Standardized Uptake Value Ratio Research Articles

Sex and family history differences in Aβ and tau vulnerability in preclinical Alzheimer’s disease

AbstractBackgroundFemales and individuals with a family history (FH) of Alzheimer’s disease (AD) are considered at higher risk of sporadic AD. However, how sex and maternal/paternal heredity affects in vivo AD biomarkers is not well understood. Our objectives were to 1) assess if females or individuals with a first‐degree maternal FH of AD accumulate amyloid‐beta (Aβ) and/or tau faster than males or individuals with a first‐degree paternal FH of AD and 2) assess if both could influence the rate of Aβ driving tau in preclinical AD.MethodTwo hundred and thirty‐five older adults (age 68.3 ± 5.1 years, 69.8% female) from the PREVENT‐AD cohort, cognitively unimpaired at baseline, underwent [18F]‐NAV4694 and [18F]‐AV1451 positron emission tomography (PET) scans. Longitudinal PET scans were available for 106 individuals (4.3 ± 0.4 years follow‐up). We extracted and averaged the standard uptake value ratio (SUVr) in fronto‐parietal regions for Aβ and in temporal regions for tau. We performed t‐tests and ANOVA models to assess sex or maternal/paternal FH (FHsex) differences in Aβ and tau burden or annual change. We then performed linear regression models with an interaction term between Aβ and sex (or Aβ and FHsex) on tau burden and annual change, plus additional models to adjust for age and education.ResultSex and FHsex differences on Aβ and tau burden or annual rate of change did not reach significance although females tended to have higher tau SUVr at baseline (p = 0.053) (Figure 1 & 2). We found an interaction between Aβ and sex (𝛽 = ‐0.13, p = 0.008), and between Aβ and FHsex (𝛽 = 0.11, p = 0.03), on tau at baseline (Figure 3) suggesting that, for the same level of Aβ burden, females and individuals with paternal FH of AD had higher tau burden than males and individuals with maternal FH of AD. Results were similar when adjusted for age and education.ConclusionFemales and individuals with a paternal FH of AD might need less Aβ before developing AD‐related tau, but did not accumulate tau faster. Identifying individuals more vulnerable to AD pathology, by disentangling sex‐specific effects, would help to design personalized interventions for AD.

Posterior Primary Progressive Prosopagnosia: Imaging and Neuropathology

AbstractBackgroundProsopagnosia is common with right temporal lesions, often in the fusiform gyrus when caused by vascular pathology. When caused by frontotemporal dementia, the lesion typically begins in the temporal tip. We are reporting advanced imaging, including tau and inflammation, as well as neuropathology in a patient with pathology centered at the posterior extent of the fusiform gyrus.MethodA 69‐year‐old man with apperceptive prosopagnosia and a negative amyloid positron emission tomogram (PET) underwent MRI and PET using 11C‐PBR28, an inflammation tracer, and 18F‐flortaucipir. V T values for 11C‐PBR28 were calculated with the Logan plot and a metabolite‐corrected arterial input function. For 18F‐flortaucipir, the SUV ratio over the cerebellar gray matter was calculated for t = 80‐100 min. A neuropathological examination was conducted using standard procedures as well as phospho‐tau histochemistry.ResultAtrophy and 18F‐flortaucipir uptake involved a similar region at the posterior extent of the right fusiform gyrus and, minimally, a symmetrical region of the left fusiform gyrus and an area in right premotor cortex. Involving the same regions, the 11C‐PBR28 signal was however more extensive than atrophy or 18F‐flortaucipir signal. At autopsy, the patient had corticobasal degeneration (CBD), with severe 4R tau involvement of temporo‐occipital, inferior parietal, and frontal cortices, as well as limbic regions and subcortical nuclei. The location of CBD pathology in this patient was highly atypical, as shown by comparing the neuropathological findings with the findings in two typical CBD patients.ConclusionAlthough prosopagnosia from ischemic and other lesions in the right posterior temporo‐occipital region is common, primary progressive prosopagnosia in the absence of amyloid has been described mostly with involvement of the right anterior temporal region. As exemplified by our patient, it can rarely happen with posterior temporal involvement and in this case the pathology was not TDP‐43 type C, as present in most patients with anterior temporal involvement, but corticobasal degeneration, a 4R tauopathy.

Posterior Primary Progressive Prosopagnosia: Imaging and Neuropathology

AbstractBackgroundProsopagnosia is common with right temporal lesions, often in the fusiform gyrus when caused by vascular pathology. When caused by frontotemporal dementia, the lesion typically begins in the temporal tip. We are reporting advanced imaging, including tau and inflammation, as well as neuropathology in a patient with pathology centered at the posterior extent of the fusiform gyrus.MethodA 69‐year‐old man with apperceptive prosopagnosia and a negative amyloid positron emission tomogram (PET) underwent MRI and PET using 11C‐PBR28, an inflammation tracer, and 18F‐flortaucipir. VT values for 11C‐PBR28 were calculated with the Logan plot and a metabolite‐corrected arterial input function. For 18F‐flortaucipir, the SUV ratio over the cerebellar gray matter was calculated for t = 80‐100 min. A neuropathological examination was conducted using standard procedures as well as phospho‐tau histochemistry.ResultAtrophy and 18F‐flortaucipir uptake involved a similar region at the posterior extent of the right fusiform gyrus and, minimally, a symmetrical region of the left fusiform gyrus and an area in right premotor cortex. Involving the same regions, the 11C‐PBR28 signal was however more extensive than atrophy or 18F‐flortaucipir signal. At autopsy, the patient had corticobasal degeneration (CBD), with severe 4R tau involvement of temporo‐occipital, inferior parietal, and frontal cortices, as well as limbic regions and subcortical nuclei. The location of CBD pathology in this patient was highly atypical, as shown by comparing the neuropathological findings with the findings in two typical CBD patients.ConclusionAlthough prosopagnosia from ischemic and other lesions in the right posterior temporo‐occipital region is common, primary progressive prosopagnosia in the absence of amyloid has been described mostly with involvement of the right anterior temporal region. As exemplified by our patient, it can rarely happen with posterior temporal involvement and in this case the pathology was not TDP‐43 type C, as present in most patients with anterior temporal involvement, but corticobasal degeneration, a 4R tauopathy.

