Pittsburgh Compound Research Articles

BLSA Plasma Biomarkers and Prediction of Amyloid PET Status

AbstractBackgroundIt’s crucial to quantify and compare the accuracies of plasma biomarkers in predicting amyloid PET status.MethodThe sample included a cross‐sectional sample of 212 participants from Baltimore Longitudinal Study of Aging. Amyloid PET status was determined from Pittsburgh compound B (PiB) PET using a Gaussian mixture model (140 PiB– and 72 PiB+). Using the Quanterix SIMOA Neuro‐4‐plex, three plasma biomarkers (amyloid‐beta 42 to 40 ratio [Aβ42/Aβ40], glial fibrillary acidic protein [GFAP], and neurofilament light chain [NfL]) were evaluated. We used receiver operating characteristic (ROC) curve analysis to estimate area under the curve (AUC) for each of the three biomarkers in predicting amyloid PET status. AUC estimates were cross validated using leave‐one‐out method. Finally, from a set of potential features (i.e., the three plasma biomarkers, age and APOE‐ε4 carrier status), we applied stepwise logistic regression to find the best subset of features to predict amyloid PET status.ResultParticipant characteristics are presented in Table 1. Each of the 3 biomarkers performed better than a random classifier, with GFAP having the highest validated AUC (0.692), followed by Aβ42/Aβ40 (AUC=0.677), and NfL (AUC=0.625) (Figure 1). The only statistically significant AUC difference is between GFAP and NfL (p = 0.029) (Table 2). Based on stepwise logistic regression, the model with Aβ42/Aβ40, GFAP and APOE‐ε4 status was selected as the final model with a moderate AUC of 0.732 (Figure 2). Odds ratios associated with each predictor are reported in Table 3.ConclusionOf the three Quanterix SIMOA plasma biomarkers, Aβ42/Aβ40 and GFAP have similar AUCs and are better at predicting amyloid PET status compared with NfL, although all AUCs are modest. The final multivariable logistic regression model, which included Aβ42/Aβ40, GFAP and APOE‐ε4 status, had a modest AUC of 0.732. Future studies with larger samples and more biomarkers, especially p‐tau measure, will be necessary to develop better prediction models.

Amyloid PET in the Lewy Body disease continuum

AbstractBackgroundβ‐amyloid plaques, a pathological hallmark of Alzheimer’s disease, are common in dementia with Lewy bodies (DLB). However, little is known about when β‐amyloid levels increase throughout the Lewy body disease (LBD) continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD), to a stage of mild cognitive impairment‐Lewy bodies (MCI‐LB), and finally DLB. Our objective was to investigate β‐amyloid deposition throughout the LBD continuum, as well as the influence of sex and APOE ε4 status, as potential factors contributing to Alzheimer’s disease pathological changes.MethodPatients with iRBD (n=24), MCI‐LB (n=62), and DLB (n=82) from the Mayo Clinic Alzheimer’s Disease Research Center and Center for Sleep Medicine were included. β‐amyloid levels were measured by Pittsburgh compound B (PiB) PET and global cortical standard uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared to each other and to cognitively unimpaired individuals (CU; n=100) balanced on age and sex from the Mayo Clinic Study of Aging (MCSA). Clinical groups were compared using ANCOVA after adjusting by age.ResultMCI‐LB and DLB patients had significantly higher global cortical PiB SUVR than CU participants, while PiB SUVR in iRBD patients was comparable to that of CU participants (Figure 1). DLB patients also had significantly higher global cortical PiB SUVR compared to iRBD patients (p=0.004). In MCI‐LB and DLB, global cortical PiB SUVR was higher in APOE ε4 carriers compared to APOE ε4 non‐carriers (p<0.001), and women had higher global cortical PiB SUVR compared to men (p=0.024).ConclusionIn this cross‐sectional study, β‐amyloid pathology gradually increased throughout the clinically defined LBD continuum. Whereas β‐amyloid levels are comparable to cognitively unimpaired individuals in iRBD, a significant elevation in β‐amyloid levels coincides with cognitive impairment observed in MCI‐LB and DLB. Specifically, women and APOE ε4 carriers tend to have higher β‐amyloid levels than men and APOE ε4 non‐carriers. These findings have important implications for targeting patients within the LBD continuum, who may benefit from amyloid modifying therapies.

