Diagnostic yield of whole-body 18F-FDG PET/CT in patients with suspected cardiac sarcoidosis.

BACKGROUND: Whole-body F-18 FDG PET has been included in the 2014 Heart Rhythm Society guidelines for cardiac sarcoidosis evaluation to identify alternate sites of biopsy prior to endomyocardial biopsy. The purpose of this study was to evaluate the diagnostic yield of whole-body F-18 FDG PET/CT. METHODS: All adult patients with suspected cardiac sarcoidosis undergoing same-day cardiac F-18 FDG PET/CT and whole-body F-18 FDG PET/CT between 10/1/2016 and 6/14/2021 to assess potential biopsy sites were retrospectively identified. Clinical indications, findings, recommendations, and outcomes were assessed. RESULTS: Eighty-eight patients were included. Extracardiac PET findings suggestive of sarcoidosis were present in 30 patients (34%), 27 of which had thoracic findings (90%). Sarcoidosis was diagnosed in 11% of patients. Only 1% (1/88) was diagnosed by extrathoracic biopsy of a whole-body PET finding. Incidental findings were common (31%), resulting in 11 additional tests or interventions. Recommendations from extrathoracic findings affected treatment in one case: a drainage catheter placement into an unsuspected pelvic abscess. CONCLUSION: Addition of whole-body F-18 FDG PET/CT to cardiac F-18 FDG PET/CT for the identification of extrathoracic sites of biopsy in patients with suspected cardiac sarcoidosis has marginal diagnostic yield but commonly results in incidental findings that rarely affect patient outcome.

Quantifying cardiac sympathetic denervation: first studies of 18F-fluorohydroxyphenethylguanidines in cardiomyopathy patients.

PURPOSE: 4-18F-Fluoro-m-hydroxyphenethylguanidine (18F-4F-MHPG) and 3-18F-fluoro-p-hydroxyphenethylguanidine (18F-3F-PHPG) were developed for quantifying regional cardiac sympathetic nerve density using tracer kinetic analysis. The aim of this study was to evaluate their performance in cardiomyopathy patients. METHODS: Eight cardiomyopathy patients were scanned with 18F-4F-MHPG and 18F-3F-PHPG. Also, regional resting perfusion was assessed with 13N-ammonia. 18F-4F-MHPG and 18F-3F-PHPG kinetics were analyzed using the Patlak graphical method to obtain Patlak slopes Kp (mL/min/g) as measures of regional nerve density. Patlak slope polar maps were used to evaluate the pattern and extent of cardiac denervation. For comparison, "retention index" (RI) values (mL blood/min/mL tissue) were also calculated and used to assess denervation. Perfusion polar maps were used to estimate the extent of hypoperfusion. RESULTS: Patlak analysis of 18F-4F-MHPG and 18F-3F-PHPG kinetics was successful in all subjects, demonstrating the robustness of this approach in cardiomyopathy patients. Substantial regional denervation was observed in all subjects, ranging from 25 to 74% of the left ventricle. Denervation zones were equal to or larger than the size of corresponding areas of hypoperfusion. The two tracers provided comparable metrics of regional nerve density and the extent of left ventricular denervation. 18F-4F-MHPG exhibited faster liver clearance than 18F-3F-PHPG, reducing spillover from the liver into the inferior wall. 18F-4F-MHPG was also metabolized more consistently in plasma, which may allow application of population-averaged metabolite corrections. CONCLUSION: The advantages of 18F-4F-MHPG (more rapid liver clearance, more consistent metabolism in plasma) make it the better imaging agent to carry forward into future clinical studies in patients with cardiomyopathy. TRIAL REGISTRATION: Registered at the ClinicalTrials.gov website (NCT02669563). URL: https://clinicaltrials.gov/ct2/show/NCT02669563.

Differential cholinergic systems' changes in progressive supranuclear palsy versus Parkinson's disease: an exploratory analysis.

