PIB-PET Scans Research Articles

Brain amyloid load, subjective memory complaints, and cognitive trajectories in older individuals at risk for dementia.

This study evaluated associations of brain amyloid with 2-year objective and subjective cognitive measures in a trial-ready older general population at risk for dementia. Forty-eight participants in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability underwent 11C-Pittsburgh compound B (PiB) positron emission tomography (PET) scans and assessment of cognition (modified Neuropsychological Test Battery [NTB]) and subjective memory complaints (Prospective and Retrospective Memory Questionnaire). Mean age was 71.4 ± 5.06 years, and 20 participants (42%) had positive baseline PiB-PET scans. Amyloid positivity was associated with lower NTB executive function at baseline and less favorable 2-year NTB total score and memory trajectories, but not with other objective or subjective cognitive measures. Overall, there was little cognitive decline during 2 years. Amyloid accumulation may affect objective but not necessarily subjective cognition from a very early at-risk stage, although substantial decline likely requires >2 years to occur.

Simultaneous assessment of blood flow and myelin content in the brain white matter with dynamic [11C]PiB PET: a test-retest study in healthy controls.

Exploring the relationship between oxygen supply and myelin damage would benefit from a simultaneous quantification of myelin and cerebral blood flow (CBF) in the brain's white matter (WM). To validate an analytical method for quantifying both CBF and myelin content in the WM using dynamic [11C]PiB positron emission tomography (PET). A test-retest study was performed on eight healthy subjects who underwent two consecutive dynamic [11C]PiB-PET scans. Three quantitative approaches were compared: simplified reference tissue model 2 (SRTM2), LOGAN graphical model, and standardized uptake value ratio (SUVR). The sensitivity of methods to the size of the region of interest was explored by simulating lesion masks obtained from 36 subjects with multiple sclerosis. Reproducibility was assessed using the relative difference and interclass correlation coefficient. Repeated measures correlations were used to test for cross-correlations between metrics. Among the CBF measures, the relative delivery (R1) of the simplified reference tissue model 2 (SRTM2) displayed the best reproducibility in the white matter, with a strong influence of the size of regions analyzed, the test-retest variability being below 10% for regions above 68 mm3 in the supratentorial white matter. [11C]PiB PET-derived proxies of CBF demonstrated lower perfusion of white matter compared to grey matter with an overall ratio equal to 1.71 ± 0.09 when the SRTM2-R1 was employed. Tissue binding in the white matter was well estimated by the Logan graphical model through estimation of the distribution volume ratio (LOGAN-DVR) and SRTM2 distribution volume ratio (SRTM2-DVR), with test-retest variability being below 10% for regions exceeding 106 mm3 for LOGAN-DVR and 300 mm3 for SRTM2-DVR. SRTM2-DVR provided a better contrast between white matter and grey matter. The interhemispheric variability was also dependent on the size of the region analyzed, being below 10% for regions above 103 mm3 for SRTM2-R1 and above 110 mm3 for LOGAN-DVR. Whereas the 1 to 8-minute standardized uptake value ratio (SUVR1-8) showed an intermediary reproducibility for CBF assessment, SUVR0-2 for perfusion or SUVR50-70 for tissue binding showed poor reproducibility and correlated only mildly with SRTM2-R1 and LOGAN-DVR estimations respectively. [11C]PiB PET imaging can simultaneously quantify perfusion and myelin content in WM diseases associated with focal lesions. For longitudinal studies, SRTM2-R1 and DVR should be preferred over SUVR for the assessment of regional CBF and myelin content, respectively. European Union Clinical Trials Register EUDRACT; EudraCT Number: 2008-004174-40; Date: 2009-03-06; https//www.clinicaltrialsregister.eu ; number 2008-004174-40.

Multicenter Experience with Good Manufacturing Practice Production of [11C]PiB for Amyloid Positron Emission Tomography Imaging.