Developing early vulnerable area aggregates for PET detection of beta‐amyloid based on young and middle‐aged adults from the Framingham Heart Study

AbstractBackgroundAs Alzheimer’s clinical trials shift earlier and earlier in the disease process, current global PET measures of beta‐amyloid (Aβ) positivity may be insufficient for detecting the earliest Aβ deposits. Regional PET measures may better detect the earliest deposits. Previous efforts to identify early‐accumulating regions have inferred which regions may be most vulnerable based on older adults. Our aim was to identify early vulnerable areas by looking earlier in the lifespan.Method235 clinically‐normal adults ages 33‐74 from the Framingham Heart Study (FHS) underwent one time‐point of dynamic Pittsburgh Compound B (PIB) PET (Tab.1). PIB was regionally quantified in Desikan regions using distribution volume ratio (DVR, cerebellar reference). Linear and quadratic (Age + Age2) models were run to determine association of age with region of interest (ROI) PIB DVR, and ROIs with significantly increasing DVRs were selected for the generation of candidate early vulnerable area (EVA) aggregates. Multiple aggregate EVA DVRs (EVA2‐EVA11) were generated by sequential addition of regions in rank order of descending Age2 estimate. EVA positivity was derived from both full‐sample GMM and <45 sample mean+2SD thresholds. Finally, EVA aggregates were tested using an independent cohort of older adults from the Harvard Aging Brain Study (HABS) that were imaged under an identical protocol (n=250, ages 50‐92), computing sensitivity and specificity of each aggregate at baseline to predict progression to global PIB positivity 3 years later.ResultOf 35 Desikan regions each evaluated on the left and right, 11 emerged as quadratic age relationships (p<0.05; Fig.1) and were used to generate EVA aggregates (Fig.2). Independent validation in baseline global PIB‐ individuals from HABS indicated EVA9 and EVA10 best predicted future accumulation (Fig.3). GMM‐based thresholds provided excellent specificity (SP=1.0) but weak sensitivity (SE=0.41) to predict progression to global PIB positivity 3 years later, while the more liberal mean+2SD thresholds improved sensitivity but decreased specificity (SE=0.88, SP=0.88).ConclusionUtilizing lifespan data from FHS, we identified a set of early vulnerable regions that are predictive of future accumulation in an independent sample of older adults. These findings are potentially useful in identifying the earliest deposits of Aβ for use in clinical trial design.

Abstract 10806: Ten Year Atherosclerotic Cardiovascular Disease Risk in Mid Life Predicts Late-Life Amyloid and Tau Deposition on Brain Imaging

Introduction: Risk factors of ASCVD have been associated with Alzheimer’s disease (AD) dementia. This association may be mediated by arteriosclerosis (ART), which have been implicated in incident dementia. However, the relationships among ASCVD risk factors, ART, and AD brain biomarkers (amyloid and tau) remains elusive. We investigated the association of the mid-life 10y ASCVD risk and subclinical ASCVD with late-life AD pathology. Methods: Participants >65y enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study between 2003-2005 (mid-life) underwent brain PET scans in 2018-2020 (late-life) to detect and quantify AD-specific amyloid [Pittsburgh Compound B (PiB)] and tau deposition. Mid-life 10-year ASCVD risk was categorized as borderline (5%-7.4%), intermediate (7.5%-14.9%), or high (≥15%). Logistic regression was used to calculate OR (95% CI) for association of late-life cortical amyloid and tau with mid-life ASCVD risk and marker of ART (vascular stiffness). Results: In 135 participants (mean age ~79y), global tau uptake had a graded association with increasing mid-life ASCVD risk categories (OR ASCVD high vs low risk% 11.00 [2.82-47.49]; p<0.05 ) while no significant association was found with PiB uptake on PET (Table) after mean 16y follow up. In fully adjusted models, Tau uptake was mainly driven by Black race ( OR 10.07 [3.25-36.39] ) and age ( OR 1.24 [1.10-1.41] ); all p<0.05. Midlife vascular stiffness showed a trend of association with late-life PiB retention (OR 1.76 [0.71-4.30]; p 0.05) but not with Tau . Conclusions: In an asymptomatic middle-aged biracial cohort, 10y ASCVD risk was predictive of late-life tau deposition but not amyloid. Vascular stiffness did not independently predict AD pathology. A simple mid-life ASCVD risk calculation may predict late-life AD risk. Further mechanistic studies are warranted to elucidate the race-related differences in the links between ASCVD risk and Alzheimer’s disease.

