Associations Between Perceived Fatigability and Amyloid Status in the Baltimore Longitudinal Study of Aging

Higher level of and greater longitudinal increase in perceived fatigability are linked to cognitive decline and lower brain volumes in older adults. However, it remains unclear whether perceived fatigability is associated with Alzheimer’s disease-related brain pathology. In the BLSA, 163 participants without neurological disease or cognitive impairment (aged 74.7+/-8.4 years, 45% men) were assessed for perceived fatigability using rating of perceived exertion after a 5-minute (0.67 m/s) treadmill walk and Aß burden using 11C-Pittsburgh compound B (PiB) positron emission tomography. Forty-four participants were PiB+ based on a mean cortical distribution volume ratio (DVR) cut point of 1.066. After adjusting for demographics, body composition, comorbidities and ApoE-e4, higher perceived fatigability was not associated with PiB+ status (OR=0.84; 95% CI: 0.69, 1.05). Results suggest perceived fatigability may contribute to cognitive decline through pathways other than Aß pathology. Future studies should target other mechanisms linking perceived fatigability and cognitive decline.

Evaluation of [18F]-JNJ-64326067-AAA tau PET tracer in humans

The [18F]-JNJ-64326067-AAA ([18F]-JNJ-067) tau tracer was evaluated in healthy older controls (HCs), mild cognitive impairment (MCI), Alzheimer’s disease (AD), and progressive supranuclear palsy (PSP) participants. Seventeen subjects (4 HCs, 5 MCIs, 5 ADs, and 3 PSPs) received a [11C]-PIB amyloid PET scan, and a tau [18F]-JNJ-067 PET scan 0-90 minutes post-injection. Only MCIs and ADs were amyloid positive. The simplified reference tissue model, Logan graphical analysis distribution volume ratio, and SUVR were evaluated for quantification. The [18F]-JNJ-067 tau signal relative to the reference region continued to increase to 90 min, indicating the tracer had not reached steady state. There was no significant difference in any bilateral ROIs for MCIs or PSPs relative to HCs; AD participants showed elevated tracer relative to controls in most cortical ROIs (P < 0.05). Only AD participants showed elevated retention in the entorhinal cortex. There was off-target signal in the putamen, pallidum, thalamus, midbrain, superior cerebellar gray, and white matter. [18F]-JNJ-067 significantly correlated (p < 0.05) with Mini-Mental State Exam in entorhinal cortex and temporal meta regions. There is clear binding of [18F]-JNJ-067 in AD participants. Lack of binding in HCs, MCIs and PSPs suggests [18F]-JNJ-067 may not bind to low levels of AD-related tau or 4 R tau.

Abnormal neuroinflammation in fibromyalgia and CRPS using [11C]-(R)-PK11195 PET

Purpose Fibromyalgia (FM) and complex regional pain syndrome (CRPS) share many pathological mechanisms related to chronic pain and neuroinflammation, which may contribute to the multifactorial pathological mechanisms in both FM and CRPS. The aim of this study was to assess neuroinflammation in FM patients compared with that in patients with CRPS and healthy controls. Methods Neuroinflammation was measured as the distribution volume ratio (DVR) of [11C]-(R)-PK11195 positron emission tomography (PET) in 12 FM patients, 11 patients with CRPS and 15 healthy controls. Results Neuroinflammation in FM patients was significantly higher in the left pre (primary motor cortex) and post (primary somatosensory cortex) central gyri (p < 0.001), right postcentral gyrus (p < 0.005), left superior parietal and superior frontal gyri (p < 0.005), left precuneus (p < 0.01), and left medial frontal gyrus (p = 0.036) compared with healthy controls. Furthermore, the DVR of [11C]-(R)-PK11195 in FM patients demonstrated decreased neuroinflammation in the medulla (p < 0.005), left superior temporal gyrus (p < 0.005), and left amygdala (p = 0.020) compared with healthy controls. Conclusions To the authors’ knowledge, this report is the first to describe abnormal neuroinflammation levels in the brains of FM patients compared with that in patients with CRPS using [11C]-(R)-PK11195 PET. The results suggested that abnormal neuroinflammation can be an important pathological factor in FM. In addition, the identification of common and different critical regions related to abnormal neuroinflammation in FM, compared with patients with CRPS and healthy controls, may contribute to improved diagnosis and the development of effective medical treatment for patients with FM.

