favorable biodistribution and safety profiles, and compatibility with the radiochemistry and imaging routines of clinical PET centers. Several approaches are being developed to address this challenge, all based on novel small-molecule structures targeting various steps of the apoptotic cascade. This novel concept of small-molecule PET probes for apoptosis is the focus of this review.
Abstract It is of great clinical value to identify subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust ...difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.3 ± 7.8 (S.D.) years) underwent PET studies with11 C-PIB, and18 F-fluoro-deoxy-glucose (FDG) to measure cerebral glucose metabolism, as well as assessment of cognitive function and CSF sampling. Reference group data from 27 AD patients and 6 healthy controls, respectively, were used for comparison. The mean cortical PIB retention for the MCI patients was intermediate compared to HC and AD. Seven MCI patients that later at clinical follow-up converted to AD (8.1 ± 6.0 (S.D.) months) showed significant higher PIB retention compared to non-converting MCI patients and HC, respectively ( p s < 0.01). The PIB retention in MCI converters was comparable to AD patients ( p > 0.01). Correlations were observed in the MCI patients between PIB retention and CSF Aβ1-42 , total Tau and episodic memory, respectively.
Issue Title: Memory Patients suffering from Alzheimer's disease (AD) experience a marked reduction in cortical nicotinic acetylcholine receptors (nAChRs). In particular, selective loss of the α4β2 ...nAChR subtype was observed in postmortem AD brain tissue. The α4 and α7 nAChR subunits were suggested to play an important role in cognitive function. Positron emission tomography (PET) has so far been used to visualize neuronal nAChRs in vivo by 11C-nicotine binding. To investigate the relationship between measures of cognitive function and in vivo 11C-nicotine binding in mild AD brain as assessed by PET. Twenty-seven patients with mild AD were recruited in this study. A dual tracer model with administration of 15O-water for regional cerebral blood flow and (S)(-)11C-nicotine was used to assess nicotine binding sites in the brain by PET. Cognitive function was assessed using neuropsychological tests of global cognition, episodic memory, attention, and visuospatial ability. Mean cortical 11C-nicotine binding significantly correlated with the results of attention tests Digit Symbol test (r=-0.44 and p=0.02) and Trail Making Test A (TMT-A) (r=0.42 and p=0.03). No significant correlation was observed between 11C-nicotine binding and the results of tests of episodic memory or visuospatial ability. Regional analysis showed that 11C-nicotine binding in the frontal and parietal cortex, which are the main areas for attention, correlated significantly with the Digit Symbol test and TMT-A results. Cortical nicotinic receptors in vivo in mild AD patients are robustly associated with the cognitive function of attention. PUBLICATION ABSTRACT
Introduction: Gamma-aminobutyric acid (GABA) deficiency is suggested in depressive disorders, along with alterations in cortical excitability. However, whether these excitability changes are related ...to GABA A receptor availability is largely unknown. Our aim was to assess the correlation between these measures in depressed patients and healthy controls. Methods: Twenty-eight patients with a major depressive episode, measured before and after participating in a clinical trial with repetitive transcranial magnetic stimulation (TMS), and 15 controls underwent 11 Cflumazenil positron emission tomography to assess GABA A receptor availability and paired pulse TMS (ppTMS) to evaluate cortical excitability. Both whole-brain voxel-wise GABA A receptor availability and mean values from left hand motor cortex and left paracentral lobule were correlated to the ppTMS outcomes: short-interval intracortical inhibition reflecting GABA A receptor activity, long-interval intracortical inhibition representing GABA B receptor activity, intracortical facilitation reflecting glutamate N-methyl-D-aspartate-receptor activity, as well as the resting motor threshold (rMT), considered a global measure of corticospinal excitability. Results: No significant differences in baseline GABA A receptor availability or cortical excitability were found between patients and controls. Additionally, no correlations were observed between baseline measurements of GABA A receptor availability and TMS outcomes. Changes in GABA A receptor availability in the hand motor cortex, between pre- and post-assessments, were inversely related to pre-post changes in hand rMT. Conclusion: We found that a change in GABA A receptor availability was inversely related to a change in rMT, suggesting a link between GABA deficiency and increased rMT previously observed in depressive episodes. The results highlight the complex mechanisms governing cortical excitability measures and offer new insight into their properties during the depressive state.
