PET Standardized Uptake Value Research Articles

Porphyrin-Based Self-Assembled Nanoparticles for PET/MR Imaging of Sentinel Lymph Node Metastasis.

Diagnosing of lymph node metastasis is challenging sometimes, and multimodal imaging offers a promising method to improve the accuracy. This work developed porphyrin-based nanoparticles (68Ga-F127-TAPP/TCPP(Mn) NPs) as PET/MR dual-modal probes for lymph node metastasis imaging by a simple self-assembly method. Compared with F127-TCPP(Mn) NPs, F127-TAPP/TCPP(Mn) NPs synthesized by amino-porphyrins (TAPP) doping can not only construct PET/MR bimodal probes but also improve the T1 relaxivity (up to 456%). Moreover, T1 relaxivity can be adjusted by altering the molar ratio of TAPP/TCPP(Mn) and the concentration of F127. However, a similar increase in T1 relaxivity was not observed in the F127-TCPP/TCPP(Mn) NPs, which were synthesized using carboxy-porphyrins (TCPP) doping. In a breast cancer lymph node metastasis mice model, subcutaneous injection of 68Ga-F127-TAPP/TCPP(Mn) NPs through the hind foot pad, the normal lymph nodes and metastatic lymph nodes were successfully distinguished based on the difference of PET standard uptake values and MR signal intensities. Furthermore, the dark brown F127-TAPP/TCPP(Mn) NPs demonstrated the potential for staining and mapping lymph nodes. This study provides valuable insights into developing and applying PET/MR probes for lymph node metastasis imaging.

DOTATATE PET/MR Imaging Differentiates Secondary-Progressive from de Novo World Health Organization Grade 3 Meningiomas.

WHO grade 3 meningiomas are rare and poorly understood and have a higher propensity for recurrence, metastasis, and worsened clinical outcomes compared with lower-grade meningiomas. The purpose of our study was to prospectively evaluate the molecular profile, PET characteristics, and outcomes of patients with World Health Organization grade 3 meningiomas who were imaged with gallium 68 (68Ga) DOTATATE PET/MR imaging. Patients with World Health Organization grade 3 meningiomas enrolled in our prospective observational cohort evaluating the utility of (68Ga) DOTATATE PET/MR imaging in somatostatin receptor positive brain tumors were included. We stratified patients by de novo-versus-secondary-progressive status and evaluated the differences in the PET standard uptake value, molecular profiles, and clinical outcomes. Patients met the inclusion criteria (secondary-progressive: 7/14; de novo: 7/14). The secondary-progressive cohort had a significantly higher per-patient number of surgeries (4.1 versus 1.6; P = .011) and trended toward a higher number of radiation therapy courses (2.4 versus 1.6; P = .23) and cumulative radiation therapy doses (106Gy versus 68.3Gy; P = .31). The secondary-progressive cohort had a significantly lower progression-free survival compared with the de novo cohort (4.8 versus 37.7 months; P = .004). Secondary-progressive tumors had distinct molecular pathology profiles with higher numbers of mutations (3.5 versus 1.2; P = .024). Secondary-progressive tumors demonstrated higher PET standard uptake values (17.1 versus 12.4; P = .0021). Our study confirms prior work illustrating distinct clinical outcomes in secondary-progressive and de novo World Health Organization grade 3 meningiomas. Furthermore, our findings support (68Ga) DOTATATE PET/MR imaging as a useful management strategy in World Health Organization grade 3 meningiomas and provide insight into meningioma biology, as well as clinical management implications.

Clinical Outcomes and Tau Pathology in Retired Football Players: Associations With Diagnosed and Witnessed Sleep Apnea.

Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players. The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested. Approximately 36.7% of NFL players had diagnosed SA compared with 30% of the former college football players and 16.7% of the controls. Former NFL players and college football players also had higher ESS scores compared with the controls. Years of football play was not associated with any of the sleep metrics. Among the former NFL players, diagnosed SA was associated with worse Executive Function and Psychomotor Speed factor scores, greater BDI-II scores, and higher flortaucipir PET standard uptake value ratios, independent of age, race, body mass index, and APOE ε4 gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup. Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health.

Ga68] DOTATATE PET/MRI-guided radiosurgical treatment planning and response assessment in meningiomas.