Alzheimer's disease (AD) is a neurodegenerative disorder with increasing global prevalence and accounts for over half of all dementia cases. Early diagnosis is paramount for not only the management of the disease, but also for the development of new AD treatments. The current golden standard for diagnosis is performed by positron emission tomography (PET) scans with the tracer [11C]Pittsburg Compound B ([11C]PiB), which targets amyloid beta protein (Aβ) that builds up as plaques in the brain of AD patients. The increasing demand for AD diagnostics is in turn expected to drive an increase in [11C]PiB-PET scans and the setup of new [11C]PiB production lines at PET centers globally. Here, we present the [11C]PiB production setups, experiences, and use from four Danish PET facilities and discuss the challenges and potential pitfalls of [11C]PiB production. We report on the [11C]PiB production performed with the 6-OH-BTA-0 precursor dissolved in either dry acetone or 2-butanone and by using either [11C]CO2 or [11C]CH4 as 11C- precursors on three different commercial synthesis modules: TracerLab FX C Pro, ScanSys, or TracerMaker. It was found that the [11C]CO2 method gives the highest radioactive yield (1.5 to 3.2 GBq vs. 0.8 ± 0.3 GBq), while the highest molar activity (98.0 ± 61.4 GBq/μmol vs. 21.2 to 95.6 GBq/μmol) was achieved using [11C]CH4. [11C]PiB production with [11C]CO2 on a TracerLab FX C Pro offered the most desirable results, with the highest yield of 3.17 ± 1.20 GBq and good molar activity of 95.6 ± 44.2 GBq/μmol. Moreover, all reported methods produced [11C]PiB in quantities suitable for clinical applications, thus providing a foundation for other PET facilities seeking to establish their own [11C]PiB production.

Association Between β-Amyloid Accumulation and Incident Dementia in Individuals 80 Years or Older Without Dementia.

While the highest prevalence of dementia occurs in individuals older than 80 years, most imaging studies focused on younger populations. The rates of β-amyloid (Aβ) accumulation and the effect of Alzheimer disease (AD) pathology on progression to dementia in this age group remain unexplored. In this study, we examined the relationship between changes in Aβ deposition over time and incident dementia in nondemented individuals followed during a period of 11 years. We examined 94 participants (age 85.9 + 2.8 years) who had up to 5 measurements of Pittsburgh compound-B (PiB)-PET and clinical evaluations from 2009 to 2020. All 94 participants had 2 PiB-PET scans, 76 participants had 3 PiB-PET scans, 18 participants had 4 PiB-PET scans, and 10 participants had 5 PiB-PET scans. The rates of Aβ deposition were compared with 120 nondemented individuals younger than 80 years (69.3 ± 5.4 years) from the Australian Imaging, Biomarker, and Lifestyle (AIBL) study who had 3 or more annual PiB-PET assessments. By 2020, 49% of the participants developed dementia and 63% were deceased. There was a gradual increase in Aβ deposition in all participants whether they were considered Aβ positive or negative at baseline. In a Cox model controlled for age, sex, education level, APOE-4 allele, baseline Mini-Mental State Examination, and mortality, short-term change in Aβ deposition was not significantly associated with incident dementia (HR 2.19 (0.41-11.73). However, baseline Aβ burden, cortical thickness, and white matter lesions volume were the predictors of incident dementia. Aβ accumulation was faster (p = 0.01) in the older cohort (5.6%/year) when compared with AIBL (4.1%/year). In addition, baseline Aβ deposition was a predictor of short-term change (mean time 1.88 years). There was an accelerated Aβ accumulation in cognitively normal individuals older than 80 years. Baseline Aβ deposition was a determinant of incident dementia and short-term change in Aβ deposition suggesting that an active Aβ pathologic process was present when these participants were cognitively normal. Consequently, age may not be a limiting factor for the use of the emergent anti-Aβ therapies.

Predicting cognitive decline: Which is more useful, baseline amyloid levels or longitudinal change?

The use of biomarkers for the early detection of Alzheimer’s disease (AD) is crucial for developing potential therapeutic treatments. Positron Emission Tomography (PET) is a well-established tool used to detect β-amyloid (Aβ) plaques in the brain. Previous studies have shown that cross-sectional biomarkers can predict cognitive decline (Schindler et al.,2021). However, it is still unclear whether longitudinal Aβ-PET may have additional value for predicting time to cognitive impairment in AD. The current study aims to evaluate the ability of baseline- versus longitudinal rate of change in-11C-Pittsburgh compound B (PiB) Aβ-PET to predict cognitive decline. A cohort of 153 participants who previously underwent PiB-PET scans and comprehensive clinical assessments were used in this study. Our analyses revealed that baseline Aβ is significantly associated with the rate of change in cognitive composite scores, with cognition declining more rapidly when baseline PiB Aβ levels were higher. In contrast, no signification association was identified between the rate of change in PiB-PET Aβ and cognitive decline. Additionally, the ability of the rate of change in the PiB-PET measures to predict cognitive decline was significantly influenced by APOE ε4 carrier status. These results suggest that a single PiB-PET scan is sufficient to predict cognitive decline and that longitudinal measures of Aβ accumulation do not improve the prediction of cognitive decline once someone is amyloid positive.