Prior studies indicate more severe brainstem cholinergic deficits in Progressive Supranuclear Palsy (PSP) compared to Parkinson's disease (PD), but the extent and topography of subcortical deficits remains poorly understood. The objective of this study is to investigate differential cholinergic systems changes in progressive supranuclear palsy (PSP, n = 8) versus Parkinson's disease (PD, n = 107) and older controls (n = 19) using vesicular acetylcholine transporter [18F]-fluoroethoxybenzovesamicol (FEOBV) positron emission tomography (PET). A whole-brain voxel-based PET analysis using Statistical Parametric Mapping (SPM) software (SPM12) for inter-group comparisons using parametric [18F]-FEOBV DVR images. Voxel-based analyses showed lower FEOBV binding in the tectum, metathalamus, epithalamus, pulvinar, bilateral frontal opercula, anterior insulae, superior temporal pole, anterior cingulum, some striatal subregions, lower brainstem, and cerebellum in PSP versus PD (p < 0.05; false discovery rate-corrected). More severe and diffuse reductions were present in PSP vs controls. Higher frequency of midbrain cholinergic losses was seen in PSP compared to the PD participants using 5th percentile normative cut-off values (χ2 = 4.12, p < 0.05). When compared to PD, these findings suggested disease-specific cholinergic vulnerability in the tectum, striatal cholinergic interneurons, and projections from the pedunculopontine nucleus, medial vestibular nucleus, and the cholinergic forebrain in PSP.

Cholinergic system changes of falls and freezing of gait in Parkinson's disease.

OBJECTIVE: Postural instability and gait difficulties (PIGDs) represent debilitating disturbances in Parkinson's disease (PD). Past acetylcholinesterase positron emission tomography (PET) imaging studies implicate cholinergic changes as significant contributors to PIGD features. These studies were limited in quantification of striatal cholinergic synapse integrity. Vesicular acetylcholine transporter (VAChT) PET ligands are better suited for evaluation of high binding areas. We examined associations between regional VAChT expression and freezing of gait (FoG) and falls. METHODS: Ninety-four PD subjects underwent clinical assessment and VAChT ([18 F]FEOBV) PET. RESULTS: Thirty-five subjects (37.2%) reported a history of falls, and 15 (16%) had observed FoG. Univariate volume-of-interest analyses demonstrated significantly reduced thalamic (p = 0.0016) VAChT expression in fallers compared to nonfallers. VAChT expression was significantly reduced in the striatum (p = 0.0012) and limbic archicortex (p = 0.004) in freezers compared to nonfreezers. Whole-brain voxel-based analyses of FEOBV PET complemented these findings and showed more granular changes associated with falling history, including the right visual thalamus (especially the right lateral geniculate nucleus [LGN]), right caudate nucleus, and bilateral prefrontal regions. Freezers had prominent VAChT expression reductions in the bilateral striatum, temporal, and mesiofrontal limbic regions. INTERPRETATION: Our findings confirm and extend on previous PET findings of thalamic cholinergic deficits associated with falling history and now emphasize right visual thalamus complex changes, including the right LGN. FoG status is associated with reduced VAChT expression in striatal cholinergic interneurons and the limbic archicortex. These observations suggest different cholinergic systems changes underlying falls and FoG in PD. Ann Neurol 2019;85:538-549.

Topography of Cholinergic Changes in Dementia With Lewy Bodies and Key Neural Network Hubs.