EPCT-12. PNOC015: PHASE 1 STUDY OF MTX110 (AQUEOUS PANOBINOSTAT) DELIVERED BY CONVECTION ENHANCED DELIVERY (CED) IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PREVIOUSLY TREATED WITH RADIATION THERAPY

OBJECTIVE To determine safety and distribution of MTX110 delivered by CED in newly diagnosed DIPG patients. METHODS DIPG patients (3–21 years) were enrolled after radiation. CED of MTX110 combined with gadoteridol was completed based on dose levels (DL) (30–90 µM with volumes ranging from 3 cc (single dose) to 2 consecutive doses of 6 cc; total number of DL=7). Catheter position was chosen to maximize tumor coverage. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4–8 weeks if tolerated. Quality of life (QOL) assessments using PedsQL Generic Core and Brain Tumor modules were obtained at baseline (n=5), 3-months (n=3), and end of therapy (n=2). Single-cell RNA sequencing and analysis of histone modifications was performed to assess pharmacodynamic effects on DIPG cells. RESULTS Between May 2018-Dec 2019, 6 patients were enrolled (median age 8 years, range 5–21). Dose limiting toxicities included: grade 3 gait disturbance (DL7; cycle 1); grade 3 muscle weakness/vagus nerve disorder (DL5; cycle 4) and grade 2 intolerable dysphagia (DL7; cycle 4). Twelve CED procedures were completed at DL7 and repeated cycles ranged from 2 to 7. Infusion to distribution volume ratio was approximately 1:3.5. There were no significant changes in self-reported QOL. Parent ratings of patients’ worry (p = 0.04) and overall QOL (p = 0.03) significantly decreased at 3-months. CONCLUSION Repeat CED of MTX110 at the highest dose is tolerable. Tissue concentrations are likely to be substantially higher compared to oral dosing. Pharmacodynamic effects will be presented.

DDRE-21. PNOC015: PHASE 1 STUDY OF MTX110 DELIVERED BY CONVECTION ENHANCED DELIVERY (CED) IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PREVIOUSLY TREATED WITH RADIATION THERAPY

OBJECTIVE To determine safety and distribution of MTX110 delivered by CED in newly diagnosed DIPG patients. METHODS DIPG patients (3–21 years) were enrolled after radiation. CED of MTX110 combined with gadoteridol was completed based on dose levels (DL) (30–90 µM with volumes ranging from 3 cc (single dose) to 2 consecutive doses of 6 cc; total number of DL=7). Catheter position was chosen to maximize tumor coverage. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4–8 weeks if tolerated. Quality of life (QOL) assessments using PedsQL Generic Core and Brain Tumor modules were obtained at baseline (n=5), 3-months (n=3), and end of therapy (n=2). Single-cell RNA sequencing and analysis of histone modifications was performed to assess pharmacodynamic effects on DIPG cells. RESULTS Between May 2018-Dec 2019, 6 patients were enrolled (median age 8 years, range 5–21). Dose limiting toxicities included: grade 3 gait disturbance (DL7; cycle 1); grade 3 muscle weakness/vagus nerve disorder (DL5; cycle 4) and grade 2 intolerable dysphagia (DL7; cycle 4). Twelve CED procedures were completed at DL7 and repeated cycles ranged from 2 to 7. Infusion to distribution volume ratio was approximately 1:3.5. There were no significant changes in self-reported QOL. Parent ratings of patients’ worry (p = 0.04) and overall QOL (p = 0.03) significantly decreased at 3-months. CONCLUSION Repeat CED of MTX110 at the highest dose is tolerable. Tissue concentrations are likely to be substantially higher compared to oral dosing. Pharmacodynamic effects will be presented.

Insights into disseminated MS brain pathology with multimodal diffusion tensor and PET imaging

ObjectiveTo evaluate in vivo the co-occurrence of microglial activation and microstructural white matter (WM) damage in the MS brain and to examine their association with clinical disability.Methods18-kDa translocator protein (TSPO) brain PET imaging was performed for evaluation of microglial activation by using the radioligand [11C](R)-PK11195. TSPO binding was evaluated as the distribution volume ratio (DVR) from dynamic PET images. Diffusion tensor imaging (DTI) and conventional MRI (cMRI) were performed at the same time. Mean fractional anisotropy (FA) and mean (MD), axial, and radial (RD) diffusivities were calculated within the whole normal-appearing WM (NAWM) and segmented NAWM regions appearing normal in cMRI. Fifty-five patients with MS and 15 healthy controls (HCs) were examined.ResultsMicrostructural damage was observed in the NAWM of the MS brain. DTI parameters of patients with MS were significantly altered in the NAWM compared with an age- and sex-matched HC group: mean FA was decreased, and MD and RD were increased. These structural abnormalities correlated with increased TSPO binding in the whole NAWM and in the temporal NAWM (p < 0.05 for all correlations; p < 0.01 for RD in the temporal NAWM). Both compromised WM integrity and increased microglial activation in the NAWM correlated significantly with higher clinical disability measured with the Expanded Disability Status Scale score.ConclusionsWidespread structural disruption in the NAWM is linked to neuroinflammation, and both phenomena associate with clinical disability. Multimodal PET and DTI allow in vivo evaluation of widespread MS pathology not visible using cMRI.