Relationship between APOE risk score and myelin in Alzheimer’s disease

AbstractBackgroundPostmortem brain tissue analysis suggests that apolipoprotein E (APOE) ε4 is associated with lower brain myelination (Blanchard et al. 2022). However, in vivo evidence for this association is lacking. Here, we examined the relationship between APOE genotype and myelin content in the brain using multicomponent relaxometry (mcDESPOT) imaging and an APOE neuropathologic risk score (Deming et al, 2023).Methods121 cognitively unimpaired participants from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention completed at least one mcDESPOT MRI scan and were APOE genotyped. Myelin content was quantified using mcDESPOT‐derived myelin water fraction (MWF) maps. Amyloid positivity was determined using CSF Aβ42/Aβ40 or a [C‐11]PiB PET scan. Cutoffs for amyloid positivity was a CSF Aβ42/Aβ40 ratio of <0.046 (Van Hulle et al, 2020) or a global PiB DVR threshold >1.19 (Betthauser et al, 2020). MWF maps were registered to MNI space and smoothed with an 8mm FWHM kernel. We conducted a voxel‐wise regression analysis to determine the relationship between APOE risk and myelin content. Covariates included age, age difference between MRI and amyloid acquisition, gender, race, amyloid status, APOE by amyloid status interaction, and APOE by gender interaction. We followed up these analyses examining specific brain regions implicated in AD. All analyses were corrected for multiple comparisons.ResultsParticipant characteristics are shown in Table 1. Voxel‐wise analysis indicated that MWF was negatively associated with age in the superior longitudinal fasciculus and small regions of the brainstem (Figure 1). MWF was not associated with APOE risk, gender, or race. ROI analysis showed a significant APOE by amyloid status interaction in the left (β = 0.006, p‐value = 0.035) and right cingulum (β = ‐0.013, p‐value = 0.037; Table 2). However, these interactions did not survive FDR correction.ConclusionThese findings suggest that myelin content decreases with age. Although APOE ε4 increases risk for developing AD dementia, it was not associated with brain myelin content in this cohort. In preclinical participants harboring amyloid pathology, APOE risk may impact myelin content although our findings did not survive FDR correction. More research is needed to fully elucidate this relationship.

Developing Topics.

Both 11C-Pittsburgh compound-B (PiB) and 18F-Flutemetamol (FMT) have off-target white matter (WM) signal that increases with age, but WM uptake is stronger with FMT than PiB. Although their WM patterns are comparably associated with age, the difference between them may impact visual and quantitative assessments of cortical amyloid-β uptake. Our objective was to determine whether PiB PET and FMT PET visual assessments agree with quantitative cortical amyloid-β evaluations. A cohort of cognitively unimpaired (CU) younger adults with median (range) of 39 (30, 48) years (N = 30), CU older adults with age of 67 (61, 83) years (N = 30) and older adults with AD dementia with age of 67 (54-84) years (N = 23) underwent MRI, PiB PET and FMT PET. PiB-PET and FMT PET scans were evaluated visually by two nuclear medicine specialists blinded to participant information. Disagreements were reconciled with a second, joint round of visual reads. Readers applied standard visual assessment criteria using the absence of regional gray matter (GM) and WM contrast as an indication of a positive scan. The global cortical PiB standard uptake value ratio (SUVr) was obtained referencing to cerebellar crus uptake and converted to centiloid values. Participants were classified as PiB positive/negative using a centiloid cut-off of 22. PiB and FMT visual positivity agreed with quantitative positivity on PiB-based centiloid values in 69/83 for PiB and 78/83 for FMT. There were 10 disagreements with PiB, 1 disagreement with FMT and 4 disagreements with both. Few disagreements occurred near the centiloid threshold. Interestingly, all disagreements between visual reads (amyloid-β positive) and centiloid (amyloid-β negative) in the CU younger were with PiB. FMT disagreements were always in the CU older and AD groups. Disagreements between amyloid-β positivity on visual reads and quantitative measurements (centiloid) may depend on age and tracer. PiB WM uptake is lower than FMT WM uptake, which may lead to reduced contrast between GM and WM (part of the standard criteria for visual reads), especially in younger ages. In contrast, WM uptake increases at older ages, and increased WM signal may bleed more into cortical regions, hiding subtle, near-threshold cortical uptake, especially with FMT.