GRADUATE I and II: Subgroup analysis and correlations of biomarkers

AbstractBackgroundGantenerumab is a subcutaneous fully human monoclonal antibody targeting aggregated forms of amyloid‐beta. Phase III GRADUATE I (NCT03444870) and II (NCT03443973) trials were designed based on previous key learnings to provide evidence on the benefit:risk profile of subcutaneous gantenerumab in early symptomatic AD. Although primary endpoints were not met, gantenerumab showed treatment effects on amyloid positron emission tomography (PET), volumetric magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) and plasma biomarkers. Correlations of biomarkers with clinical outcomes in the GRADUATE studies were assessed to further evaluate their utility.MethodParticipants aged 50‐90 years with mild cognitive impairment due to AD or mild AD dementia were randomised 1:1 to subcutaneous gantenerumab or placebo. Gantenerumab was up‐titrated over 36 weeks to target dose of 510 mg every 2 weeks. Changes in amyloid centiloid levels were obtained from [18F]Florbetaben or [18F]Flutemetamol PET. Regional changes in tau standardised uptake value ratio were obtained with [18F]GTP1 PET. Whole brain and regional atrophy were assessed via volumetric MRI. Fluid pharmacodynamics biomarkers were measured using Elecsys® immunoassays from Roche Diagnostics.ResultSignificant (but not corrected for multiple testing) treatment effects of gantenerumab on change from baseline to Week 116 were observed for CSF biomarkers (pooled GRADUATE I and II population) including Aβ40 (–10.42%, p = 0.0188), Aβ42 (26.06%, p<0.0001), tTau (–16.49%, p<0.0001), pTau181 (–23.35%; p < 0.0001), NfL (10.76%; p = 0.0159), GFAP (–5.49%; p = 0.0003), and plasma biomarkers including Aβ42 (GRADUATE I: 65.1%, p<0.0001; GRADUATE II: 54.9%, p<0.0001) and pTau181 (GRADUATE I: –17.2%, p<0.0001; GRADUATE II: –15.3%, p<0.0001). Preliminary biomarker analyses showed changes in amyloid PET in gantenerumab‐treated participants had a numerically higher correlation with changes in plasma Aβ42 (R = –0.43), versus pTau181 (R = 0.34) and GFAP (R = 0.16). Biomarker changes in subgroups will also be presented.ConclusionPhase III GRADUATE I and II study results provide evidence of the effect of subcutaneous gantenerumab on biomarkers of AD pathology and neurodegeneration in subgroups.

CSF sTREM2 and YKL‐40 modify the balance between soluble and fibrillary β‐amyloid in non‐demented individuals

AbstractBackgroundCerebrospinal fluid (CSF) Aβ concentrations and Positron Emission Tomography (PET) imaging provide information of two different Aβ pools. Identifying the factors affecting the balance between soluble and deposited Aβ may inform on the mechanism of cerebral Aβ aggregation. Microglia and astroglia respond to Aβ pathology, yet their role in promoting the aggregation of Aβ plaques is unclear. We addressed whether CSF sTREM2 and YKL‐40 modulate the association between soluble and deposited Aβ in a cohort of middle‐aged cognitively unimpaired (CU) individuals.MethodThe first consecutive 320 CU individuals of the ALFA+ study with a [18F]flutemetamol (FTM) PET scan and CSF samples were included. CSF Aβ40, Aβ42, sTREM2, and YKL‐40 were measured with the Roche NeuroToolKit robust prototype immunoassays (Roche Diagnostics International Ltd). Standardized uptake value ratio images were calculated and a voxel‐wise regression was performed to predict FTM uptake. The interaction terms between CSF Aβ42/40 and either CSF sTREM2 or YKL‐40 served as predictors, while adjusting for age, sex, years of education, and APOE‐ε4. Statistical threshold was set to p<0.001 with a cluster extent correction of 100 voxels.ResultTable 1 describes the sample’s characteristics. As expected, CSF Aβ42/40 concentrations were negatively associated with Aβ PET uptake in widespread areas of the brain, but this association was modified by CSF sTREM2 and YKL‐40. Higher levels of CSF sTREM2 were associated with a reduced Aβ PET uptake for any level of CSF Aβ42/40 in the hippocampus bilaterally. Conversely, higher CSF YKL‐40 related to a higher Aβ PET uptake as a function of CSF Aβ42/40 in the precuneus, prefrontal cortex, and inferior parietal areas.ConclusionIn CU individuals, microglia and astroglia reactivity modify the association between soluble (CSF) and deposited (amyloid PET) Aβ. While TREM2‐mediated microglial response (as measured by CSF sTREM2) may prevent Aβ deposition in individuals with decreased soluble Aβ, astroglial reactivity (as measured by CSF YKL‐40) may have the opposite effect.