Beta amyloid is one of the major histopathological hallmarks of Alzheimer's disease. We recently reported in vivo imaging of amyloid in 16 Alzheimer patients, using the PET ligand ...N-methyl11C2-(4′-methylaminophenyl)-6-hydroxy-benzothiazole (PIB). In the present study we rescanned these 16 Alzheimer patients after 2.0 ± 0.5 years and have described the interval change in amyloid deposition and regional cerebral metabolic rate for glucose (rCMRGlc) at follow-up. Sixteen patients with Alzheimer's disease were re-examined by means of PET, using PIB and 2-18Ffluoro-2-deoxy-d-glucose (FDG) after 2.0 ± 0.5 years. The patients were all on cholinesterase inhibitor treatment and five also on treatment with the N-methyl-d-aspartate (NMDA) antagonist memantine. In order to estimate the accuracy of the PET PIB measurements, four additional Alzheimer patients underwent repeated examinations with PIB within 20 days (test–retest). Relative PIB retention in cortical regions differed by 3–7% in the test–retest study. No significant difference in PIB retention was observed between baseline and follow-up while a significant (P < 0.01) 20% decrease in rCMRGlc was observed in cortical brain regions. A significant negative correlation between rCMRGlc and PIB retention was observed in the parietal cortex in the Alzheimer patients at follow-up (r = 0.67, P = 0.009). A non-significant decline in Mini-Mental State Examination (MMSE) score from 24.3 ± 3.7 (mean ± standard deviation) to 22.7 ± 6.1 was measured at follow-up. Five of the Alzheimer patients showed a significant decline in MMSE score of >3 (21.4 ± 3.5 to 15.6 ± 3.9, P < 0.01) (AD-progressive) while the rest of the patients were cognitively more stable (MMSE score = 25.6 ± 3.1 to 25.9 ± 3.7) (AD-stable) compared with baseline. A positive correlation (P = 0.001) was observed in the parietal cortex between Rey Auditory Verbal Learning (RAVL) test score and rCMRGlc at follow-up while a negative correlation (P = 0.018) was observed between RAVL test and PIB retention in the parietal at follow-up. Relatively stable PIB retention after 2 years of follow-up in patients with mild Alzheimer's disease suggests that amyloid deposition in the brain reaches a plateau by the early clinical stages of Alzheimer's disease and therefore may precede a decline in rCMRGlc and cognition. It appears that anti-amyloid therapies will need to induce a significant decrease in amyloid load in order for PIB PET images to detect a drug effect in Alzheimer patients. FDG imaging may be able to detect a stabilization of cerebral metabolism caused by therapy administered to patients with a clinical diagnosis of Alzheimer's disease.
To investigate the particular pathology of the Arctic APP (APParc) early-onset familial Alzheimer disease (eoFAD) mutation for the first time in vivo with PET in comparison with other eoFAD mutations ...and sporadic Alzheimer disease (sAD).
We examined 2 APParc mutation carriers together with 5 noncarrier siblings cross-sectionally with (11)C-labeled Pittsburgh compound B (PiB) and (18)F-fluorodeoxyglucose (FDG) PET, as well as MRI, CSF biomarkers, and neuropsychological tests. Likewise, we examined 7 patients with sAD, 1 carrier of a presenilin 1 (PSEN1) mutation, 1 carrier of the Swedish APP (APPswe) mutation, and 7 healthy controls (HCs).
Cortical PiB retention was very low in the APParc mutation carriers while cerebral glucose metabolism and CSF levels of Aβ(1-42), total and phosphorylated tau were clearly pathologic. This was in contrast to the PSEN1 and APPswe mutation carriers revealing high PiB retention in the cortex and the striatum in combination with abnormal glucose metabolism and CSF biomarkers, and the patients with sAD who showed typically high cortical PiB retention and pathologic CSF levels as well as decreased glucose metabolism when compared with HCs.
The lack of fibrillar β-amyloid (Aβ) as visualized by PiB PET in APParc mutation carriers suggests, given the reduced glucose metabolism and levels of Aβ(1-42) in CSF, that other forms of Aβ such as oligomers and protofibrils are important for the pathologic processes leading to clinical Alzheimer disease.
PDF
![Comparability of [18F]THK53...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0271-678X_1559-7016/small "Comparability of [18F]THK5317 and [11C]PIB blood flow proxy images with [18F]FDG positron emission tomography in Alzheimer’s disease")