Abstract 162: Molecular And Microstructural Alterations In Cerebral Amyloid Angiopathy-related Hemorrhagic Manifestations

Background and Purpose: We aimed to compare the amyloid load and degree of microstructural injury among Cerebral Amyloid Angiopathy (CAA) patients with either higher lobar cerebral microbleed (CMB) counts or higher cortical superficial siderosis (cSS) extent against CAA patients with lower hemorrhagic load. Methods: The study included 38 cognitively healthy probable CAA patients with lobar intracerebral hemorrhage (ICH) and 38 age, sex-matched healthy controls (HC) who underwent advanced MRI, and Pittsburgh Compound B (PiB) PET scans. Patients were categorized into CMB-Dominant (CMB-D) and cSS-Dominant (cSS-D) based on the number and extent of CMB and cSS using previously identified cutoffs (Figure). The mean global cortical amyloid load was calculated from PiB-PET scans and represented by PiB-DVR. Within the CAA cohort, the Peak Width of Skeletonized Mean Diffusivity (PSMD) was calculated from diffusion MRIs and used as a marker of microstructural integrity. Results: Patients with CAA had significantly higher PiB-DVR than HCs (1.40±0.24 vs. 1.19±0.22, p<0.001). Both CMB-D and cSS-D CAA patients had significantly higher amyloid and increased (worse) PSMD compared to CAA patients with a non-dominant low hemorrhagic load (Figure). These results did not change in separate regression models corrected for age and sex. PiB-DVR significantly correlated with increased PSMD (r=0.346, p=0.033). Conclusions: Our findings support the view that vascular amyloid load drives higher CMB counts, more extensive cSS, and microstructural injury in patients with CAA. Furthermore, the correlations among these markers suggest that these MRI-based categorizations (CMB-D and cSS-D patients) can be used for disease staging and further research.

Proteomic indicators of health relate to Alzheimer’s and neurodegenerative disease biomarkers

AbstractBackgroundPrior studies suggest that peripheral health and comorbid disease can influence Alzheimer’s disease (AD) pathology and neurodegenerative processes. However, no studies to date have comprehensively examined how measures of peripheral health and risk for non‐neurological disease relate to biomarkers commonly used in AD research. The present study examined the association between 16 protein‐based health indicators and plasma biomarkers of brain amyloid‐β (Aβ) accumulation, phosphorylated tau, neurodegeneration, and reactive astrogliosis.MethodPlasma‐based biomarkers of AD pathology (Aβ42/40 ratio, pTau‐181), neurodegeneration (neurofilament light chain [NfL]), and reactive astrogliosis (glial fibrillary acidic protein [GFAP]) were measured in Baltimore Longitudinal Study of Aging participants using Quanterix SIMOA assays. Concurrently, the SomaScan proteomic platform was used to measure 7000 proteins, from which 16 proteomic signatures of health and disease risk were derived (i.e., SomaSignal Tests). A subset of participants also received PiB PET scans to assess cortical amyloid. We examined the relationship between health indicators and AD/neurodegeneration biomarkers using Pearson and Spearman correlations and linear regression analyses adjusted for age, sex, race, education, and APOEe4.ResultThe primary analysis included 720 participants (Table 1). Correlation analyses revealed several strong associations between measures of health/disease risk and plasma Aβ42/40 ratio, pTau‐181, NfL, and GFAP levels (Figure 1a). Notably, higher risk scores for heart failure, primary and secondary cardiovascular disease, and kidney disease were consistently positively associated with greater pTau‐181, NfL, and GFAP, and lower with Aβ42/40 ratio. Measures of body fat percentage, lean body mass, and visceral fat were associated with pTau‐181, NfL, and GFAP, whereas resting energy rate was only associated with NfL and GFAP. These relationships were maintained after adjusting for demographic factors and APOEe4 status (Figure 1b). Only heart failure and secondary cardiovascular disease risk scores were associated with elevated cortical amyloid (PiB+; Figure 2); these measures varied positively with cortical amyloid among participants who were PiB+, but not PiB‐ (Figure 3).ConclusionIndicators of peripheral health and disease risk demonstrate robust relationships with plasma AD, neurodegeneration, and reactive astrogliosis biomarkers. Peripheral health factors, particularly cardiovascular health, may play an important role in the pathophysiology of AD.

Change in CAIDE Dementia Risk Score and Neuroimaging Biomarkers During a 2-Year Multidomain Lifestyle Randomized Controlled Trial: Results of a Post-Hoc Subgroup Analysis.