Our purpose was to determine the utility of [68Ga]-DOTATATE PET/MRI in meningioma response assessment following radiosurgery. Patients with meningioma prospectively underwent postoperative DOTATATE PET/MRI. Co-registered PET and gadolinium-enhanced T1-weighted MRI were employed for radiosurgery planning. Follow-up DOTATATE PET/MRI was performed at 6-12 months post-radiosurgery. Maximum absolute standardized uptake value (SUV) and SUV ratio (SUVRSSS) referencing superior sagittal sinus (SSS) blood pool were obtained. Size change was determined by Response Assessment in Neuro-Oncology (RANO) criteria. Association of SUVRSSS change magnitude and progression-free survival (PFS) was evaluated using Cox regression. Twenty-seven patients with 64 tumors (26% World Health Organization [WHO]-1, 41% WHO-2, 26% WHO-3, and 7% WHO-unknown) were prospectively followed post stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT; mean dose: 30 Gy, modal dose 35 Gy, mean of 5 fractions). Post-irradiation SUV and SUVRSSS decreased by 37.4% and 44.4%, respectively (P < .0001). Size product decreased by 8.9%, thus failing to reach the 25% significance threshold as determined by RANO guidelines. Mean follow-up time was 26 months (range: 6-44). Overall mean PFS was 83% and 100%/100%/54% in WHO-1/-2/-3 subcohorts, respectively, at 34 months. At maximum follow-up (42-44 months), PFS was 100%/83%/54% in WHO-1/-2/-3 subcohorts, respectively. Cox regression analyses revealed a hazard ratio of 0.48 for 10-unit reduction in SUVRSSS in the SRS cohort. DOTATATE PET SUV and SUVRSSS demonstrated marked, significant decrease post-radiosurgery. Lesion size decrease was statistically significant; however, it was not clinically significant by RANO criteria. DOTATATE PET/MR thus represents a promising imaging biomarker for response assessment in meningiomas treated with radiosurgery. NCT04081701.

Bile acid profile associated with CSF and PET biomarkers in Alzheimer’s disease

BackgroundRecent studies have shown that gut microbiota can affect the development of Alzheimer’s disease (AD) through various mechanisms. Bile acids (BAs), which are the final byproducts of cholesterol metabolism created through both the human body and gut microbiome, appear to be influenced by gut microbiota and may impact AD pathological characteristics such as the accumulation of tau and amyloid-β. We aimed to investigate the associations between various serum BAs and CSF biomarkers (including Aβ, total tau, and p-tau). Additionally, we sought to examine the longitudinal changes in brain Aβ and tau through PET imaging in relation to BAs profile.MethodsThe data of 828 subjects including 491 diagnosed with mild cognitive impairment (MCI), 119 patients diagnosed with AD, and 267 cognitively normal (CN) participants were obtained from ADNI. The baseline and longitudinal [18F] florbetapir and [18F] flortaucipir PET standard uptake value ratios (SUVR) measures were obtained to assess the accumulation of tau and Aβ. Moreover, baseline levels of serum BAs and CSF Aβ1–42, tau, and p-tau were used.ResultsAfter FDR correction we observed that five BAs level and relevant calculated ratios were associated with CSF p-tau and tau, three with CSF Aβ1–42. Furthermore, three BAs level and relevant calculated ratios were associated with the tau-PET rate of change, and two with the Aβ rate of change.ConclusionThe findings from our study suggest a correlation between altered profiles of BAs and CSF and imaging biomarkers associated with AD. These results provide supporting evidence for the link between the gut microbiome and the pathological features of AD.

Differences in lobar microbleed topography in cerebral amyloid angiopathy and hypertensive arteriopathy

Lobar cerebral microbleeds are a characteristic neuroimaging finding in cerebral amyloid angiopathy (CAA) but can also be found in hypertensive arteriolosclerosis. We aimed to investigate whether CAA is more associated with intracortical lobar microbleeds than hypertensive arteriosclerosis. Ninety-one survivors of spontaneous intracerebral hemorrhage with at least one lobar microbleed were included and underwent brain MRI and amyloid PET. We categorized lobar microbleeds as intracortical, juxtacortical, or subcortical. We assessed the associations between the lobar microbleed categories and microangiopathy subtypes or cerebral amyloid load based on the Pittsburgh Compound-B PET standardized uptake value ratio (SUVR). Patients with CAA had a higher prevalence of intracortical lobar microbleeds (80.0% vs. 50.8%, P = 0.011) and lower prevalence of subcortical lobar microbleeds (13.3% vs. 60.1%, P < 0.001) than patients with hypertensive arteriolosclerosis. Strictly intracortical/juxtacortical lobar microbleeds were associated with CAA (OR 18.9 [1.9–191.4], P = 0.013), while the presence of subcortical lobar microbleeds was associated with hypertensive arteriolosclerosis (OR 10.9 [1.8–68.1], P = 0.010). Amyloid retention was higher in patients with strictly intracortical/juxtacortical CMBs than those without (SUVR = 1.15 [1.05–1.52] vs. 1.08 [1.02–1.19], P = 0.039). Amyloid retention positively correlated with the number of intracortical lobar microbleeds (P < 0.001) and negatively correlated with the number of subcortical lobar microbleeds (P = 0.018). CAA and cortical amyloid deposition are more strongly associated with strictly intracortical/juxtacortical microbleeds than subcortical lobar microbleeds. Categorization of lobar microbleeds based on anatomical location may help differentiate the underlying microangiopathy and potentially improve the accuracy of current neuroimaging criteria for cerebral small vessel disease.