Circadian rhythms in older adults are associated with sleep quality, cognitive function, and ß‐amyloid burden: an accelerometry analysis of the Lifestyle Enriching Activities for Research in Neuroscience Intervention Trial ‐ LEARNit

AbstractBackgroundSeveral studies demonstrate circadian rhythm disturbances in patients with Alzheimer’s disease. However, less is known about circadian rhythms in older adults with early mild cognitive impairment. Wrist‐worn accelerometers provide continuous, objective, high resolution quantification of 24‐hour rest activity rhythms. This study examines the relationship between circadian rhythms and sleep, cognition, and ß‐amyloid (Aß) burden.MethodThis study examines baseline data from the “Lifestyle Enriching Activities for Research in Neuroscience Intervention Trial” (LEARNit). Sixty‐six older adults ages 55‐80 experiencing early cognitive changes wore a GENEActiv accelerometer for approximately 30 consecutive days. Accelerometer data was analyzed using the R package GGIR (version 2.8‐1), and circadian rhythm measures were extracted using the GGIR secondary package ActCR (version 0.3.0). Circadian rhythm variables include intradaily variability (fragmentation), interdaily stability (rhythm synchronization to light‐dark cycle), acrotime (peak activity time), and Midline Estimated Statistics of Rhythm or MESOR (mean activity level). Up‐MESOR and Down‐MESOR represent the timing of activity increasing above or decreasing below MESOR, respectively—lower values of each indicate a phase advance (shift towards morning), whereas higher values indicate a phase delay (shift towards evening). Sleep was assessed as mean sleep efficiency and Wake After Sleep Onset, or WASO (accumulated wakefulness after sleep onset). Cognitive tests include the Montreal Cognitive Assessment (MoCA) for global cognition and attention/processing speed (Digit Symbol Task). Aß burden was measured by positron emission tomography standard uptake value ratio for fifty‐six participants. Age‐adjusted linear regression models were used to test associations between circadian rhythms and sleep, cognition, and Aß.ResultParticipant characteristics are summarized in Table 1 and results are summarized in Figure 1. Intradaily variability (b = ‐0.095, p = 0.03) and interdaily stability (b = 0.34, p = 0.01) were both associated with mean sleep efficiency. Intradaily variability (b = 1.41, p<0.001) and interdaily stability (b = ‐4.45, p<0.001) were associated with WASO. Up‐MESOR was associated with MoCA total score (b = ‐0.41, p = 0.03). Up‐MESOR (b = ‐2.12, p = 0.006), Down‐MESOR (b = ‐1.99, p = 0.02), and acrotime (b = ‐4.20, p<0.001) were associated with Digit Symbol score. Down‐MESOR was significantly associated with Aß (b = ‐0.029, p = 0.02).ConclusionCircadian rhythm robustness is positively associated with better sleep quality. Participants with dynamic circadian rhythm phases demonstrated poorer cognition and higher Aß burden.

Regional glymphatic abnormality in behavioral variant frontotemporal dementia

AbstractBackgroundThe pattern of glymphatic inflow overlaps with the geographic pattern of behavioral variant frontotemporal dementia (bvFTD). The glymphatic function has not yet been explored in bvFTD. The spatial correlation between regional glymphatic function and bvFTD remain unknown.MethodA total of 60 patients with bvFTD and 61 age‐ and sex‐matched healthy controls (HCs) were selected from two independent cohorts (discovery dataset from Xuanwu Hospital and replication dataset from the Frontotemporal Lobar Degeneration Neuroimaging Initiative study). All participant underwent neuropsychological assessment. Glymphatic measures evaluated from multimodal neuroimaging data, including choroid plexus volume, diffusion along perivascular space (DTI‐ALPS) index, and coupling between blood‐oxygen‐level‐dependent signals and cerebrospinal fluid signals (BOLD‐CSF coupling), were compared between the two groups. To evaluate glymphatic regional function, DTI‐ALPS and BOLD‐CSF coupling were further divided into anterior, middle, and posterior parts. BvFTD‐related metabolic pattern was identified using spatial covariance analysis based on [l8F]‐FDG‐PET.ResultPatients with bvFTD showed higher choroid plexus volume (P < 0.001); middle DTI‐ALPS (P < 0.001); and weaker anterior BOLD‐CSF coupling (P < 0.05) than HCs after controlling for cortical gray matter volume in both datasets. In bvFTD from the discovery dataset, the anterior DTI‐ALPS was negatively associated with the expression of the bvFTD‐related metabolic pattern (r = ‐0.51, P = 0.029) and positively related with regional standardized uptake value ratios of [l8F]‐FDG‐PET in bvFTD‐related brain regions (r = 0.44–0.60, P range: 0.008–0.039). Worse glymphatic function is associated with more severe global cognition decline, disease severity, and neuropsychiatric symptoms. In addition, anterior DTI‐ALPS was higher than posterior DTI‐ALPS (P < 0.001), whereas anterior BOLD‐CSF coupling was lower than posterior BOLD‐CSF coupling (P < 0.001).ConclusionOur findings reveal abnormal glymphatic function, especially in the anterior and middle regions of brain in bvFTD. Regional glymphatic dysfunction may contribute to the pathogenesis of bvFTD.