OBJECTIVES: The authors investigated the topography of cholinergic vulnerability in patients with dementia with Lewy bodies (DLB) using positron emission tomography (PET) imaging with the vesicular acetylcholine transporter (VAChT) [18F]-fluoroethoxybenzovesamicol ([18F]-FEOBV) radioligand. METHODS: Five elderly participants with DLB (mean age, 77.8 years [SD=4.2]) and 21 elderly healthy control subjects (mean age, 73.62 years [SD=8.37]) underwent clinical assessment and [18F]-FEOBV PET. RESULTS: Compared with the healthy control group, reduced VAChT binding in patients with DLB demonstrated nondiffuse regionally distinct and prominent reductions in bilateral opercula and anterior cingulate to mid-cingulate cortices, bilateral insula, right (more than left) lateral geniculate nuclei, pulvinar, right proximal optic radiation, bilateral anterior and superior thalami, and posterior hippocampal fimbria and fornices. CONCLUSIONS: The topography of cholinergic vulnerability in DLB comprises key neural hubs involved in tonic alertness (cingulo-opercular), saliency (insula), visual attention (visual thalamus), and spatial navigation (fimbria/fornix) networks. The distinct denervation pattern suggests an important cholinergic role in specific clinical disease-defining features, such as cognitive fluctuations, visuoperceptual abnormalities causing visual hallucinations, visuospatial changes, and loss of balance caused by DLB.

Effects of Tumor Burden on Reference Tissue Standardized Uptake for PET Imaging: Modification of PERCIST Criteria.

Purpose To examine the effect metabolic burden (tumor and/or cardiac myocyte uptake) has on fluorine 18 fluorodeoxyglucose (FDG) distribution in organs and tissues of interest. Materials and Methods Positron emission tomographic (PET)/computed tomographic (CT) scans at the Ann Arbor Veterans Affairs hospital from January to July 2015 were reviewed. A total of 107 scans (50 patients; mean age, 64.3 years ± 13.2 [standard deviation]) had metabolic tissue burden assessed by using total lesion glycolysis (TLG) obtained from autosegmentation of the tumor and/or cardiac tissue. Standardized uptake value (SUV) and subsequent normalized SUV uptake in target organs and tissues were compared with 436 FDG PET/CT scans previously reported in 229 patients as a function of TLG to describe the effect(s) that metabolic burden has on reference tissue (blood pool, liver, and brain) FDG uptake. Subsequent regression by using linear mixed-effects models was used. If the slope of the regression was significantly (P < .05) different than zero, then an effect from TLG was present. Results There was a negative inverse relationship (P < .0001) between FDG uptake within reference tissues (blood pool, liver, and brain) and TLG in comparison to the study population at similar blood glucose levels. This TLG effect was no longer statistically significant (P > .05) when FDG uptake was normalized to a reference tissue (eg, blood pool or liver). Conclusion Metabolic tissue burden can have a significant effect on SUV measurements for PET imaging. This effect can be mitigated by normalizing FDG uptake to a reference tissue. © RSNA, 2018.

Molecular Imaging and Updated Diagnostic Criteria in Lewy Body Dementias.

PURPOSE OF REVIEW: The aims of the study were to review recent advances in molecular imaging in the Lewy body dementias (LBD) and determine if these may support the clinical but contested temporal profile distinction between Parkinson disease (PD) with dementia (PDD) versus dementia with Lewy bodies (DLB). RECENT FINDINGS: There do not appear to be major regional cerebral metabolic or neurotransmitter distinctions between PDD and DLB. However, recent studies highlight the relative discriminating roles of Alzheimer proteinopathies. PDD patients have lower cortical ß-amyloid deposition than DLB. Preliminary tau PET studies suggest a gradient of increasing tau binding from cognitively normal PD (absent to lowest) to cognitively impaired PD (low) to DLB (intermediate) to Alzheimer disease (AD; highest). However, tau binding in DLB, including the medial temporal lobe, is substantially lower than in AD. Alzheimer-type proteinopathies appear to be more common in DLB compared to PDD with relative but no absolute differences. Given the spectrum of overlapping pathologies, future α-synuclein ligands are expected to have the best potential to distinguish the LBD from pure AD.

Post-Mortem evaluation of amyloid-dopamine terminal positron emission tomography dementia classifications.

