Amyloid positron-emission-tomography (PET) offers an important research and diagnostic tool for investigating Alzheimer's disease (AD). The majority of amyloid PET studies have used the cerebellum as ...a reference region, and clinical studies have not accounted for atrophy-based partial volume effects (PVE). Longitudinal studies using cerebellum as reference tissue have revealed only small mean increases and high inter-subject variability in amyloid binding. We aimed to test the effects of different reference regions and PVE-correction (PVEC) on the discriminatory power and longitudinal performance of amyloid PET.
We analyzed 18F-AV45 PET and T1-weighted MRI data of 962 subjects at baseline and two-year follow-up data of 258 subjects. Cortical composite volume-of-interest (VOI) values (COMP) for tracer uptake were generated using either full brain atlas VOIs, gray matter segmented VOIs or gray matter segmented VOIs after VOI-based PVEC. Standard-uptake-value ratios (SUVR) were calculated by scaling the COMP values to uptake in cerebellum (SUVRCBL), brainstem (SUVRBST) or white matter (SUVRWM). Mean SUV, SUVR, and changes after PVEC were compared at baseline between diagnostic groups of healthy controls (HC; N=316), mild cognitive impairment (MCI; N=483) and AD (N=163). Receiver operating characteristics (ROC) were calculated for the discriminations between HC, MCI and AD, and expressed as area under the curve (AUC). Finally, the longitudinal 18F-AV45-PET data were used to analyze the impact of quantitation procedures on apparent changes in amyloid load over time.
Reference region SUV was most constant between diagnosis groups for the white matter. PVEC led to decreases of COMP-SUV in HC (−18%) and MCI (−10%), but increases in AD (+7%). Highest AUCs were found when using PVEC with white matter scaling for the contrast between HC/AD (0.907) or with brainstem scaling for the contrast between HC/MCI (0.658). Longitudinal increases were greatest in all diagnosis groups with application of PVEC, and inter-subject variability was lowest for the white matter reference.
Thus, discriminatory power of 18F-AV45-PET was improved by use of a VOI-based PVEC and white matter or brainstem rather than cerebellum reference region. Detection of longitudinal amyloid increases was optimized with PVEC and white matter reference tissue.
•Different reference regions were compared for 18F-AV45 PET quantification.•Effects of segmentation and partial volume effect correction (PVEC) were assessed.•White matter (WM) SUV was most stable between diagnosis groups.•WM and brainstem reference improved discriminatory power compared to cerebellum.•WM reference including PVEC distinctly improved longitudinal PET assessment.
Purpose
Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several β-amyloid and first-generation ...tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer
18
FPI-2620 as a potential substitute for
18
Ffluorodeoxyglucose (
18
FFDG).
Methods
Twenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson’s disease, multi-system atrophy, Parkinson's disease, frontotemporal dementia) and received a dynamic
18
FPI-2620 tau-PET (0–60 min p.i.) and static
18
FFDG-PET (30–50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R
1
) of
18
FPI-2620-PET were correlated with corresponding quantification of
18
FFDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase
18
FPI-2620 tau-PET and
18
FFDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers.
Results
Highest agreement with
18
FFDG-PET quantification was reached for
18
FPI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest
R
= 0.69) and cerebellar scaling (lowest
R
= 0.63). Correlation coefficients (summed 0.5–2.5 min SUVr & R
1
) displayed strong agreement in all cortical target regions for global mean (R
SUVr
0.76,
R
R1
= 0.77) and cerebellar normalization (R
SUVr
0.68,
R
R1
= 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and
18
FFDG-PET. There were no relevant differences between more and less experienced readers.
Conclusion
Early-phase imaging of
18
FPI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional
18
FFDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.
To determine whether a new surgical method using a flexible endoscope (FlexVATS) to perform sparing debridement and apply negative-pressure therapy without extensive decortication may be an ...alternative treatment option for empyema. Surgical treatment of pleural empyema is associated with considerable postoperative complications and mortality rates, and alternative treatment options are being explored to improve patient outcomes. This was a prospective case series. Seventeen consecutive patients treated with FlexVATS between February 2021 and August 2022 were included in the study. Only patients for whom FlexVATS was the first therapeutic intervention for pleural empyema were included. Treatment success, defined as infection resolution, was the primary endpoint of the study. The secondary endpoints were length of hospital stay, 90-day mortality, and empyema cavity volume reduction. Patients who had previously been treated for pleural empyema by either drainage or surgery were excluded. The trial was performed as a single-centre study at a tertiary medical centre in Germany. In total, 17 patients with pleural empyema were included in the study. The median (IQR) duration of vacuum treatment was 15 days (8-35 days). Twelve of the 17 (71%) patients were successfully treated, and a significant reduction in the empyema cavity volume was observed. 41% of the dressing changes were performed outside the operating room. Compared with a historic cohort of conventionally treated patients (decortication via VATS or thoracotomy), the 90-day mortality rates tended to be lower without reaching statistical significance. Three patients (18%) died in hospital during treatment. No negative pressure-therapy-related complications were observed. FlexVATS therapy is a promising alternative therapy for both healthy and debilitated patients with pleural empyema. Larger randomised trials are required to validate this treatment option.