Topological Network Analysis of Beta‐Amyloid and Tau in Alzheimer’s Disease Using PET Imaging Data

AbstractBackgroundAlzheimer’s disease (AD) is characterized by the presence of beta‐amyloid (Aβ) and tau in the brain. Understanding the interplay between these proteins and their spatial distribution may provide insights into disease progression. This study aims to investigate the topological features of Aβ and tau networks in AD, mild cognitive impairment (MCI), and normal cognition (NC) groups using PET images from the ADNI dataset.MethodPartial correlation matrices between the standardized uptake value ratio of 68 regions of interest (ROI’s) were used to generate networks for the AD, MCI, and NC groups, with nodes representing ROI’s and edges representing correlation coefficients. Topological features, including H0 features (connected components), H1 features (loops), and landscape functions of H1 features, were calculated for each sample’s persistent homology. For each group, 100 bootstrapping samples were used to generate the 95% confidence intervals for landscape functions. The connected components were further studied by representing the samples as hierarchical tree structures. In the tree space, the first few generated connections, representing the most consistent pairs of regions positive for Aβ and tau, were compared across groups. Clustering performances were compared using Wasserstein distance of H0 features, Wasserstein distance of H1 features, landscape function distance, and geodesic distance in tree space respectively.ResultThe geodesic distance in tree space showed the best clustering accuracy in both Aβ and tau analyses. Compared with Aβ, H1 features and the corresponding landscape functions performed better for tau. Unique connections in AD and MCI groups were identified, with AD showing more unique connections than MCI compared to NC samples. Dominant unique connections in the AD group included left‐right isthmus cingulate and left fusiform‐left inferior temporal for Aβ, and left‐right paracentral and left cuneus‐left pericalcarine for tau. These connections indicate region pairs with related concentrations of Aβ and tau in AD.ConclusionTopological network analysis can reveal complex underlying structures in PET images and identify consistent patterns in ROI’s associated with Aβ and tau localization. Tau aggregation exhibits more complex behavior than Aβ and is more strongly associated with AD. The identified unique connections in the AD group may serve as potential biomarkers for disease progression.

The influence of widowhood on amyloid positivity status in cognitively normal older adults

AbstractBackgroundWidowhood and associated spousal bereavement is a life event that may lead to stress, loneliness, and depression. Previous research found associations between widowhood and an elevated risk of dementia. However, no direct relationship has been evidenced between widowhood and beta‐amyloid (Aβ) pathology, which is a hallmark of Alzheimer’s disease. Additionally, little is known about whether particular demographic or background factors might contribute to potential influences of widowhood on Aβ levels in older adults. Our objective was to evaluate the relationship between widowhood and Aβ positivity status in older adults, and to determine whether subgroups based on age, gender, educational attainment, or APOE ε4 status are driving effects.MethodCognitively normal (CN) subjects (n = 182) who were either widowed (including widows and widowers) or married from the Alzheimer’s Disease Neuroimaging Initiative were included in this study that underwent [18F]Florbetapir PET imaging on the baseline study visit. Multivariable logistic regression interrogated associations between widowhood status and Aβ positivity classification based on a global standardised uptake value ratio threshold of 1.11. This analysis included age, gender, APOE ε4 allele possession, education, and MMSE score as covariates. Regressions were also run in subgroups of CN subjects based on gender (male vs. female), APOE ε4 allele possession (carriers vs. non‐carriers), age (youngest, middle, oldest tertiles), and education (at least an undergraduate degree vs. no undergraduate degree).ResultIn CN subjects, there was overall no significant association between widowhood status and Aβ positivity (p = 0.114). When examining subgroups, widowhood was significantly associated with an increased risk of Aβ positivity in CN individuals with an undergraduate degree or higher (p = 0.025) or in the oldest age tertile (ages ranging from 76.3 to 89) (p = 0.024).ConclusionFindings from this cross‐sectional study indicated that a positive relationship between widowhood and in vivo Aβ neuropathology measured by PET exists specifically in those that are highly educated or undergoing advanced ageing. Whereas cognitive reserve is often hypothesised to mediate links between social isolation, depression and dementia risk, these results suggest that there may also be a direct effect on Alzheimer’s disease neuropathology.

Amyloid/Tau/Neurodegeneration (ATN) image‐based biomarker trajectories of Alzheimer’s disease through 5‐year longitudinal follow‐up

AbstractBackgroundTo investigate the progression of Alzheimer’s disease (AD) in image‐based Amyloid/Tau/Neurodegeneration (ATN) biomarkers through 5‐year longitudinal follow‐up.MethodAmong the participants who completed 18F‐florbetaben (FBB) for amyloid and 18F‐flortaucipir (FTP) for tau positron emission tomography (PET), and brain magnetic resonance (MR) imaging for neurodegeneration at a first visit, we enrolled the 145 participants who the studies at least twice [67 amyloid negative cognitive unimpaired (A‐CU), 10 amyloid positive cognitive unimpaired (A+CU), 68 amyloid positive cognitive impaired (A+CI)]. 70 participants completed the scans twice (25.2±3.1, months), and 75 participants completed the scans three times (57.9±7.4, months). We estimated the temporal trajectories of ATN biomarkers using a restricted cubic spline model and modified Euler method between baseline and annual change rates. The standardized uptake value ratio of FBB/FTP PET and hippocampal volume were used for representing each ATN biomarker, respectively.ResultThe FBB curve of the global cortex and AD‐specific regions reaches a plateau with a sigmoid appearance. FTP curves in the regions for Braak stages I‐II and III‐IV show similar sigmoid appearance while the global cortical and stage V‐VI tau curves show an exponential increase continuously. The hippocampal volume curve shows a linear decrease until the time point when the tau accumulation begins in the Braak stage I‐II, then decreases to a reversed sigmoid appearance.ConclusionLike the already known saturation of amyloid burden, it was also shown that the tau burden of the region for Braak stages I‐II and III‐IV saturated, but not in Braak stages V‐VI. Hippocampal atrophy seems to accelerate when tau begins to accumulate in early Braak stage regions. In future work, it is necessary to enroll patients at an advanced stage and collaborate with an international cohort.