Clinical classification of early dementia and mild cognitive impairment (MCI) is imprecise. We reported previously that molecular imaging classification of early dementia and MCI with dual amyloid and dopamine terminal positron emission tomography differs significantly from expert clinical classification. We now report pathological diagnoses in a substantial subset of our previously imaged subjects. Among 36 subjects coming to autopsy, imaging classifications and pathological diagnosis were concordant in 33 cases (κ = 0.85). This approach enhanced specificity of Alzheimer's disease diagnosis. The strong concordance of imaging-based classifications and pathological diagnoses suggests that this imaging approach will be useful in establishing more accurate and convenient classification biomarkers for dementia research.

Striatal and Cortical ß-Amyloidopathy and Cognition in Parkinson's Disease.

INTRODUCTION: Although most previous cognitive studies of ß-amyloidopathy in PD focused on cortical plaque deposition, recent postmortem studies point to an important role of striatal ß-amyloid plaque deposition. The aim of this study was to investigate the relative contributions of striatal and cortical ß-amyloidopathy to cognitive impairment in PD. METHODS: Patients with PD (n = 62; age, 68.9 ± 6.4 years; H & Y stage: 2.7 ± 0.5; MoCA score: 25.2 ± 3.0) underwent [(11) C]Pittsburgh compound B ß-amyloid, [(11) C]dihydrotetrabenazine monoaminergic, and [(11) C]methyl-4-piperidinyl propionate acetylcholinesterase brain PET imaging and neuropsychological assessment. [(11) C]Pittsburgh compound B ß-amyloid data from young to middle-aged healthy subjects were used to define elevated [(11) C]Pittsburgh compound B binding in patients. RESULTS: Elevated cortical and striatal ß-amyloid deposition were present in 37% and 16%, respectively, of this predominantly nondemented cohort of patients with PD. Increased striatal ß-amyloid deposition occurred in half of all subjects with increased cortical ß-amyloid deposition. In contrast, increased striatal ß-amyloid deposition did not occur in the absence of increased cortical ß-amyloid deposition. Analysis of covariance using global composite cognitive z scores as the outcome parameter showed significant regressor effects for combined striatal and cortical ß-amyloidopathy (F = 4.18; P = 0.02) after adjusting for covariate effects of cortical cholinergic activity (F = 5.67; P = 0.02), caudate nucleus monoaminergic binding, duration of disease, and age (total model: F = 3.55; P = 0.0048). Post-hoc analysis showed significantly lower cognitive z score for combined striatal and cortical ß-amyloidopathy, compared to cortical-only ß-amyloidopathy and non-ß-amyloidopathy subgroups. CONCLUSIONS: The combined presence of striatal and cortical ß-amyloidopathy is associated with greater cognitive impairment than cortical ß-amyloidopathy alone in PD.

Prevalence of impaired odor identification in Parkinson disease with imaging evidence of nigrostriatal denervation.

There is wide variability in the reported prevalence rates of abnormal smell in Parkinson disease (PD). This study assessed the prevalence of abnormal smell, using the University of Pennsylvania Smell Identification Test (UPSIT), in 183 patients with PD with confirmed PET imaging evidence of nigrostriatal denervation. Impaired olfaction in this sample was nearly universal (97.8 %). Wide-ranging prior olfactory impairment estimates may reflect not only uncertainty regarding diagnostic classification, but also the use of inaccurate normative data and differences in olfactory tests used.

Clinical markers for identifying cholinergic deficits in Parkinson's disease.