Characteristics of discordance between amyloid positron emission tomography and plasma amyloid-β 42/40 positivity

Various plasma biomarkers for amyloid-β (Aβ) have shown high predictability of amyloid PET positivity. However, the characteristics of discordance between amyloid PET and plasma Aβ42/40 positivity are poorly understood. Thorough interpretation of discordant cases is vital as Aβ plasma biomarker is imminent to integrate into clinical guidelines. We aimed to determine the characteristics of discordant groups between amyloid PET and plasma Aβ42/40 positivity, and inter-assays variability depending on plasma assays. We compared tau burden measured by PET, brain volume assessed by MRI, cross-sectional cognitive function, longitudinal cognitive decline and polygenic risk score (PRS) between PET/plasma groups (PET−/plasma−, PET−/plasma+, PET+/plasma−, PET+/plasma+) using Alzheimer’s Disease Neuroimaging Initiative database. Additionally, we investigated inter-assays variability between immunoprecipitation followed by mass spectrometry method developed at Washington University (IP-MS-WashU) and Elecsys immunoassay from Roche (IA-Elc). PET+/plasma+ was significantly associated with higher tau burden assessed by PET in entorhinal, Braak III/IV, and Braak V/VI regions, and with decreased volume of hippocampal and precuneus regions compared to PET−/plasma-. PET+/plasma+ showed poor performances in global cognition, memory, executive and daily-life function, and rapid cognitive decline. PET+/plasma+ was related to high PRS. The PET−/plasma+ showed intermediate changes between PET−/plasma− and PET+/plasma+ in terms of tau burden, hippocampal and precuneus volume, cross-sectional and longitudinal cognition, and PRS. PET+/plasma− represented heterogeneous characteristics with most prominent variability depending on plasma assays. Moreover, IP-MS-WashU showed more linear association between amyloid PET standardized uptake value ratio and plasma Aβ42/40 than IA-Elc. IA-Elc showed more plasma Aβ42/40 positivity in the amyloid PET-negative stage than IP-MS-WashU. Characteristics of PET−/plasma+ support plasma biomarkers as early biomarker of amyloidopathy prior to amyloid PET. Various plasma biomarker assays might be applied distinctively to detect different target subjects or disease stages.

Aortic Vascular Graft and Endograft Infection-Patient Outcome Cannot Be Determined Based on Pre-Operative Characteristics.

Vascular graft/endograft infection (VGEI) is a serious complication after aortic surgery. This study investigates VGEI and patient characteristics, PET/CT quantification before surgical or conservative management of VGEI and post-intervention outcomes in order to identify patients who might benefit from such a procedure. PET standard uptake values (SUV) were quantitatively assessed and compared to a non-VGEI cohort. The primary endpoints were in-hospital mortality and aortic reintervention-free survival at six months. Ninety-three patients (75% male, 65 ± 10 years, 82% operated) were included. The initial operation was mainly for aneurysm (67.7%: 31% EVAR, 12% TEVAR, 57% open aortic repair). Thirty-two patients presented with fistulae. PET SUVTLR (target-to-liver ratio) showed 94% sensitivity and 89% specificity. Replacement included silver-coated Dacron (21.3%), pericardium (61.3%) and femoral vein (17.3%), yet the material did not influence the overall survival (p = 0.745). In-hospital mortality did not differ between operative and conservative treatment (19.7% vs. 17.6%, p = 0.84). At six months, 50% of the operated cohort survived without aortic reintervention. Short- and midterm morbidity and mortality remained high after aortic graft removal. Neither preoperative characteristics nor the material used for reconstruction influenced the overall survival, and, with limitations, both the in-hospital and midterm survival were similar between the surgically and conservatively managed patients.

Association of β‐amyloid, microglial activation, hypermetabolism and hypertrophy in Alzheimer’s disease