The CAIDE (Cardiovascular Risk Factors, Aging and Dementia) Risk Score is a validated tool estimating dementia risk. It was previously associated with imaging biomarkers. However, associations between dementia risk scores (including CAIDE) and dementia-related biomarkers have not been studied in the context of an intervention. This study investigated associations between change in CAIDE score and change in neuroimaging biomarkers (brain magnetic resonance imaging [MRI] and Pittsburgh Compound B-positron emission tomography [PiB-PET] measures) during the 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) (post-hoc analyses). FINGER targeted at-risk older adults, aged 60–77 years, from the general population. Participants were randomized to either multidomain intervention (diet, exercise, cognitive training, and vascular risk management) or control group (general health advice). Neuroimaging (MRI and PiB-PET) data from baseline and 2-year visits were used. A toal of 112 participants had repeated brain MRI measures (hippocampal, total gray matter, and white matter lesion volumes, and Alzheimer’s disease signature cortical thickness). Repeated PiB-PET scans were available for 39 participants. Reduction in CAIDE score (indicating lower dementia risk) during the intervention was associated with less decline in hippocampus volume in the intervention group, but not the control group (Randomization group × CAIDE change interaction β coefficient = −0.40, p = .02). Associations for other neuroimaging measures were not significant. The intervention may have benefits on hippocampal volume in individuals who succeed in improving their overall risk level as indicated by a reduction in CAIDE score. This exploratory finding requires further testing and validation in larger studies.

Test-Retest Variability of Relative Tracer Delivery Rate as Measured by [11C]PiB

PurposeModerate-to-high correlations have been reported between the [11C]PiB PET-derived relative tracer delivery rate R1 and relative CBF as measured using [15O]H2O PET, supporting its use as a proxy of relative CBF. As longitudinal PET studies become more common for measuring treatment efficacy or disease progression, it is important to know the intrinsic variability of R1. The purpose of the present study was to determine this through a retrospective data analysis.ProceduresTest-retest data belonging to twelve participants, who underwent two 90 min [11C]PiB PET scans, were retrospectively included. The voxel-based implementation of the two-step simplified reference tissue model with cerebellar grey matter as reference tissue was used to compute R1 images. Next, test-retest variability was calculated, and test and retest R1 measures were compared using linear mixed effect models and a Bland-Altman analysis.ResultsTest-retest variability was low across regions (max. 5.8 %), and test and retest measures showed high, significant correlations (R2=0.92, slope=0.98) and a negligible bias (0.69±3.07 %).ConclusionsIn conclusion, the high precision of [11C]PiB R1 suggests suitable applicability for cross-sectional and longitudinal studies.

In vivo detection of beta-amyloid at the nasal cavity and other skull-base sites: a retrospective evaluation of ADNI1/GO.

Amyloid beta (Aβ) is partially cleared from the CSF via skull base perivascular and perineural lymphatic pathways, particularly at the nasal cavity. In vivo differences in Aβ level at the nasal cavity between patients with Alzheimer's disease (AD), subjects with mild cognitive impairment (MCI) and cognitively normal (CN) individuals have not been previously assessed. This is a retrospective evaluation of subject level data from the ADNI-1/GO database. Standardized uptake value ratio (SUVR) maximum on 11C-Pittsburgh compound-B (PiB)-PET was assessed at the nasal cavity on 223 scans. Exploratory ROI analysis was also performed at other skull base sites. SUVR maximum values and their differences between groups (CN, MCI, AD) were assessed. CSF Aβ levels and CSF Aβ 42/40 ratios were correlated with SUVR maximum values. 103 subjects with 223 PiB-PET scans (47 CN, 32 AD and 144 MCI) were included in the study. The SUVR maxima at the nasal cavity were significantly lower in subjects with AD [1.35 (± 0.31)] compared to CN [1.54 (± 0.30); p = 0.024] and MCI [1.49 (± 0.33); p = 0.049]. At very low CSF Aβ, less than 132pg/ml, there was significant correlation with nasal cavity SUVR maximum. The summed averaged SUVR maximum values were significantly lower in subjects with AD [1.35 (± 0.16)] compared to CN [1.49 (± 0.17); p = 0.003] and MCI [1.40 (± 0.17); p = 0.017]. Patients with AD demonstrate reduced nasal cavity PiB-PET radiotracer uptake compared to MCI and CN, possibly representing reduced Aβ clearance via perineural/perivascular lymphatic pathway. Further work is necessary to elucidate the true nature of this finding.