BACKGROUND: Cholinergic projection systems degeneration is associated with dopamine nonresponsive features of Parkinson's disease (PD). Cholinergic deficits are variable in nondemented PD. Identification of cholinergic deficits in PD may help with selection of suitable patients for targeted cholinergic drug treatment in PD. The objective of this retrospective multivariate predictor analysis study was to identify clinical markers indicative of cholinergic deficits in PD patients, as assessed by acetylcholinesterase ([(11) C]PMP) positron emission tomography. METHODS: One hundred thirty-seven PD patients (34 female) participated; median modified Hoehn and Yahr score was 2.5 (range, 1-4), average age 65.6 ± 7.4 years, and average duration of motor disease symptoms of 6.0 ± 4.2 years. Subjects were dichotomized as "normocholinergic" or "hypocholinergic" based on a 5(th) percentile cutoff from normal for the basal forebrain-cortical and pedunculopontine nucleus-thalamic cholinergic projection systems. Previously identified clinical indices of cholinergic denervation were used for statistical prediction of cholinergic deficits. Logistic regression determined which risk factors predicted cholinergic deficits. Sensitivity, specificity, and accuracy were determined for the (combinations of) significant predictor variables. RESULTS: Forty-nine (35.8%) hypocholinergic PD subjects were identified. The combination of rapid eye movement (REM) sleep behavior disorder (RBD) symptoms and fall history showed highest diagnostic accuracy (81.1%) for predicting combined thalamic and cortical cholinergic deficits. A combined assessment of 8.5 m walk time and lower score on the Montreal cognitive assessment scale provided diagnostic accuracy of 80.7% for predicting isolated cortical cholinergic denervation. CONCLUSION: Assessment of clinical indices of cholinergic denervation may be useful for identifying suitable subjects for trials of targeted cholinergic drug treatments in PD.

Amyloid deposition in Parkinson's disease and cognitive impairment: a systematic review.

BACKGROUND: Varying degrees of cortical amyloid deposition are reported in the setting of Parkinsonism with cognitive impairment. We performed a systematic review to estimate the prevalence of Alzheimer disease (AD) range cortical amyloid deposition among patients with Parkinson's disease with dementia (PDD), Parkinson's disease with mild cognitive impairment (PD-MCI) and dementia with Lewy bodies (DLB). We included amyloid positron emission tomography (PET) imaging studies using Pittsburgh Compound B (PiB). METHODS: We searched the databases Ovid MEDLINE, PubMed, Embase, Scopus, and Web of Science for articles pertaining to amyloid imaging in Parkinsonism and impaired cognition. We identified 11 articles using PiB imaging to quantify cortical amyloid. We used the metan module in Stata, version 11.0, to calculate point prevalence estimates of patients with "PiB-positive" studies, that is, patients showing AD range cortical Aß-amyloid deposition. Heterogeneity was assessed. A scatterplot was used to assess publication bias. RESULTS: Overall pooled prevalence of "PiB-positive" studies across all three entities along the spectrum of Parkinson's disease and impaired cognition (specifically PDD, PD-MCI, and DLB) was 0.41 (95% confidence interval [CI], 0.24-0.57). Prevalence of "PiB-positive" studies was 0.68 (95% CI, 0.55-0.82) in the DLB group, 0.34 (95% CI, 0.13-0.56) in the PDD group, and 0.05 (95% CI, -0.07-0.17) in the PD-MCI group. CONCLUSIONS: Substantial variability occurs in the prevalence of "PiB-positive" studies in subjects with Parkinsonism and cognitive impairment. Higher prevalence of PiB-positive studies was encountered among subjects with DLB as opposed to subjects with PDD. The PD-MCI subjects showed overall lower prevalence of PiB-positive studies than reported findings in non-PD-related MCI. © 2015 International Parkinson and Movement Disorder Society.

Educational attainment and motor burden in Parkinson's disease.