Head-to-head comparison of tau positron emission tomography tracers [18F]flortaucipir and [18F]RO948

Purpose [18F]flortaucipir binds to paired helical filament tau and accurately identifies tau in Alzheimer’s disease (AD). However, “off-target” binding interferes with the quantification of [18F]flortaucipir in several brain regions. Recently, other tau PET tracers have been developed. Here, we compare [18F]flortaucipir with the novel tau tracer [18F]RO948 head-to-head in vivo. Methods We included 18 participants with AD, three with amyloid-β-positive amnestic mild cognitive impairment, and four healthy controls. All underwent [18F]flortaucipir (80–100 min) and [18F]RO948 (70–90) PET scans within approximately 1 month. Four study participants underwent 0–100-min dynamic scanning. Standardized uptake value ratios (SUVRs) were created using an inferior cerebellar reference region. Results Neocortical tracer retention was highly comparable using both SUVR and distribution volume ratio-1 values obtained from dynamic scans. However, [18F]RO948 retention was significantly higher in the entorhinal cortex and lower in the basal ganglia, thalamus, and choroid plexus compared with [18F]flortaucipir. Increased off-target binding was observed with age for both tracers. Several cases exhibited strong [18F]RO948 retention in the skull/meninges. This extra-cerebral signal, however, did not affect diagnostic accuracy and remained relatively unchanged when re-examining a subsample after 1 year. Kinetic modeling showed an increase in [18F]flortaucipir SUVR over the scanning interval, compared with a plateau for [18F]RO948. Conclusion [18F]RO948 and [18F]flortaucipir bound comparably in neocortical regions, but [18F]RO948 showed higher retention in the medial temporal lobe and lower intracerebral “off-target” binding. Time-dependent bias of SUVR estimates may prove less of a factor with [18F]RO948, compared with previous tau ligands.

Taylor-Couette Column for Emulsion Liquid Membrane System: Characterisation Study

Study on the application of Taylor-Couette column for emulsion liquid membrane system has been done. To optimise extraction process under TCC, a research to investigate effect of viscosity and cylinders rotation is of important. Fluid viscosity was examined by varying volume ratio of kerosene to water. TCC was characterised to determine flow regimes, shear stress, and energy loss distribution. Volume ratio of oil to water was varied at 1:1, 1:3, 1:5, and 1:6 while inner and outer cylinders speed were maintained constant at 300 and 200 rpm, respectively. Investigation on the effect of volume ratio of oil to water towards flow regime ended to same flow regime of Featureless Turbulent. There was degradation of wall shear stress from 8.57x10-2 Pa to 7.42x10-2 Pa.

Parametric methods for [18F]flortaucipir PET

[18F]Flortaucipir is a PET tau tracer used to visualize tau binding in Alzheimer’s disease (AD) in vivo. The present study evaluated the performance of several methods to obtain parametric images of [18F]flortaucipir. One hundred and thirty minutes dynamic PET scans were performed in 10 AD patients and 10 controls. Parametric images were generated using different linearization and basis function approaches. Regional binding potential (BPND) and volume of distribution (VT) values obtained from the parametric images were compared with corresponding values derived using the reversible two-tissue compartment model (2T4k_VB). Performance of SUVr parametric images was assessed by comparing values with distribution volume ratio (DVR) and SRTM-derived BPND estimates obtained using non-linear regression (NLR). Spectral analysis (SA) ( r2 = 0.92; slope = 0.99) derived VT correlated well with NLR-derived VT. RPM ( r2 = 0.95; slope = 0.98) derived BPND correlated well with NLR-derived DVR. Although SUVr80–100 min correlated well with NLR-derived DVR ( r2 = 0.91; slope = 1.09), bias in SUVr appeared to depend on uptake time and underlying level of specific binding. In conclusion, RPM and SA provide parametric images comparable to the NLR estimates. Individual SUVr values are biased compared with DVR and this bias requires further study in a larger dataset in order to understand its consequences.

Quantification of [18F]florbetapir: A test–retest tracer kinetic modelling study

Accumulation of amyloid beta can be visualized using [18F]florbetapir positron emission tomography. The aim of this study was to identify the optimal model for quantifying [18F]florbetapir uptake and to assess test–retest reliability of corresponding outcome measures. Eight Alzheimer’s disease patients (age: 67 ± 6 years, Mini-Mental State Examination (MMSE): 23 ± 3) and eight controls (age: 63 ± 4 years, MMSE: 30 ± 0) were included. Ninety-minute dynamic positron emission tomography scans, together with arterial blood sampling, were acquired immediately following a bolus injection of 294 ± 32 MBq [18F]florbetapir. Several plasma input models and the simplified reference tissue model (SRTM) were evaluated. The Akaike information criterion was used to identify the preferred kinetic model. Compared to controls, Alzheimer’s disease patients had lower MMSE scores and evidence for cortical Aβ pathology. A reversible two-tissue compartment model with fitted blood volume fraction (2T4k_VB) was the preferred model for describing [18F]florbetapir kinetics. SRTM-derived non-displaceable binding potential (BPND) correlated well (r2 = 0.83, slope = 0.86) with plasma input-derived distribution volume ratio. Test–retest reliability for plasma input-derived distribution volume ratio, SRTM-derived BPND and SUVr(50–70) were r = 0.88, r = 0.91 and r = 0.86, respectively. In vivo kinetics of [18F]florbetapir could best be described by a reversible two-tissue compartmental model and [18F]florbetapir BPND can be reliably estimated using an SRTM.