Predictive value of visually rated tau PET imaging for amyloid status, atrophy, and syndromic diagnosis across a spectrum of neurodegenerative phenotypes

AbstractBackgroundWe aimed to investigate the utility of qualitative visual rating of 18F‐flortaucipir tau PET to predict amyloid status, neurodegeneration and syndromic diagnosis across a range of phenotypes associated with underlying Alzheimer disease (AD) and non‐AD neuropathologies.MethodFTP PET, PiB PET, and high resolution T1 MRI scans were rated independently by visual inspection by two raters blinded to clinical diagnosis in n=118 subjects, a subset of whom had clinical diagnoses of amnesic MCI/dementia (n=26), posterior cortical atrophy (n=12), logopenic primary progressive aphasia (n=8), nonfluent PPA (n=7), semantic PPA (n=5), corticobasal syndrome (n=7), behavioral variant frontotemporal dementia (n=2), progressive supranuclear palsy (n=2), dementia with Lewy bodies (n=6), Parkinson disease (n=11), or control (n=20). Scans were classified based on level of uptake [no elevation, questionable or mild elevation, substantial elevation] and distribution of uptake [suggestive of typical AD, limbic predominant AD, hippocampal sparing AD, FTLD, or indeterminate]. PiB PET and MRI scans were rated with respect to level and distribution of uptake/atrophy.Result41/42 subjects with FTP scans classified with substantially elevated signal had PiB scans classified with elevated amyloid, versus 7/11 subjects with FTP classified as having questionable/mild elevation in a distribution suggesting AD, 1/30 with questionable/mild elevation in a distribution suggesting FTLD, 0/9 with questionable/mild elevation in an indeterminate distribution, and 1/26 classified with no elevation in FTP signal. Similarly, 41/42 subjects with FTP classified as having substantially elevated signal had MRI scans classified as having atrophy suggesting neurodegeneration, versus 44/50 subjects with FTP classified as having questionable/mild elevation and 14/26 with no elevation in signal. FTP scans were read to be suggestive of AD‐typ in 21/26 subjects with an amnesic syndrome, suggestive of AD‐hs in 16/20 subjects with lvPPA or PCA, and suggestive of FLTD in 14/23 subjects with bvFTD, nvPPA, svPPA, CBS, or PSP.ConclusionVisually rated tau PET imaging reliably predicts amyloid status and atrophy suggesting neurodegeneration in subjects with substantially elevated signal reflecting neocortical tau. Distribution helps both to determine likelihood of underlying AD neuropathology in cases with questionable/mild signal elevation, and in some cases to predict syndromic diagnosis within the spectrums of AD and FTLD.

FDG-PET Patterns Predict Amyloid Deposition and Clinical Profile in Corticobasal Syndrome.

Corticobasal syndrome (CBS) is an atypical parkinsonian syndrome related to multiple underlying pathologies. To investigate if individual brain [18 F]fluorodeoxyglucose-positron emission tomography (FDG-PET) patterns could distinguish CBS due to Alzheimer's disease (AD) from other pathologies based on [11 C]Pittsburgh Compound-B (PIB)-PET. Forty-five patients with probable CBS were prospectively evaluated regarding cognitive and movement disorders profile. They underwent FDG-PET and were distributed into groups: likely related to AD (CBS FDG-AD) or likely non-AD (CBS FDG-nonAD) pathology. Thirty patients underwent PIB-PET on a hybrid PET-magnetic resonance imaging equipment to assess their amyloid status. FDG and PIB-PET images were classified individually based on visual and semi-quantitative analysis, blinded to each other. Quantitative group analyses were also performed. CBS FDG-AD group demonstrated worse cognitive performances, mostly concerning attention, memory, visuospatial domains, and displayed more myoclonus and hallucinations. The non-AD metabolic group presented more often limb dystonia, ocular motor dysfunction, motor perseveration, and dysarthria. All patients classified as CBS FDG-AD tested positive at PIB-PET compared to 3 of 20 in the non-AD group. The individual FDG-PET classification demonstrated 76.92% of sensitivity, 100% of specificity and positive predictive value and 88.5% of balanced accuracy to detect positive PIB-PET scans. Individuals with positive and negative PIB-PET showed hypometabolism in posterior temporoparietal areas and in thalamus and brainstem, respectively, mainly contralateral to most affected side, disclosing possible metabolic signatures of CBS variants. FDG-PET was useful to predict AD and non-AD CBS variants depicting their specific degeneration patterns, different clinical features, and brain amyloid deposition. © 2020 International Parkinson and Movement Disorder Society.