OBJECTIVE: Greater educational attainment is a protective factor for neurodegenerative dementias. If education earlier in life leads to greater cerebral reserve, it may play a similar protective role in Parkinson's disease (PD). METHODS: We conducted a cross-sectional clinical imaging study of 142 subjects with PD. All subjects underwent [(11)C]dihydrotetrabenazine PET to confirm nigrostriatal dopaminergic denervation and brain MRI to estimate adjusted cortical gray matter volume (GMV). RESULTS: After adjusting for possible confounders, including cognitive and dopaminergic covariates, as well as nonspecific neurodegeneration covariates (age, disease duration, and total adjusted cortical GMV), lower years of education remained a significant predictor of higher total MDS-UPDRS motor score (t = -3.28; P = 0.001). Education level associated inversely with white matter (WM) hyperintensities in a post-hoc analysis (n = 83). CONCLUSIONS: Higher educational attainment is associated with lower severity of motor impairment in PD. This association may reflect an extranigral protective effect upon WM integrity.

Extra-nigral pathological conditions are common in Parkinson's disease with freezing of gait: an in vivo positron emission tomography study.

Cholinergic denervation has been associated with falls and slower gait speed and ß-amyloid deposition with greater severity of axial motor impairments in Parkinson disease (PD). However, little is known about the association between the presence of extra-nigral pathological conditions and freezing of gait (FoG). Patients with PD (n = 143; age, 65.5 ± 7.4 years, Hoehn and Yahr stage, 2.4 ± 0.6; Montreal Cognitive Assessment score, 25.9 ± 2.6) underwent [(11) C]methyl-4-piperidinyl propionate acetylcholinesterase and [(11) C]dihydrotetrabenazine dopaminergic PET imaging, and clinical, including FoG, assessment in the dopaminergic "off" state. A subset of subjects (n = 61) underwent [(11) C]Pittsburgh compound-B ß-amyloid positron emission tomography (PET) imaging. Normative data were used to dichotomize abnormal ß-amyloid uptake or cholinergic deficits. Freezing of gait was present in 20 patients (14.0%). Freezers had longer duration of disease (P = 0.009), more severe motor disease (P < 0.0001), and lower striatal dopaminergic activity (P = 0.013) compared with non-freezers. Freezing of gait was more common in patients with diminished neocortical cholinergic innervation (23.9%, χ(2) = 5.56, P = 0.018), but not in the thalamic cholinergic denervation group (17.4%, χ(2) = 0.26, P = 0.61). Subgroup analysis showed higher frequency of FoG with increased neocortical ß-amyloid deposition (30.4%, Fisher Exact test: P = 0.032). Frequency of FoG was lowest with absence of both pathological conditions (4.8%), intermediate in subjects with single extra-nigral pathological condition (14.3%), and highest with combined neocortical cholinopathy and amyloidopathy (41.7%; Cochran-Armitage trend test, Z = 2.63, P = 0.015). Within the group of freezers, 90% had at least one of the two extra-nigral pathological conditions studied. Extra-nigral pathological conditions, in particular the combined presence of cortical cholinopathy and amyloidopathy, are common in PD with FoG and may contribute to its pathophysiology. © 2014 International Parkinson and Movement Disorder Society.

Brain PET in suspected dementia: patterns of altered FDG metabolism.

The diagnosis of dementia syndromes can be challenging for clinicians, particularly in the early stages of disease. Patients with higher education levels may experience a marked decline in cognitive function before their dementia is detectable with routine testing methods. In addition, comorbid conditions (eg, depression) and the use of certain medications can confound the clinical assessment. Clinicians require a high degree of certainty before making a diagnosis of Alzheimer disease or some other neurodegenerative disorder, since the impact on patients and their families can be devastating. Moreover, accurate diagnosis is important because emerging therapeutic regimens vary depending on the cause of the dementia. Clinically based testing is useful; however, the results usually do not enable the clinician to make a definitive diagnosis. For this reason, imaging biomarkers are playing an increasingly important role in the workup of patients with suspected dementia. Positron emission tomography with 2-[fluorine-18]fluoro-2-deoxy-D-glucose allows detection of neurodegenerative disorders earlier than is otherwise possible. Accurate interpretation of these studies requires recognition of typical metabolic patterns caused by dementias and of artifacts introduced by image processing. Although visual interpretation is a vital component of image analysis, computer-assisted diagnostic software has been shown to increase diagnostic accuracy.