Purpose
It is usually easy to judge whether amyloid PET images should be interpreted as positive or negative for amyloid deposits by visual inspection or quantitative measurement standard uptake ...value ratio (SUVR), but the findings are equivocal in some cases. As conventional mean cortical SUVR (mcSUVR) measures accumulation in both gray matter (GM) and white matter, it may mis-estimate amyloid deposits. The purpose of the study was to develop a regional GM-dedicated SUVR measuring (GMSUVR) system for amyloid PET images with 3D-MRI, and evaluate its utility for detecting amyloid deposits in equivocal cases.
Methods
Of 126 subjects who underwent amyloid PET with
11
C-PiB and 3D-MRI, the area of amyloid-positive regions and the critical regional GMSUVR thresholds were first determined in 15 amyloid-positive and 15 amyloid-negative patients, using the automatic volumetric measurement of segmented brain images system. We then tested 36 amyloid-negative, 60 amyloid-positive, and 13 equivocal subjects with this GMSUVR system and with conventional mcSUVR.
Results
Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were 100%, 92%, 97%, 95%, and 100% for the GMSUVR system; and 97%, 86%, 93%, 92% and 94%, respectively, for mcSUVR. In 24 cases in which the findings were equivocal or discordant, the sensitivity, specificity, accuracy, PPV, and NPV were all 100% for the GMSUVR system; and were 90%, 33%, 83%, 90%, and 33%, respectively, for mcSUVR.
Conclusion
The regional GMSUVR measurement method was well able to discriminate between amyloid-positive and -negative subjects, even in cases where amyloid deposition was equivocal.
Relative quantitative analysis of amyloid plaque burden in Alzheimer’s disease (AD) patients can be reported as standardized uptake value ratio (SUVR) from positron emission tomography (PET). Here, ...the SUVR is the ratio of the mean amyloid radioligand retention in a composite (COMP) neocortical volume of interest (VOI) to that in a reference VOI, such as the cerebellum, brainstem (BST)/pons, or white matter (WM). Some longitudinal PET investigations show that the rate of amyloid accumulation to follow-up has an inverted U relationship with baseline amyloid SUVR relative to cerebellar or brainstem/pons reference VOIs. The corresponding association with SUVR relative to WM is unknown. To test the possible benefits of WM normalization, we analyzed
18
F-AV45 PET data from 404 subjects in the AD Neuroimaging Initiative (ADNI) database at baseline and 2-year follow-up (144 cognitively normal controls, 225 patients with mild cognitive impairment, and 35 AD patients). Reference regions included subcortical WM as well as conventional cerebellar gray matter (CBL), and BST. We tested associations between each subject’s inter-session change (∆) of SUVR and their baseline SUVR by applying linear, logarithmic, and quadratic regression analyses. Unscaled standardized uptake values (SUVs) were correlated between VOIs at baseline and follow-up, and within VOIs in the longitudinal run. The association between ∆SUVR and baseline SUVR relative to WM reference was best described by an inverted U-shaped function. Correlation analyses demonstrated a high regional and temporal correlation between COMP and WM VOI SUVs. For WM normalization, we confirm that the rate of amyloid accumulation over time follows an inverted U-shaped function of baseline amyloid burden. Reference region selection, however, has substantial effects on SUVR results. This reflects the extent of covariance between SUVs in the COMP VOI and those in the various reference VOIs. We speculate that PET labeling of amyloid deposition within target regions is partially confounded by effects of longitudinal changes of cerebral blood flow (CBF) on tracer delivery. Indeed, CBF may be the leading factor influencing longitudinal SUV changes. We suggest that SUVR relative to WM may be more robust to changes in CBF, and thus fitter for sensitive detection of amyloid accumulation in intervention studies.
Progressive supranuclear palsy (PSP) is a neurodegenerative movement disorder characterized by deposition of fibrillar aggregates of 4R tau-protein in neurons and glial cells of the brain. These ...deposits are a key neuropathological finding, allowing a diagnosis of "definite PSP," which is usually established post mortem. To date criteria for clinical diagnosis of PSP
do not include biomarkers of tau pathology. For intervention trials, it is increasingly important to (i) establish biomarkers for an early diagnosis and (ii) to develop biomarkers that correlate with disease progression of PSP.