AbstractBackgroundPlasma β‐amyloid (Aβ) Aβ42/Aβ40 measured by immunoprecipitation and liquid chromatography‐mass spectrometry assay has been demonstrated useful to identify Aβ PET positive individuals, but the concordance and discordance about the positivity of plasma Aβ42/Aβ40 (Plasma+/‐) and Aβ PET (PET+/‐) have not been fully characterized. Moreover, the association of Aβ deposition, cortical thickness (CTh), glucose metabolism, and microglial activation among different Plasma/PET profiles is poorly understood.MethodIn this study, we classified 173 ADNI participants into Plasma‐/PET‐ (N = 48), Plasma+/PET‐ (N = 43), and Plasma+/PET+ (N = 73) group based on thresholds of composite Aβ PET (18F‐florbetapir, FBP) standardized uptake value ratio (SUVR) (≥1.11) and plasma Aβ42/Aβ40 (≤0.1218). Part of them had longitudinal 18F‐fluorodeoxyglucose (FDG) PET, structural MRI, and CSF soluble Triggering Receptor Expressed on Myeloid Cell 2 (sTREM2) data. Baseline and slopes of FBP SUVRs of 68 Freesurfer‐defined ROIs were compared between different Plasma/PET groups. The associations of regional FBP SUVRs, CSF sTREM2, regional glucose metabolism (reflected in FDG‐SUVR), and CTh (measured using structural MRI) were investigated in different Plasma/PET groups.ResultPlasma Aβ42/Aβ40 might become positive earlier than Aβ PET (Fig.1A, McNemar’s test, p&lt;0.001). Longitudinally, Plasma+/PET‐ participants showed faster rates of Aβ accumulation in bilateral BANKSSTS, supramarginal, and superior parietal cortices whereas demonstrated no difference in baseline FBP SUVRs than Plasma‐/PET‐ participants (Fig.1D‐E). Higher CSF sTREM2 level and faster rate of CSF sTREM2 increase were related to slower rates of Aβ accumulation in BANKSSTS (standardized β (βstd) = ‐0.418, p = 0.002) in Plasma+/PET+ but not in Plasma+/PET‐ individuals (Fig.2A and D). In contrast, thicker CTh (Fig. 4B‐C) and higher glucose metabolism (Fig. 4H‐I) in supramarginal and superior parietal cortices were coupled to faster rates of CSF sTREM2 increase in Plasma+/PET‐ rather than in Plasma+/PET+ individuals.ConclusionThese findings suggest that plasma Aβ42/Aβ40 might become abnormal earlier than Aβ PET, and plasma Aβ42/Aβ40 positive Aβ PET negative (Plasma+/PET‐) individuals accumulate Aβ plaques faster than Plasma‐/PET‐ individuals. Activated microglia may play a role in reducing fibrillar‐Aβ increasing rates in late amyloidosis stage, whereas it may be related to hypertrophy and hypermetabolism in early amyloidosis stages.

Plasma biomarkers of Alzheimer´s disease in the continuum of dementia with Lewy bodies

AbstractBackgroundPatients with dementia with Lewy bodies (DLB) may have Alzheimer´s disease (AD) pathology. Plasma biomarkers of beta‐amyloid (Aβ), phosphorylated tau (pTau), and neurodegeneration are sensitive to AD neuropathologic changes in AD dementia. While these plasma biomarkers are well tested in the AD continuum, their performance for concomitant AD pathology in the DLB continuum is still unclear.MethodWe included patients with isolated REM sleep behavior disorder (iRBD; n = 15), with mild cognitive impairment with Lewy bodies (MCI‐LB; n = 37), and with DLB (n = 70) from the Mayo Clinic Alzheimer’s Disease Research Center. Cognitively unimpaired individuals (CU; n = 100) included from the Mayo Clinic Study of Aging were balanced on age and sex. A panel of plasma biomarkers of Aβ40, Aβ42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aβ40/42. Lower Aβ40/42 indicates increased Aβ pathology. Plasma Aβ40, Aβ42, GFAP, and NfL were measured using the Simoa® Neurology 4‐Plex E Advantage kit and pTau‐181 was measured with the Simoa® pTau‐181 Advantage V2 kit. Both were run on a Quanterix HD‐X analyzer. AD imaging biomarkers were assessed on PET using Pittsburgh compound B (PiB) for Aβ and 18F‐Flortaucipir for tau.ResultHigher levels of plasma GFAP were observed in the MCI‐LB (p = 0.014) and DLB (p&lt;0.001) groups compared to CU (Figure). DLB patients also showed higher levels of plasma pTau181 (p&lt;0.001) and NfL (p&lt;0.001). Higher amyloid and tau PET standardized uptake value ratio (SUVr) in the DLB continuum were associated with higher levels of plasma p‐tau181, NfL, and GFAP (p&lt;0.001). After accounting for age, plasma Aβ40/42 did not correlate with amyloid or tau PET SUVr.ConclusionIn the DLB continuum, abnormal levels of GFAP in plasma can be detected as early as the prodromal stages of the disease. Plasma pTau181 reached abnormal levels in the DLB stage. Higher plasma GFAP, NfL, and p‐tau181 are associated with higher amyloid and tau PET SUVr in the DLB continuum. Plasma biomarkers have the potential to contribute to screening and early diagnosis in the DLB continuum, which has implications in designing new treatments.

Tau pathology is associated with neuropsychiatric symptoms in a cohort of individuals of predominantly Mexican descent at risk for autosomal‐dominant Alzheimer’s disease