Thalamic cholinergic innervation and postural sensory integration function in Parkinson's disease.

The pathophysiology of postural instability in Parkinson's disease remains poorly understood. Normal postural function depends in part on the ability of the postural control system to integrate visual, proprioceptive, and vestibular sensory information. Degeneration of cholinergic neurons in the brainstem pedunculopontine nucleus complex and their thalamic efferent terminals has been implicated in postural control deficits in Parkinson's disease. Our aim was to investigate the relationship of cholinergic terminal loss in thalamus and cortex, and nigrostriatal dopaminergic denervation, on postural sensory integration function in Parkinson's disease. We studied 124 subjects with Parkinson's disease (32 female/92 male; 65.5 ± 7.4 years old; 6.0 ± 4.2 years motor disease duration; modified Hoehn and Yahr mean stage 2.4 ± 0.5) and 25 control subjects (10 female/15 male, 66.8 ± 10.1 years old). All subjects underwent (11)C-dihydrotetrabenazine vesicular monoaminergic transporter type 2 and (11)C-methylpiperidin-4-yl propionate acetylcholinesterase positron emission tomography and the sensory organization test balance platform protocol. Measures of dopaminergic and cholinergic terminal integrity were obtained, i.e. striatal vesicular monoaminergic transporter type 2 binding (distribution volume ratio) and thalamic and cortical acetylcholinesterase hydrolysis rate per minute (k3), respectively. Total centre of pressure excursion (speed), a measure of total sway, and sway variability were determined for individual sensory organization test conditions. Based on normative data, principal component analysis was performed to reduce postural sensory organization functions to robust factors for regression analysis with the dopaminergic and cholinergic terminal data. Factor analysis demonstrated two factors with eigenvalues >2 that explained 52.2% of the variance, mainly reflecting postural sway during sensory organization test Conditions 1-3 and 5, respectively. Regression analysis of the Conditions 1-3 postural sway-related factor [R(2)adj = 0.123, F(5,109) = 4.2, P = 0.002] showed that decreased thalamic cholinergic innervation was associated with increased centre of pressure sway speed (ß = -0.389, t = -3.4, P = 0.001) while controlling for covariate effects of cognitive capacity and parkinsonian motor impairments. There was no significant effect of cortical cholinergic terminal deficits or striatal dopaminergic terminal deficits. This effect could only be found for the subjects with Parkinson's disease. We conclude that postural sensory integration function of subjects with Parkinson's disease is modulated by pedunculopontine nucleus-thalamic but not cortical cholinergic innervation. Impaired integrity of pedunculopontine nucleus cholinergic neurons and their thalamic efferents play a role in postural control in patients with Parkinson's disease, possibly by participating in integration of multimodal sensory input information.

3-[18F]Fluoro-para-hydroxyphenethylguanidine (3-[18F]pHPG) PET-A Novel Imaging Modality for Paraganglioma.