11C]PIB amyloid quantification: effect of reference region selection

BackgroundThe standard reference region (RR) for amyloid-beta (Aβ) PET studies is the cerebellar grey matter (GMCB), while alternative RRs have mostly been utilized without prior validation against the gold standard. This study compared five commonly used RRs to gold standard plasma input-based quantification using the GMCB.MethodsThirteen subjects from a test–retest (TRT) study and 30 from a longitudinal study were retrospectively included (total: 17 Alzheimer’s disease, 13 mild cognitive impairment, 13 controls). Dynamic [11C]PiB PET (90 min) and T1-weighted MR scans were co-registered and time–activity curves were extracted for cortical target regions and the following RRs: GMCB, whole cerebellum (WCB), white matter brainstem/pons (WMBS), whole brainstem (WBS) and eroded subcortical white matter (WMES). A two-tissue reversible plasma input model (2T4k_Vb) with GMCB as RR, reference Logan and the simplified reference tissue model were used to derive distribution volume ratios (DVRs), and standardized uptake value (SUV) ratios were calculated for 40–60 min and 60–90 min intervals. Parameter variability was evaluated using TRT scans, and correlations and agreements with the gold standard (DVR from 2T4k_Vb with GMCB RR) were also assessed. Next, longitudinal changes in SUVs (both intervals) were assessed for each RR. Finally, the ability to discriminate between visually Aβ positive and Aβ negative scans was assessed.ResultsAll RRs yielded stable TRT performance (max 5.1% variability), with WCB consistently showing lower variability. All approaches were able to discriminate between Aβ positive and Aβ negative scans, with highest effect sizes obtained for GMCB (range − 0.9 to − 0.7), followed by WCB (range − 0.8 to − 0.6). Furthermore, all approaches provided good correlations with the gold standard (r ≥ 0.78), while the highest bias (as assessed by the regression slope) was observed using WMES (range slope 0.52–0.67), followed by WBS (range slope 0.58–0.92) and WMBS (range slope 0.62–0.91). Finally, RR SUVs were stable across a period of 2.6 years for all except WBS and WMBS RRs (60–90 min interval).ConclusionsGMCB and WCB are considered the best RRs for quantifying amyloid burden using [11C]PiB PET.

PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer\u2019s disease

Pathogenic variants in the PSEN1 gene are known to be the most common cause of early-onset Alzheimer’s disease but there are few data on the frequency and spectrum of PSEN1 variants in Korea. In this study, we investigated PSEN1 variants in a consecutive series of clinically suspicious early-onset familial AD (EOFAD) Korean patients and their clinical characteristics and imaging findings. From January 2007 to December 2013, EOFAD patients with very early onset AD (<50 yr), early onset AD (<60 yr) with two or more relatives with AD, and early onset AD (<60 yr) with one or more first-degree relatives with very early onset AD (<50 yr) were enrolled in this study. Sequence analysis of the PSEN1 gene was performed by Sanger sequencing. Neuroimaging data and conventional brain MRIs and FDG-PET and/or [11C] PiB-PET scans were analyzed in patients with PSEN1 variants. Among the 28 patients with EOFAD, six (21.4%, 6/28) patients had pathogenic or likely pathogenic variants in the PSEN1 gene. Two pathogenic variants were p.Glu120Lys and p.Ser170Phe and four likely pathogenic variants were p.Thr119Ile, p.Tyr159Cys, p.Leu282Pro, and p.Ala285Ser. Two patients had variants of unknown significance, p.Tyr389His and p.Tyr389Ser. EOFAD patients with PSEN1 variants showed early AD onset, frequent visuospatial dysfunction, movement disorders, and rapid disease progression. Brain MRIs revealed diffuse cortical atrophy, including parietal lobe atrophy, and/or hippocampal atrophy. FDG-PET scans also revealed significant hypometabolism in the bilateral temporo-parietal regions. Our findings provide insight to better understand the genetic background of Korean EOFAD patients.

Plasma A\u03b242/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: a cross-sectional analysis from the AB255 Study

BackgroundTo facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer’s disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aβ) levels with the presence of pathological accumulation of Aβ in the brain measured by amyloid-PET. Both plasma Aβ42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers.MethodsWe included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aβ40 and Aβ42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aβ-PET positive or negative, and the ability of TP42/40 to detect Aβ-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aβ biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification.ResultsEighteen (30.5%) subjects were Aβ-PET positive. TP42/40 ratio alone identified Aβ-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779–0.982). Discriminating performance of TP42/40 to detect Aβ-PET-positive subjects yielded sensitivity and specificity values at Youden’s cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aβ-PET scans by 64%. Combination of both FDG-PET scores and plasma Aβ biomarkers was found to be the most accurate Aβ-PET predictor, with an AUC of 0.965 (95% CI = 0.913–0.100).ConclusionsPlasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aβ positivity in preclinical and prodromal stages of Alzheimer’s disease.