AbstractBackgroundNeuropsychiatric symptoms are common in Alzheimer’s disease (AD), causing significant suffering and diminished quality of life for both individuals and caregivers. The goal of this study was to investigate the relationship between tau pathology in vivo and neuropsychiatric symptoms within a cohort of individuals of predominantly Mexican ancestry at risk for fully penetrant autosomal dominant AD (ADAD) caused by mutations in PSEN1 and APP genes (Figure 1).MethodParticipants from the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) cohort were selected based on availability of demographic variables, mutation carrier status, tau PET scans (flortaucipir), and completion of the neuropsychiatric inventory (NPI). Linear regression models were used to investigate whether regional tau PET standard uptake value ratio (SUVR) predicted total score on the NPI. Models were adjusted for age, sex, and mutation carrier status. Participants were characterized as carriers if they possessed one of the following ADAD mutations: PSEN1 A431E, PSEN1 I180F, or APP V717I. Analyses were done with and without outliers. The 12‐item total NPI score was used for all analyses. The primary brain regions of interest (i.e., medial orbitofrontal, caudal anterior cingulate, rostral anterior cingulate, parahippocampal, precuneus, and lateral occipital) were selected based on previous findings. Additional analyses were conducted only on individuals who were carriers of 1 of the ADAD mutations.ResultThe sample consisted of 31 participants (45% women, mean age±SD = 37.1±11.7 years, 71% ADAD mutation carriers [81% PSEN1 A431E, 16% PSEN1 I180F, and 3% APP V717I carriers]). A significant relationship was found between regional tau pathology and neuropsychiatric symptoms for all six brain regions (Table 1), all p’s &lt; 0.01. Within all regression models, regional tau pathology explained between 24% to 49% of the variance in neuropsychiatric symptoms. Sub‐set analyses completed on the ADAD mutation carriers sample exhibited similar results (Table 2). No significant results were found for non‐carriers.ConclusionRegional tau pathology within six distinct brain regions is strongly associated with neuropsychiatric symptoms in a cohort of individuals of predominantly Mexican ancestry at risk for fully penetrant ADAD caused by mutations in PSEN1 and APP genes.

Specific Association of Worry and Amyloid‐β Deposition in Cognitive Unimpaired Older Adults

AbstractBackgroundAnxiety symptoms are common in cognitively unimpaired (CU) older adults prior to the onset of cognitive impairment. Evidence suggests that anxiety symptoms may be sequelae of amyloid‐beta (Aβ) deposition in early Alzheimer’s disease (AD) and/or anxiety may potentiate the pathophysiologic process. Despite this pivotal role, the specific components of anxiety associated with high brain Aβ in CU older adults are relatively unknown. It was previously reported that Aβ deposition is associated with a global anxiety score measured by State‐Trait Anxiety Inventory‐6 (STAI‐6) but not depression measured by Geriatric Depression Scale (GDS) total scores. Here, we examined the specific associations of individual anxiety symptoms with Aβ.MethodOlder adult participants were screened for the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s study (“A4 study”) and underwent assessments of anxiety (STAI‐6), depression (GDS), cognitive performance (MMSE and Preclinical Alzheimer Cognitive Composite /PACC), subjective cognition (Cognitive Function Instrument/CFI) and cortical Aβ deposition using Florbetapir PET standardized uptake value ratio (SUVR). Linear regression models estimated associations of STAI‐6 items, “calm,” “tense,” “upset,” “relax,” “content,” and “worry,” with Aβ deposition, adjusting for multiple potential confounders.ResultThe sample (n = 4486) were older adults ages 65 ‐ 85 (mean [SD] age, 71.29 [4.67] years, included 2647 women (59%) and 1323 (29.5%) who were classified as Aβ+. STAI‐6 total score ranged from 6 ‐ 24 (Mean 9.9 [3.1]). A significant positive association was found between the anxiety item measuring “worry”, and Aβ, adjusting for age, sex, education, marital status, depression (GDS), objective cognition (MMSE or PACC), and subjective cognition (CFI) [Table 1]. There were other significant (negative) associations between items measuring “calm” and “relax” and Aβ in similar regression models. Only the association of “worry” with Aβ remained significant after further adjustment for global anxiety measured by the total STAI‐6 score.ConclusionIn a large, well‐characterized sample of CU older adults, worry was significantly and most strongly associated with Aβ, independent of psychosocial factors, subjective and objective cognition and global anxiety. These findings suggest that self‐reported worry may have unique explanatory value in the clinical assessment of CU older adults at high risk of AD and cognitive impairment.

Plasma biomarkers of Alzheimer´s disease in the continuum of dementia with Lewy bodies

AbstractBackgroundPatients with dementia with Lewy bodies (DLB) may have Alzheimer´s disease (AD) pathology. Plasma biomarkers of beta‐amyloid (Aß), phosphorylated tau (pTau), and neurodegeneration are sensitive to AD neuropathologic changes in AD dementia. While these plasma biomarkers are well tested in the AD continuum, their performance for concomitant AD pathology in the DLB continuum is still unclear.MethodWe included patients with isolated REM sleep behavior disorder (iRBD; n = 15), with mild cognitive impairment with Lewy bodies (MCI‐LB; n = 37), and with DLB (n = 70) from the Mayo Clinic Alzheimer’s Disease Research Center. Cognitively unimpaired individuals (CU; n = 100) included from the Mayo Clinic Study of Aging were balanced on age and sex. A panel of plasma biomarkers of Aß40, Aß42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aß40/42. Lower Aß40/42 indicates increased Aß pathology. Plasma Aß40, Aß42, GFAP, and NfL were measured using the Simoa® Neurology 4‐Plex E Advantage kit and pTau‐181 was measured with the Simoa® pTau‐181 Advantage V2 kit. Both were run on a Quanterix HD‐X analyzer. AD imaging biomarkers were assessed on PET using Pittsburgh compound B (PiB) for Aß and 18F‐Flortaucipir for tau.ResultHigher levels of plasma GFAP were observed in the MCI‐LB (p = 0.014) and DLB (p&lt;0.001) groups compared to CU (Figure). DLB patients also showed higher levels of plasma pTau181 (p&lt;0.001) and NfL (p&lt;0.001). Higher amyloid and tau PET standardized uptake value ratio (SUVr) in the DLB continuum were associated with higher levels of plasma p‐tau181, NfL, and GFAP (p&lt;0.001). After accounting for age, plasma Aß40/42 did not correlate with amyloid or tau PET SUVr.ConclusionIn the DLB continuum, abnormal levels of GFAP in plasma can be detected as early as the prodromal stages of the disease. Plasma pTau181 reached abnormal levels in the DLB stage. Higher plasma GFAP, NfL, and p‐tau181 are associated with higher amyloid and tau PET SUVr in the DLB continuum. Plasma biomarkers have the potential to contribute to screening and early diagnosis in the DLB continuum, which has implications in designing new treatments.