Apolipoprotein E4 affects locus coeruleus functional connectivity in preclinical Alzheimer’s disease

AbstractBackgroundRecent studies have demonstrated the pivotal implications of the locus coeruleus (LC) and in the early phase of Alzheimer’s disease (AD). However, the effects of apolipoprotein E4(APOE4) carrier status on the LC functional connectivity (FC) in preclinical AD remain elusive. We aimed to demonstrate disparities in LC FC in preclinical AD with regard to APOE4 carrier status.MethodsA total of 112 patients with who were amyloid beta (Aβ) positive([18F] flutemetamol +) were recruited in the study, and they all had normal cognition. Seed to voxel analysis was conducted to measure LC FC differences between APOE4 non‐carrier and carrier. In addition, group by amyloid beta (Aβ) interactive effects on FC values were analyzed with a general linear model.ResultThe LC FC with intracalcarine cortex, lingual gyrus, occipital fusiform gyrus of the both hemispheres was reduced in APOE4 carrier. Moreover, there was a statistically significant group by regional standardized uptake value ratio interactions in LC FC with frontal, occipital cortices, the precuneus and the cerebellum.ConclusionThe aforementioned findings suggest that there are differential patterns of LC FC in APOE4 non‐carrier and carrier with preclinical AD, which interact with regional Aβ deposition.

Cognitive reserve moderates Alzheimer’s disease‐related tauopathic mechanism on cognition mediated by structural connectivity networks

AbstractBackgroundCognitive reserve (CR) is the capacity of an individual to maintain cognitive function despite brain damage (Stern et al., 2002). It moderates the effect of Alzheimer’s disease (AD)‐related brain damage on cognition, which is difficult to demonstrate using residual analysis. Recent research has shown a strong effect of tauopathy on the brain damage (Renaud La Joie et al., 2020), but how the CR affects this relationship is still unknown.MethodWe obtained 121 amyloid‐positive individuals, including 15 cognitive unimpaired (CU) individuals, 44 patients with mild cognitive impairment (MCI), and 58 AD. We first identified structural connectivity subnetworks where the relationships between edges’ weights (the number of streamlines) and tauopathy (global cortical tau standard uptake value ratio, standardized by the mean and standard deviation of the amyloid‐negative CU individuals) were modified by the years of education, as a proxy for cognitive reserve, using the network‐based statistics. We chose a subnetwork where its total connectivity significantly mediated the effect of the tauopathy on memory score, based on the Baron and Kenny method (Baron, Kenny et al., 1986). Through the path analysis, we verified the moderated mediation model, in which the moderating effects of education were added to the mediation model.ResultOne subnetwork whose edges were significantly affected by the tauopathy and moderation of education showed partial mediation in the tauopathic mechanism on cognition. The moderated mediation model based on the total connectivity of the subnetwork showed an appropriate model fit (CFI = 0.999, SRMR = 0.006) and a significant moderating effect on both stages of the indirect effect path of mediation when tested using the bootstrap method with 10000 resamples. The simple slope and intercept analyses implied that the highly educated individuals on the AD continuum show higher memory function than the lower educated individuals in the absence of tauopathy, but this score decreased more rapidly as tau increased.ConclusionWe conclude that education modifies the effect of tauopathy on structural connectivity as well as the effect of structural connectivity on cognition when AD‐related tauopathy affects memory score through the structural connectivity subnetwork.

Altered anterior insular metabolic connectivity in asymptomatic MAPT P301L carriers

AbstractBackgroundThe insula is the predominant brain region impaired in behavior variant frontotemporal dementia (bvFTD). However, structural and functional changes in the sub‐insula in the asymptomatic stage of bvFTD are unknown. The aim of this study is to describe structural and functional changes in insular subregions in asymptomatic carriers of the P301L mutation of the microtubule‐associated protein tau (MAPT) gene and patients with bvFTD.MethodSix asymptomatic MAPT P301L mutation carriers and 12 MAPT negative control subjects of the same pedigree were enrolled, along with 30 patients with a clinical diagnosis of bvFTD and 30 matched controls. All subjects underwent hybrid positron emission tomography/magnetic resonance imaging. Atlas‐based parcellation using a fine‐grained Brainnetome Atlas was conducted to assess gray matter (GM) volume, metabolism, and metabolic connectivity in the sub‐insula (region of interest).ResultThere was no significant GM atrophy or hypometabolism in insula subregions in asymptomatic MAPT P301L carriers, although decreased metabolic connectivity between vIa‐middle temporal gyrus, vIa‐temporal poles, dIa‐middle temporal gyrus and dIa‐temporal poles; and increased connectivity between vIa‐orbitofrontal, vIa‐dorsal lateral superior frontal gyrus, and dIa‐orbitofrontal and dIa‐dorsal lateral superior frontal gyrus were observed. Patients with bvFTD had significant atrophy and hypometabolism in all insula subregions and decreased metabolic connectivity in the whole brain, including vIa/dIa‐middle temporal and vIa/dIa‐temporal poles. The standardized uptake value ratios of vIa and dIa were negatively associated with behavioral disinhibition scale scores.ConclusionMetabolic connectivity is altered in vIa and dIa subregions of the sub‐insula in MAPT P301L mutation carriers before the occurrence of atrophy, hypometabolism, and clinical symptoms.