F-THK5351 is a novel PET-ligand that may afford
visualization and quantification of tau-related alterations. We investigated binding characteristics of
F-THK5351 in patients with clinically diagnosed PSP and correlate tracer uptake with clinical findings. Eleven patients (68.4 ± 7.4 year;
= 6 female) with probable PSP according to current clinical criteria and nine healthy controls (71.7 ± 7.2 year;
= 4 female) underwent
F-THK5351 PET scanning. Voxel-wise statistical parametric comparison and volume-of-interest based quantification of standardized-uptake-values (SUV) were conducted using the cerebellar cortex as reference region. We correlated disease severity as measured with the help of the PSP Rating Scale (PSPRS) as well as several other clinical parameters with the individual PET findings. By voxel-wise mapping of
F-THK5351 uptake in the patient group we delineated typical distribution patterns that fit to known tau topology for PSP post mortem. Quantitative analysis indicated the strongest discrimination between PSP patients and healthy controls based on tracer uptake in the midbrain (+35%;
= 3.01E-7; Cohen's d: 4.0), followed by the globus pallidus, frontal cortex, and medulla oblongata. Midbrain
F-THK5351 uptake correlated well with clinical severity as measured by PSPRS (
= 0.66;
= 0.026). OCT and MRI delineated PSP patients from healthy controls by use of established discrimination thresholds but only OCT did as well correlate with clinical severity (
= 0.79;
= 0.024). Regional
F-THK5351 binding patterns correlated well with the established post mortem distribution of lesions in PSP and with clinical severity. The contribution of possible MAO-B binding to the
F-THK5351 signal needs to be further evaluated, but nevertheless
F-THK5351 PET may still serve as valuable biomarker for diagnosis of PSP.
Objectives:
In recent years several
18
F-labeled amyloid PET (Aβ-PET) tracers have been developed and have obtained clinical approval. There is evidence that Aβ-PET perfusion can provide surrogate ...information about neuronal injury in neurodegenerative diseases when compared to conventional blood flow and glucose metabolism assessment. However, this paradigm has not yet been tested in neurodegenerative disorders with cortical and subcortical affection. Therefore, we investigated the performance of early acquisition
18
F-flutemetamol Aβ-PET in comparison to
18
F-fluorodeoxyglucose (FDG)-PET in corticobasal syndrome (CBS).
Methods:
Subjects with clinically possible or probable CBS were recruited within the prospective Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer’s Disease (ActiGliA) observational study and all CBS cases with an available FDG-PET prior to Aβ-PET were selected. Aβ-PET was acquired 0–10 min p.i. (early-phase) and 90–110 min p.i. (late-phase) whereas FDG-PET was recorded statically from 30 to 50 min p.i. Semiquantitative regional values and asymmetry indices (AI) were compared between early-phase Aβ-PET and FDG-PET. Visual assessments of hypoperfusion and hypometabolism were compared between both methods. Late-phase Aβ-PET was evaluated visually for assessment of Aβ-positivity.
Results:
Among 20 evaluated patients with CBS, 5 were Aβ-positive. Early-phase Aβ-PET and FDG-PET SUVr correlated highly in cortical (mean
R
= 0.86, range 0.77–0.92) and subcortical brain regions (mean
R
= 0.84, range 0.79–0.90). Strong asymmetry was observed in FDG-PET for the motor cortex (mean |AI| = 2.9%), the parietal cortex (mean |AI| = 2.9%), and the thalamus (mean |AI| = 5.5%), correlating well with AI of early-phase Aβ-PET (mean
R
= 0.87, range 0.62–0.98). Visual assessments of hypoperfusion and hypometabolism were highly congruent.
Conclusion:
Early-phase Aβ-PET facilitates assessment of neuronal injury in CBS for cortical and subcortical areas. Known asymmetries in CBS are captured by this method, enabling assessment of Aβ-status and neuronal injury with a single radiation exposure at a single visit.
•The cognitive reserve hypothesis is also applicable for FTD.•The educational level predicts left-temporal hypometabolism in FTD.•Residualized cognitive performance is positively correlated with ...education.•Residualized cognitive performance is negatively correlated with hypometabolism.
Reserve is defined as the ability to maintain cognitive functions relatively well at a given level of pathology. Early life experiences such as education are associated with lower dementia risk in general. However, whether more years of education guards against the impact of brain alterations also in frontotemporal dementia (FTD) has not been shown in a large patient collective. Therefore, we assessed whether education is associated with relatively high cognitive performance despite the presence of 18F-fluorodeoxyglucose positron-emission-tomography (FDG-PET) hypometabolism in FTD.