Tau pathology is associated with neuropsychiatric symptoms in a cohort of individuals of predominantly Mexican descent at risk for autosomal‐dominant Alzheimer’s disease

AbstractBackgroundNeuropsychiatric symptoms are common in Alzheimer’s disease (AD), causing significant suffering and diminished quality of life for both individuals and caregivers. The goal of this study was to investigate the relationship between tau pathology in vivo and neuropsychiatric symptoms within a cohort of individuals of predominantly Mexican ancestry at risk for fully penetrant autosomal dominant AD (ADAD) caused by mutations in PSEN1 and APP genes (Figure 1).MethodParticipants from the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) cohort were selected based on availability of demographic variables, mutation carrier status, tau PET scans (flortaucipir), and completion of the neuropsychiatric inventory (NPI). Linear regression models were used to investigate whether regional tau PET standard uptake value ratio (SUVR) predicted total score on the NPI. Models were adjusted for age, sex, and mutation carrier status. Participants were characterized as carriers if they possessed one of the following ADAD mutations: PSEN1 A431E, PSEN1 I180F, or APP V717I. Analyses were done with and without outliers. The 12‐item total NPI score was used for all analyses. The primary brain regions of interest (i.e., medial orbitofrontal, caudal anterior cingulate, rostral anterior cingulate, parahippocampal, precuneus, and lateral occipital) were selected based on previous findings. Additional analyses were conducted only on individuals who were carriers of 1 of the ADAD mutations.ResultThe sample consisted of 31 participants (45% women, mean age±SD = 37.1±11.7 years, 71% ADAD mutation carriers [81% PSEN1 A431E, 16% PSEN1 I180F, and 3% APP V717I carriers]). A significant relationship was found between regional tau pathology and neuropsychiatric symptoms for all six brain regions (Table 1), all p’s &lt; 0.01. Within all regression models, regional tau pathology explained between 24% to 49% of the variance in neuropsychiatric symptoms. Sub‐set analyses completed on the ADAD mutation carriers sample exhibited similar results (Table 2). No significant results were found for non‐carriers.ConclusionRegional tau pathology within six distinct brain regions is strongly associated with neuropsychiatric symptoms in a cohort of individuals of predominantly Mexican ancestry at risk for fully penetrant ADAD caused by mutations in PSEN1 and APP genes.

Amyloid and Tau PET Positivity in Progressive Agrammatic Aphasia and Apraxia of Speech.

The agrammatic variant of primary progressive aphasia (PAA), primary progressive apraxia of speech (PPAOS), or a combination of both (AOS-PAA) are neurodegenerative disorders characterized by speech-language impairments and together compose the AOS-PAA spectrum disorders. These patients typically have an underlying 4-repeat tauopathy, although they sometimes show evidence of amyloid-β and tau deposition on PET, suggesting Alzheimer's disease (AD). Given the growing number of pharmacologic treatment options for AD, it is important to better understand the incidence of AD pathology in these patients. This study aimed to evaluate the frequency of amyloid-β and tau positivity in AOS-PAA spectrum disorders. Sixty-five patients with AOS-PAA underwent a clinical speech-language battery and PiB PET and flortaucipir PET imaging. Global PiB PET standardized uptake value ratios (SUVRs) and flortaucipir PET SUVRs from the temporal meta region of interest were compared between patient groups. For 19 patients who had died and undergone autopsy, their PET and pathology findings were also compared. The results showed that although roughly half of the patients are positive for at least one biomarker, their clinical symptoms and biomarker status were not related, suggesting that AD is not the primary cause of their neurodegeneration. All but one patient in the autopsy subset had a Braak stage of IV or less, despite four being positive on tau PET imaging. Inclusion criteria for clinical trials should specify clinical presentation or adjust the evaluation of such treatments to be specific to disease diagnosis beyond the presence of certain imaging biomarkers.