CSF sTREM2 and YKL‐40 modify the balance between soluble and fibrillary β‐amyloid in non‐demented individuals

AbstractBackgroundCerebrospinal fluid (CSF) Aβ concentrations and Positron Emission Tomography (PET) imaging provide information of two different Aβ pools. Identifying the factors affecting the balance between soluble and deposited Aβ may inform on the mechanism of cerebral Aβ aggregation. Microglia and astroglia respond to Aβ pathology, yet their role in promoting the aggregation of Aβ plaques is unclear. We addressed whether CSF sTREM2 and YKL‐40 modulate the association between soluble and deposited Aβ in a cohort of middle‐aged cognitively unimpaired (CU) individuals.MethodThe first consecutive 320 CU individuals of the ALFA+ study with a [18F]flutemetamol (FTM) PET scan and CSF samples were included. CSF Aβ40, Aβ42, sTREM2, and YKL‐40 were measured with the Roche NeuroToolKit robust prototype immunoassays (Roche Diagnostics International Ltd). Standardized uptake value ratio images were calculated and a voxel‐wise regression was performed to predict FTM uptake. The interaction terms between CSF Aβ42/40 and either CSF sTREM2 or YKL‐40 served as predictors, while adjusting for age, sex, years of education, and APOE‐ε4. Statistical threshold was set to p<0.001 with a cluster extent correction of 100 voxels.ResultTable 1 describes the sample’s characteristics. As expected, CSF Aβ42/40 concentrations were negatively associated with Aβ PET uptake in widespread areas of the brain, but this association was modified by CSF sTREM2 and YKL‐40. Higher levels of CSF sTREM2 were associated with a reduced Aβ PET uptake for any level of CSF Aβ42/40 in the hippocampus bilaterally. Conversely, higher CSF YKL‐40 related to a higher Aβ PET uptake as a function of CSF Aβ42/40 in the precuneus, prefrontal cortex, and inferior parietal areas.ConclusionIn CU individuals, microglia and astroglia reactivity modify the association between soluble (CSF) and deposited (amyloid PET) Aβ. While TREM2‐mediated microglial response (as measured by CSF sTREM2) may prevent Aβ deposition in individuals with decreased soluble Aβ, astroglial reactivity (as measured by CSF YKL‐40) may have the opposite effect.

Longitudinal changes of amyloid (A) and tau (T) image‐based biomarker in Alzheimer’s disease spectrum

AbstractBackgroundTo investigate long‐term changes in dichotomous profiles of amyloid (A) and tau (T) image‐based biomarker in Alzheimer’s disease (AD) spectrum.MethodDuring the initial visit (V1), a total of 275 participants [96 cognitively unimpaired (CU), 108 mild cognitive impairment (MCI), and 71 AD] who completed 18F‐florbetaben and 18F‐flortaucipir PET studies were followed up to three times. Two years later, 189 participants (74 CU, 77 MCI, and 38 AD) were enrolled in the second visit (V2), and 83 participants (34 CU, 39 MCI, and 10 AD) were enrolled in the third visit (V3) five years later (mean 4.8 years) to complete the same PET studies. The A and T biomarker profile was determined based on the cut‐off standardized uptake value ratio of the most vulnerable region in each pathology.ResultIn A‐ participants, 5.4% (6/111) of participants converted to A+ at V2 and 17.9% (7/39) converted to A+ at V3. Likewise, 2.9% (4/138) of participants in T‐ participants converted to T+ at V2, and 17.7% (11/62) converted from T‐ to T+ at V3. Compared to the low conversion rate from T‐ to T+ in A‐T‐ participants [0.9% (1 A‐T+ / 106 A‐T‐) at V2 and 5.1% (2 A+T+ / 39 A‐T‐)] at V3, A+T‐ participants showed higher conversion rates from T‐ to T+ [9.4% (3 A+T+ / 32 A+T‐) at V2 and 39.1% (9 A+T+ / 23 A+T‐) at V3].ConclusionThe conversion of the at biomarker profile was observed more prominently in the long term than in the short term, and the conversion of the T biomarker in A+ compared to A‐ was over seven times more frequent in five years follow‐up.

Developing Topics.