Sixty-six FTD subjects (age 67 ± 8 years) and twenty-four cognitively healthy controls (HC) were evaluated. Brain regions with FTD-related glucose hypometabolism in the contrast against HC and brain regions that correlate with the cognitive function were defined by a voxel-based analysis and individual FDG-PET values were extracted from all frontotemporal brain areas. Linear regression analysis served to test if education is associated with residualized cognitive performance and regional FDG-PET hypometabolism after controlling for global cognition.
Compared to healthy controls, patients with FTD showed glucose hypometabolism in bilateral frontal and temporal brain areas whereas cognition was only associated with deteriorated glucose metabolism in the left temporal lobe. The education level was significantly correlated with the residualized cognitive performance (residuals from regression analysis between hypometabolism and cognitive function as a quantitative index of reserve) and also negatively correlated with left temporal FDG-PET hypometabolism after controlling for cognition.
In patients with FTD, the education level predicts the existing left temporal FDG-PET hypometabolism at the same cognition level, supporting the cognitive reserve hypothesis in FTD.
Neurodegenerative parkinsonian syndromes comprise a number of disorders that are characterized by similar clinical features but are separated on the basis of different pathologies, i.e. aggregates of ...α-synuclein or tau protein. Due to the overlap of signs and symptoms a precise differentiation is often difficult, especially early in the disease course. Enormous efforts have been taken to develop tau-selective PET imaging agents, but strong off-target binding to MAO-B has been observed across first generation ligands. Nonetheless, astrogliosis related MAO-B elevation is a common histopathological known feature of all parkinsonian syndromes and might be itself an interesting imaging target. Therefore, this study aimed to investigate the performance of 18F-THK5351, a combined MAO-B and tau tracer for differential diagnosis of parkinsonian syndromes. 18F-THK5351 PET was performed in 34 patients: six with Parkinson’s disease (PD), nine with multiple system atrophy with predominant parkinsonism (MSA-P), six with MSA with predominant cerebellar ataxia (MSA-C) and 13 with progressive supranuclear palsy (PSP) Richardson’s syndrome. Volume-of-interest based quantification of standardized-uptake-values was conducted in different parkinsonian syndrome related target regions. PET results were subjected to multinomial logistic regression to create a prediction model discriminating among groups. Furthermore, we correlated tracer uptake with clinical findings. Elevated 18F-THK5351 uptake in midbrain and diencephalon differentiated PSP patients from PD and MSA-C. MSA-C patients were distinguishable by high tracer uptake in the pons and cerebellar deep white matter when compared to PSP and PD patients, whereas MSA-P patients tended to show higher tracer uptake in the lentiform nucleus. A multinomial logistic regression classified 33/34 patients into the correct clinical diagnosis group. Tracer uptake in the pons, cerebellar deep white matter and striatum was closely associated with the presence of cerebellar and parkinsonian symptoms of MSA patients. The current study demonstrates that combined MAO-B and tau binding of THK5351 facilitates differential diagnosis of parkinsonian syndromes. Furthermore, our data indicate a correlation of MSA phenotype with 18F-THK5351 uptake in certain brain regions, illustrating their relevance for the emergence of clinical symptoms and underlining the potential of THK5351 PET as a biomarker that correlates with pathological changes as well as with disease stage.
Purpose
In subjects with amyloid deposition, striatal accumulation of
11
C-Pittsburgh compound B (PiB) demonstrated by positron emission tomography (PET) is related to the stage of Alzheimer’s ...disease (AD). In this study, we investigated the correlation between striatal and cortical non-displaceable binding potential (
BP
ND
).
Methods
Seventy-three subjects who complained of cognitive disturbance underwent dynamic PiB-PET studies and showed positive PiB accumulation were retrospectively selected. These subjects included 34 AD, 26 mild cognitive impairment, 2 frontotemporal lobar degeneration, 2 Parkinson’s disease, 5 dementia with Lewy bodies, and 4 undefined diagnosis patients. Individual
BP
ND
images were produced from the dynamic data of the PiB-PET study, and voxel-based analyses were performed to estimate the correlations between striatal and other regional cortical
BP
ND
measures.
Results
There were highly significant correlations between striatal and prefrontal
BP
ND
, with the highest correlation being demonstrated in left Brodmann area 11. We found that almost all of the high cortical
BP
ND
values correlated with striatal
BP
ND
values, with the exception of the occipital cortex with low correlation.
Conclusion
Our study demonstrated positive correlations in amyloid deposits between the striatum and other cortical areas with functional and anatomical links. The amyloid distribution in the brain is not random, but spreads following the functional and anatomical connections.
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