44 Can Clinical Trial data Inform our Understanding of the role of Depressive Symptoms in Alzheimer's Disease?

Objective:Neuropsychiatric symptoms concerning mood are common in Alzheimer's disease (AD), but it is unclear if they are etiologically related to AD pathophysiology or due to factors considered to be non-pathogenic, such as small vessel cerebrovascular disease. New generation clinical trials for AD often enroll participants with evidence of AD pathophysiology, indexed by amyloid PET scanning, but who are cognitively asymptomatic. We used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study to examine the extent to which depressive symptoms are associated with amyloid pathophysiology and small vessel cerebrovascular disease, in the form of white matter hyperintensities (WMH).Participants and Methods:The A4 study randomizes cognitively healthy older adults with evidence of amyloid pathophysiology on PET scanning. We used screening data, which included amyloid status (positive, negative) by visual read, amyloid PET standard uptake value ratio (SUVR) in cortical regions, and MRI data acquired in a subset (n=1,197, mean age 71.6 +/- 4.8 years, 57% women) to quantitate total WMH volume. Depressive symptoms were evaluated with the 15-item Geriatric Depression Scale, which we used both as a continuous variable and to define 'depressed' and 'non-depressed' groups, based on a cut score of &gt; 5. We examined whether 1) depressive symptoms and proportion of depressed individuals differed between amyloid positive and negative groups, 2) there is a relationship between amyloid SUVR and depressive symptoms that differs as a function of amyloid positivity status, and 3) there is a relationship between WMH volume and depressive symptoms that differs as a function of amyloid positivity status.Results:Although depressive symptom severity did not differ between groups (t=0.14, p=0.88), a greater proportion of individuals were classified as depressed in the amyloid negative group than the amyloid positive group (3.5% vs. 1.9%, X2=4.60, p=0.032). Increased amyloid SUVR was associated with increased GDS scores among amyloid positive individuals (r=0.117, p=0.002) but not among amyloid negative individuals (r=0.006, p=0.68, Positivity Status x SUVR interaction on GDS: ß=0.817, p=0.029). Increased WMH was associated with higher GDS scores (ß=0.105, p=0.017) but not differentially in amyloid positive and negative participants (Positivity Status x WMH interaction on GDS: ß=-0.010, p=0.243).Conclusions:These analyses have several implications. First, individuals who are screened to participate in a clinical trial but do not have evidence of amyloidosis may be misattributing concerns about underlying AD pathophysiology to depressive symptoms. Second, the severity of AD pathophysiology, indexed by amyloid PET SUVR, may drive a small increase in depressive symptomatology among individuals over visual diagnostic thresholds. Third, small vessel cerebrovascular changes are additionally associated with depressive symptoms but in a manner that is independent of AD pathophysiology. Overall, depressive symptoms and depression are likely multiply determined among prospective clinical trial participants for preclinical AD.

The Mediating Roles of Neurobiomarkers in the Relationship Between Education and Late-Life Cognition.

The mediating roles of neuropathologies and neurovascular damage in the relationship between early-life education and later-life cognitive function are unknown. To examine whether Alzheimer's and neurovascular biomarkers mediate the relationships between education and cognitive functions. Data were from 537 adults aged 55-94 in the Alzheimer's Disease Neuroimaging Initiative 3. We tested whether the relationships between education (continuous, years) and cognitive function (memory, executive functioning, and language composites) were mediated by neuroimaging biomarkers (hippocampal volumes, cortical gray matter volumes, meta-temporal tau PET standard uptake value ratio, and white matter hyperintensity volumes). Models were adjusted for age, race, sex/gender, cardiovascular history, body mass index, depression, and Apolipoprotein E-ɛ4 status. Hippocampal volumes and white matter hyperintensities partially mediated the relationships between education and cognitive function across all domains (6.43% to 15.72% mediated). The direct effects of education on each cognitive domain were strong and statistically significant. Commonly measured neurobiomarkers only partially mediate the relationships between education and multi-domain cognitive function.

Use of Oral Empagliflozin to Obtain Optimal Blood Sugar Levels for Conducting 18 F-FDG PET-CT in Patients with Hyperglycemia-A Pilot Study.