A previous comparative analysis of plasma Aβ42/40 immunoassays and mass spectrometry-based assays conducted in 2021 found that several assays had strong performance in predicting amyloid PET status (Zicha et al., 2022). In the spirit of enabling the National Institute on Aging and the Alzheimer's Association framework for classifying Alzheimer's disease (AD) utilizing measures of pathology for amyloid, tau, and neurodegeneration (ATN), we have added to this comparative analysis a newly developed immunoassay on an automated, scalable platform. Robustly validated plasma Aβ assays represent a non-invasive and cost-effective alternative to CSF or neuroimaging for early detection of Alzheimer's disease pathology and screening participants for enrollment into clinical trials. The project team consists of pharmaceutical industry, patient advocacy, governmental, and academic representatives. The current study utilized an additional aliquot of the same 130 plasma samples provided by ADNI that were previously tested on three immunoassays and three mass spectrometry-based assays. The statistical analysis plan was performed as published previously to determine if the measurement of plasma Aβ with age and APOE ε4 status performs better than age and APOE ε4 status alone in determining amyloid PET status. In this sample cohort, the new automated immunoassay with age and APOE genotype had similar prediction of amyloid status compared to mass spectrometry-based assays, with an ROC AUC of 85.7 (95% CI: 79.1 - 92.4) for the immunoassay and 84.2 (95% CI: 77.0 - 91.3) for the best- performing mass spectrometry-based assay. The Spearman correlation of plasma Aβ42/40 with amyloid PET (florbetapir standardized uptake value ratio) for the new immunoassay was -0.567 (p < 0.001) compared to -0.536 (p < 0.001) for the best performing mass spectrometry-based assay. The new immunoassay significantly improved the prediction of amyloid positivity beyond age and APOE ε4 genotype (p = 0.003). Results from this comparative analysis together with the continued advancement in plasma assay technology identify a potential use for plasma Aβ42/40 measurement in addressing the amyloid component of the ATN framework. Further evaluation of plasma Aβ42/40 in addition to p-tau in plasma is planned using longitudinal samples to determine the ability of plasma biomarkers to detect amyloidosis.

Cerebral hypometabolism mediates the effect of stroke volume on cognitive impairment in heart failure patients.

The present study aimed to phenotype the cerebral structural and glucose metabolic alterations in patients with heart failure (HF) using simultaneous positron emission tomography (PET)/magnetic resonance (MR) and to investigate their relationship to cardiac biomarkers and cognitive performance. Forty-two HF patients caused by ischaemic heart disease (mean age 67.2±10.4, 32 males) and 32 age- and sex-matched healthy volunteers (mean age 61.3±4.8, 18 males) were included in this study. Participants underwent simultaneous cerebral fluorine-18 (18 F) fluorodeoxyglucose PET/MR followed by cardiac MR scan, and neuropsychological scores were obtained to assess cognitive performance. The grey matter volume (GMV) and standardized uptake value ratio (SUVR) were calculated to examine cerebral structural and metabolic alterations. Cardiac biomarkers included cardiac MR parameters and cardiac serum laboratory tests. Mediation analysis was performed to explore the associations among cerebral alterations, cardiac biomarkers, and cognitive performance. HF patients demonstrated notable cognitive impairment compared with normal controls (P<0.001). Furthermore, HF patients exhibited regional brain hypometabolism in the bilateral calcarine cortex, caudate nucleus, thalamus, hippocampus, precuneus, posterior cingulate cortex, lingual and olfactory cortex, and GMV reduction in bilateral thalamus and hippocampus (cluster level at P<0.05, Gaussian random field correction). The SUVR of the hypometabolic brain regions was correlated with the Montreal Cognitive Assessment (MoCA) scores (r=0.55, P = 0.038) and cardiac stroke volume (r=0.49, P=0.002). Cerebral hypometabolism played a key role in the relationship between the decreased stroke volume and MoCA scores, with a mediation effect of 33.2%. HF patients suffered cerebral metabolic and structural alterations in regions associated with cognition. The observed correlation between cardiac stroke volume and cognitive impairment underscored the potential influence of cerebral hypometabolism, suggesting that cerebral hypometabolism due to chronic systemic hypoperfusion may significantly contribute to cognitive impairment in HF patients.

Clinical Value of 68Ga-Pentixafor PET/CT in Subtype Diagnosis of Primary Aldosteronism Patients with Adrenal Micronodules.

Our objective was to investigate the clinical value of 68Ga-pentixafor PET/CT in subtype diagnosis of primary aldosteronism (PA) patients with adrenal micronodules less than 1 cm in diameter and compare it with the routine clinical methods. Methods: We used prospective enrollment of PA patients with adrenal micronodules identified by adrenal CT scans to undergo 68Ga-pentixafor PET/CT. Patients were divided into surgically eligible and ineligible groups based on surgical pathology and postoperative follow-up or adrenal venous sampling (AVS) results. Patient management was discussed by a multidisciplinary team. The semiquantitative parameters of PET/CT included SUVmax for adrenal lesion and SUV ratios for lesion to liver and lesion to normal adrenal gland. Results: In total, 123 PA patients with adrenal micronodules were examined using 68Ga-pentixafor PET/CT, and 104 patients who underwent surgery or successful AVS were included in the analysis (48 ± 10 y old). The sensitivity, specificity, and accuracy of visual analysis using 68Ga-pentixafor PET/CT to identify surgically eligible patients were 90.2%, 72.7%, and 86.5%, respectively, which were significantly higher than those of adrenal CT (73.1%, 53.8%, and 68.3%, respectively) and yielded consistent results in different CT morphologic or age subgroups. In 36 patients who had both AVS and 68Ga-pentixafor PET/CT, the tests showed a 66.7% concordance rate. However, PET/CT was significantly more concordant with surgical outcomes than was AVS in 17 patients who underwent adrenalectomy (82.4% vs. 68.86%). Among the 183 adrenal micronodules included in the study, the semiquantitative diagnostic thresholds for 92 lesions eligible for surgical treatment were an SUVmax of at least 4.55, an SUV ratio of at least 2.17 for lesion to liver, and an SUV ratio of at least 1.90 for lesion to normal adrenal gland. All patients benefited from surgical removal of 68Ga-pentixafor-avid microlesions. Conclusion: In PA patients with adrenal micronodules, 68Ga-pentixafor PET/CT demonstrated promising diagnostic accuracy in classification and appeared to perform better than adrenal CT. Furthermore, there was also a suggestion of some potential in predicting postoperative efficacy compared with AVS, although these observations require further investigation and verification in larger cohorts.