Context: Functional positron emission tomography (PET) imaging for the characterization of pheochromocytoma and paraganglioma (PCC/PGL) and for detection of metastases in malignant disease, offers valuable clinical insights that can significantly guide patient treatment. Objective: This work aimed to evaluate a novel PET radiotracer, 3-[18F]fluoro-para-hydroxyphenethylguanidine (3-[18F]pHPG), a norepinephrine analogue, for its ability to localize PCC/PGL. Methods: 3-[18F]pHPG PET/CT whole-body scans were performed on 16 patients (8 male:8 female; mean age 47.6 ± 17.6 years; range, 19-74 years) with pathologically confirmed or clinically diagnosed PCC/PGL. After intravenous administration of 304 to 475 MBq (8.2-12.8 mCi) of 3-[18F]pHPG, whole-body PET scans were performed at 90 minutes in all patients. 3-[18F]pHPG PET was interpreted for abnormal findings consistent with primary tumor or metastasis, and biodistribution in normal organs recorded. Standardized uptake value (SUV) measurements were obtained for target lesions and physiological organ distributions. Results: 3-[18F]pHPG PET showed high radiotracer uptake and trapping in primary tumors, and metastatic tumor lesions that included bone, lymph nodes, and other solid organ sites. Physiological biodistribution was universally present in salivary glands (parotid, submandibular, sublingual), thyroid, heart, liver, adrenals, kidneys, and bladder. Comparison [68Ga]DOTATATE PET/CT was available in 10 patients and in all cases showed concordant distribution. Comparison [123I]meta-iodobenzylguanidine [123I]mIBG planar scintigraphy and SPECT/CT scans were available for 4 patients, with 3-[18F]pHPG showing a greater number of metastatic lesions. Conclusion: We found the kinetic profile of 3-[18F]pHPG PET affords high activity retention within benign and metastatic PCC/PGL. Therefore, 3-[18F]pHPG PET imaging provides a novel modality for functional imaging and staging of malignant paraganglioma with advantages of high lesion affinity, whole-body coregistered computed tomography, and rapid same-day imaging.

SPECT/CT Image-Derived Absorbed Dose to Red Marrow Correlates with Hematologic Toxicity in Patients Treated with [177Lu]Lu-DOTATATE.

Hematologic toxicity, although often transient, is the most common limiting adverse effect during somatostatin peptide receptor radionuclide therapy. This study investigated the association between Monte Carlo-derived absorbed dose to the red marrow (RM) and hematologic toxicity in patients being treated for their neuroendocrine tumors. Methods: Twenty patients each receiving 4 treatment cycles of [177Lu]Lu-DOTATATE were included. Multiple-time-point 177Lu SPECT/CT imaging-based RM dosimetry was performed using an artificial intelligence-driven workflow to segment vertebral spongiosa within the field of view (FOV). This workflow was coupled with an in-house macroscale/microscale Monte Carlo code that incorporates a spongiosa microstructure model. Absorbed dose estimates to RM in lumbar and thoracic vertebrae within the FOV, considered as representations of the whole-body RM absorbed dose, were correlated with hematologic toxicity markers at about 8 wk after each cycle and at 3- and 6-mo follow-up after completion of all cycles. Results: The median of absorbed dose to RM in lumbar and thoracic vertebrae within the FOV (D median,vertebrae) ranged from 0.019 to 0.11 Gy/GBq. The median of cumulative absorbed dose across all 4 cycles was 1.3 Gy (range, 0.6-2.5 Gy). Hematologic toxicity was generally mild, with no grade 2 or higher toxicity for platelets, neutrophils, or hemoglobin. However, there was a decline in blood counts over time, with a fractional value relative to baseline at 6 mo of 74%, 97%, 57%, and 97%, for platelets, neutrophils, lymphocytes, and hemoglobin, respectively. Statistically significant correlations were found between a subset of hematologic toxicity markers and RM absorbed doses, both during treatment and at 3- and 6-mo follow-up. This included a correlation between the platelet count relative to baseline at 6-mo follow up: D median,vertebrae (r = -0.64, P = 0.015), D median,lumbar (r = -0.72, P = 0.0038), D median,thoracic (r = -0.58, P = 0.029), and D average,vertebrae (r = -0.66, P = 0.010), where D median,lumbar and D median,thoracic are median absorbed dose to the RM in the lumbar and thoracic vertebrae, respectively, within the FOV and D average,vertebrae is the mass-weighted average absorbed dose of all vertebrae. Conclusion: This study found a significant correlation between image-derived absorbed dose to the RM and hematologic toxicity, including a relative reduction of platelets at 6-mo follow up. These findings indicate that absorbed dose to the RM can potentially be used to understand and manage hematologic toxicity in peptide receptor radionuclide therapy.