Background Flourine-18 fluorodeoxyglucose positron emission tomography-computed tomography ( 18 F-FDG PET-CT) is a well-established imaging modality for the evaluation of patients with oncological and nononcological conditions. The underlying principle of imaging is the preferentially increased glucose consumption by cancer cells, due to overexpression of glucose type 1 receptors that are insulin independent. Thus, one of the factors that leads to decreased sensitivity of an 18 F-FDG PET-CT is elevated blood sugar levels, leading to decreased glucose uptake by cancer cells due to competitive inhibition. A significant percentage of patients scheduled for PET-CT scan has diabetes mellitus type II as a comorbid condition and often has elevated random blood sugar (RBS) precluding an upfront PET-CT evaluation. Such cases must be rescheduled. This causes delay in the evaluation and management of such patients. Empagliflozin is a novel sodium glucose type 2 inhibitor that prevents tubular reabsorption of glucose and increases renal glycosuria resulting in decreased blood sugar. This drug does not cause significant hypoglycemia or increase endogenous insulin secretion. This study was undertaken to evaluate a potential role for empagliflozin in facilitating optimal blood sugar control in patients with hyperglycemia on the day of the scheduled PET scan. Methods This is an interventional prospective study and patients detected to have RBS more than 200 mg/dL on the day of the scheduled scan were included in the study. The patients were administered two tablets of 10 mg empagliflozin and kept under observation. Samples for RBS were taken at approximately 2nd and 4th hour post administration by bedside method. These patients underwent scan on the same day after adequate sugar control and when an RBS of less than 200 mg/dL was achieved. The primary outcome studied was change in RBS values in the patient cohort and evaluation of PET SUV (standardized uptake value) compared with the rest of the patients scheduled on the same day. Secondary outcome was assessment of any side effects in the patients. Results Total of 10 patients were found to have elevated blood sugar (RBS > 200 mg/dL; irrespective of being on medication) and did not meet the evaluation criteria for a PET-CT scan on the scheduled day. Following administration of the drug, all 10 patients were able to attain blood sugar levels and fulfill the criteria for undergoing a PET-CT scan. No obvious side effect was noted in any of the patient. The SUV values of the patient cohort were comparable with the rest of the patient scanned on the day. Conclusion In this pilot study, 20 mg of empagliflozin (2 tablets of 10 mg) appears to be a safe and effective method for achieving optimal decrease in the RBS without causing hypoglycemia or hyperinsulinemia. It can be safely employed in the subset of population with RBS between 201 and 300 mg/dL to adequately bring the sugar levels at acceptable levels RBS less than 200 mg/dl and fulfill the FDG PET-CT criteria as per European Association of Nuclear Medicine (EANM) norms.

CT radiomics analysis of primary colon cancer patients with or without liver metastases: a correlative study with [18F]FDG PET uptake values.

Utilizing [18F]Fluoro-2-deoxy-D-glucose Positron Emission Tomography/Computed Tomography ([18F]FDG PET/CT) scans on primary colon cancer (CC) patients including with liver metastases (LM), we aimed to determine the relationship between structural CT radiomic features and metabolic PET standard uptake value (SUV) in these patients. A retrospective analysis was performed on 60 patients with primary CC, of which 40 had liver metastases that were more than 2 cm in diameter. [18F]FDG PET/CT was used to calculate SUVmax, and 42 CT radiomic characteristics were extracted from non-enhanced CT images. Tumors were manually segmented on fused PET/CT scans by two experienced nuclear medicine physicians. Sixty primary CC and forty LM lesions were segmented accordingly. In the cases of multiple LM lesions, the lesion with the largest diameter was chosen for segmentation. In a univariate analysis approach, we used Spearman correlation with multiple testing correction (Benjamini-Hutchberg false discovery rate (FDR), α=0.05) to ascertain the relationship between SUVmax and CT radiomic features. Twenty-two (52.3%) and twenty-six (61.9%) CT radiomic features were found to be significantly correlated with SUVmax values of primary CC (n=60) and LM (n=40) lesions, respectively (FDR-corrected p value <0.05 and 0.6 < |ρ| < 1). GLCM_homogeneity (ρ = 0.839), GLCM_dissimilarity (ρ = -0.832), GLZLM_ZLNU (ρ = 0.827), and GLCM_contrast (ρ = -0.815) were the 4 features most correlated with SUVmax in CC. On the other hand, in LM, the 4 features most correlated with SUVmax were GLRLM_LRHGE (ρ = 0.859), GLRLM_LRE (ρ = 0.859), GLRLM_LRLGE (ρ = 0.857), and GLRLM_RP (ρ = -0.820). We investigated the relationship between SUVmax of preoperative primary CC lesions and their LM with CT radiomic features. We found some CT radiomic features having relationships with the metabolic characteristics of lesions. This work suggests that non-invasive predictive imaging biomarkers for precision medicine can be derived from CT radiomic.

Sex and APOE genotype differences in amyloid deposition and cognitive performance along the Alzheimer’s Continuum

Conflicting findings exist regarding the differences in amyloid burden and cognitive performance based on sex and apolipoprotein E (APOE) genotype. This study aimed to investigate the brain amyloid-β (Aβ) burden and cognitive performances by sex and APOE genotype in a cohort of Aβ-positron emission tomography (PET)–positive participants. Brain Aβ burden was assessed using 18F-florbetapir PET standard uptake value ratios. Cognitive performance was evaluated using standardized neuropsychological tests. In the cognitively normal participants, females had a higher Aβ burden than males in APOE ε4 noncarriers, whereas APOE ε4 carriers had a higher Aβ burden than noncarriers in males. In the cognitively impaired participants, APOE ε4 carriers were more likely to have a higher Aβ burden than noncarriers in the brain regions of the lateral parietal gyrus, frontal gyrus, and precuneus. In addition, females were more likely to have poorer language and visuospatial performance compared to males, while the APOE genotype did not significantly impact cognitive performance. These findings further elucidate the impact of sex and APOE genotype on brain Aβ burden and sex-related cognitive performance should be considered in the Alzheimer’s Continuum.