Hippocampal Perfusion Affects Motor and Cognitive Functions in Parkinson Disease: An Early Phase 18 F-FP-CIT Positron Emission Tomography Study.

We investigated whether hippocampal perfusion changes are associated with cognitive decline, motor deficits, and the risk of dementia conversion in patients with Parkinson disease (PD). We recruited patients with newly diagnosed and nonmedicated PD and healthy participants who underwent dual phase 18 F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane positron emission tomography scans. Patients were classified into 3 groups according to hippocampal perfusion measured by standard uptake value ratios (SUVRs): (1) PD hippocampal hypoperfusion group (1 standard deviation [SD] below the mean hippocampal SUVR of healthy controls; PD-hippo-hypo), (2) PD hippocampal hyperperfusion group (1 SD above the mean; PD-hippo-hyper), and (3) the remaining patients (PD-hippo-normal). We compared the baseline cognitive performance, severity of motor deficits, hippocampal volume, striatal dopamine transporter (DAT) availability, and risk of dementia conversion among the groups. We included 235 patients (PD-hippo-hypo, n = 21; PD-hippo-normal, n = 157; PD-hippo-hyper, n = 57) and 48 healthy participants. Patients in the PD-hippo-hypo group were older and had smaller hippocampal volumes than those in the other PD groups. The PD-hippo-hypo group showed less severely decreased DAT availability in the putamen than the other groups despite similar severities of motor deficit. The PD-hippo-hypo group had a higher risk of dementia conversion compared to the PD-hippo-normal (hazard ratio = 2.59, p = 0.013) and PD-hippo-hyper (hazard ratio = 3.73, p = 0.006) groups, despite similar cognitive performance at initial assessment between groups. Hippocampal hypoperfusion may indicate a reduced capacity to cope with neurodegenerative processes in terms of the development of motor deficits and cognitive decline in patients with PD. ANN NEUROL 2024;95:388-399.

Longitudinal PET/CT Imaging with Iodine ( 124I) Evuzamitide Reveals Organ Response to Plasma Cell Immunotherapy in a Patient with AL Amyloidosis

Background:Iodine-124-evuzamitide is a novel amyloidophilic peptide (p5+14), labeled with iodine-124, for detecting amyloid by positron emission/x-ray computed tomographic (PET/CT) imaging ( Pharmaceuticals 2023 Apr 21;16(4):629). PET is an inherently quantitative modality and thus 124I-evuzamitide may be useful for monitoring disease progression and response to therapy. Amyloid deposits can impact any organ in patients with light chain-associated amyloidosis (AL); thus, tissue-specific changes in amyloid load, based on PET/CT imaging, may be informative. Currently, response to therapy is assessed by anatomic imaging and measurement of serum or urinary biomarkers. However, the correlation between these metrics and concomitant changes in amyloid load remains enigmatic. Here, we report a case of a patient with AL amyloidosis, on long-term daratumumab therapy, who underwent longitudinal 124I-evuzamitide PET/CT imaging over 4 years (NCT03678259 and NCT05968846). Patient and Methods: A 70-year-old male presented with abnormal liver function tests, notably an elevated serum alkaline phosphatase (ALK) of 465 IU/L. Biopsies of both the liver and celiac nodes revealed the characteristic apple-green birefringence of Congo red stain, indicating the presence of amyloid. The patient began daratumumab immunotherapy 14 months prior to his enrollment in the 124I-evuzamitide imaging study and over the 4-year course of serial imaging. During this time, regular serial serum biomarkers were evaluated as standard of care. PET/CT images were acquired at 0, 23, and 45 months. For each imaging session, the patient received 2 mCi iodine-124-labeled tracer via intravenous injection and was imaged at 5 h post injection. Image data were assessed for visual uptake of radiotracer and quantified by manual 2D region-of-interest analysis where the semi-quantitative mean standard uptake value ratio (SUVR mean) was calculated using blood pool as the reference tissue. Results: Over the 45 months of evaluation, there was a 59% and 73% reduction in 124I-evuzamitide SUVR in the liver and spleen. This was accompanied by decreases in the weight-scaled organ volume (cc/kg) for both the liver (15.2%) and spleen (30.0%) based on segmentation of the organ volume from CT images. This reduction in radiotracer uptake coincided with a sustained decrease in serum FLC, from 38.3 mg/L to 19.1 mg/L, and a positive liver response, where ALK levels dropped from ~200 IU/L to ~120 IU/L. In contrast, renal radiotracer uptake increased slightly in the context of stable creatinine levels, and a modest decline in eGFR. Cardiac uptake of 124I-evuzamitide remained positive and relatively stable, concordant with serum NT-proBNP levels. These data suggest that organ-specific amyloid response, in the context of a sustained hematologic response, may occur independently and at different rates. Conclusion: Previous reports have demonstrated the resolution of AL amyloid. However, this is the first report using an amyloid-binding radiotracer, capable of visualizing all major organs including the heart, demonstrating the complex pattern of organ response and regression of AL amyloid in the context of concurrent biomarker improvement and changes in organ volume. PET/CT imaging using 124I-evuzamitide may, therefore, play a valuable role in both diagnosing amyloidosis and monitoring changes in organ-specific amyloid load. Additional longitudinal imaging studies are needed to support this clinical application.