Amyloid β deposition in subcortical stroke patients and effects of educational achievement: A pilot study

A direct causal relationship of cerebrovascular risk factors/stroke to amyloid β (Aβ) deposition has yet to be shown. We conducted [11 C] Pittsburgh compound B (PiB)-positron emission tomography (PET) analysis on subacute ischemic stroke patients and healthy controls. We hypothesized that subacute ischemic stroke patients would show focal Aβ accumulation in cortical regions, which would increase and extend over time during the chronic phase after stroke onset. Patients were recruited 14 to 28days after acute subcortical ischemic stroke and examined with [11 C]PiB-PET scans. Regional time-activity data were analyzed with the Logan graphical method. Whole brain voxel-based analysis was conducted to compare stroke patients with healthy controls. We also performed longitudinal comparison of patients with successive [11 C]PiB-PET scans 1year after stroke. Voxel-based analysis revealed a significant increase of [11 C]PiB-BPND of the precuneus/posterior cingulate cortex (PCu/PCC) in stroke patients at the subacute stage. Based on stepwise multiple regression analysis of [11 C]PiB-BP changes during follow-up as the dependent variable, years of education was the best independent correlate. There was a significant negative relationship between changes in [11 C]PiB-BP and years of education. Our results suggest that processes before and after the onset of ischemic stroke may trigger Aβ deposition in the PCu/PCC, whereby amyloid deposition begins at an early stage of Alzheimer's disease (AD). Our findings support the existence of a cooperative association between vascular risk factors/stroke and AD progression. Further, educational achievement had a protective effect against the increase in Aβ accumulation.

Subcortical amyloid relates to cortical morphology in cognitively normal individuals.

Amyloid (Aβ) brain deposition can occur in cognitively normal individuals and is associated with cortical volume abnormalities. Aβ-related volume changes are inconsistent across studies. Since volume is composed of surface area and thickness, the relative contribution of Aβ deposition on each of these metrics remains to be understood in cognitively normal individuals. A group of 104 cognitively normal individuals underwent neuropsychological assessment, PiB-PET scan, and MRI acquisition. Surface-based cortical analyses were performed to investigate the effects of cortical and subcortical Aβ burden on cortical volume, thickness, and surface area. Mediation analyses were used to study the effect of thickness and surface area on Aβ-associated volume changes. We also investigated the relationships between structural metrics in clusters with abnormal morphology and regions underlying resting-state functional networks and cognitive performance. Cortical Aβ was not associated with cortical morphology. Subcortical Aβ burden was associated with changes in cortical volume, thickness, and surface area. Aβ-associated volume changes were driven by cortical surface area with or without thickness but never by thickness alone. Aβ-associated changes overlapped greatly with regions from the default mode network and were associated with lower performance in visuospatial abilities, episodic memory, and working memory. In cognitively normal individuals, subcortical Aβ is associated with cortical volume, and this effect was driven by surface area with or without thickness. Aβ-associated cortical changes were found in the default mode network and affected cognitive performance. Our findings demonstrate the importance of studying subcortical Aβ and cortical surface area in normal ageing.

Brain Amyloid PET Tracer Delivery is Related to White Matter Integrity in Patients with Mild Cognitive Impairment.

Amyloid deposition, tau neurofibrillary tangles, and cerebrovascular dysfunction are important pathophysiologic features in Alzheimer's disease. Pittsburgh compound B ([11 C]-PIB) is a positron emission tomography (PET) radiotracer used to quantify amyloid deposition in vivo. In addition, certain models of [11 C]-PIB delivery reflect cerebral blood flow rather than amyloid plaques. As cerebral blood flow and perfusion deficits are associated with white matter pathology, we hypothesized that [11 C]-PIB delivery in white matter regions may reflect white matter integrity. We obtained [11 C]-PIB-PET scans and quantified white matter hyperintensities and global fractional anisotropy on magnetic resonance images as biomarkers of white matter pathology in 34 older participants with mild cognitive impairment with or without a history of major depressive disorder. We analyzed the [11 C]-PIB time-activity curve data with models associated with cerebral blood flow: the early maximum standard uptake value and the relative delivery parameter R1. We used a global white matter region of interest. Both of the partial-volume corrected PET parameters were correlated with white matter hyperintensities and fractional anisotropy. Future studies are warranted to explore whether [11 C]-PIB PET is a "triple biomarker" that may provide information about amyloid deposition, cerebral blood flow, and white matter pathology.