Defining the clinical utility of PET or PET-CT in idiopathic inflammatory myopathies: A systematic literature review

ObjectivesPositron emission tomography (PET), often combined with computed tomography (CT), is a well-established tool for diagnosing malignancy and inflammatory disease. The idiopathic inflammatory myopathies (IIM) are chronic, multi-system diseases characterised by skeletal muscle inflammation, the potential for extramuscular manifestations such as interstitial lung disease (ILD) and an increased risk of malignancy. We performed a systematic literature review to evaluate the utility of PET or PET-CT in evaluation of IIM. MethodsA search of Medline and EMBASE from 1990 to 2022 using keywords related to IIM and PET was performed. English language studies of adults with IIM who had PET or PET-CT were included. ResultsOur search identified 1173 potentially relevant abstracts, 19 of which were included. The majority of studies used [18F] fluorodeoxyglucose (FDG) PET or PET-CT scans, while the remainder used [18F] florbetapir and [11C] Pittsburgh compound B ([11C] PIB). The sensitivity and specificity of 18F-FDG-PET or 18F-FDG-PET-CT for diagnosing malignancy compared with standard detection methods was 66.7–94% and 80–97.8%, respectively. The sensitivity of 18F-FDG PET-CT for ILD was 93–100% when high-resolution CT was used as the reference standard. 18F-PET and 18F-FDG-PET-CT appear to accurately detect muscle inflammation, although correlations with clinical measures of IIM disease activity were variable. [18F] florbetapir PET-CT and [11C] PIB PET were able to differentiate sporadic inclusion body myositis (IBM) from non-IBM IIM. ConclusionPET-CT holds promise as a single tool that can simultaneously evaluate multiple aspects of IIM. These include screening for associated malignancy, achieving an early diagnosis of ILD and evaluating muscle inflammation.

Higher amyloid correlates to greater loneliness during the COVID-19 pandemic

Background: Little is known about psychosocial characteristics, including loneliness, anxiety, and depression, present in preclinical Alzheimer disease (AD). The purpose of this cross-sectional study was to examine the relationship between these psychosocial characteristics and amyloid accumulation in cognitively normal older adults with and without preclinical AD during the COVID-19 pandemic. Methods: A global Clinical Dementia Rating ® Scale score of 0 was required for enrollment. Cortical amyloid burden was measured using [11C] Pittsburgh compound B or [18F]-Florbetapir PET tracers. Centiloids were used to synchronize measures. Demographic characteristics and measures of loneliness, anxiety, and depression were collected via self-report. Spearman’s correlation was used to examine relationships between amyloid and psychosocial characteristics. Results: The 108 participants had a mean age of 75.0 and an average amyloid burden of 22.2. Higher amyloid accumulation was significantly associated with greater loneliness. Conclusions: Additional research is needed with a larger, more diverse sample to examine these psychosocial characteristics in preclinical AD.

The Associations Between Intracranial Stenosis, Brain Amyloid-beta, and Cognition in a Memory Clinic Sample.

Intracranial stenosis (ICS) and brain amyloid-beta (Aβ) have been associated with cognition and dementia. We aimed to investigate the association between ICS and brain Aβ and their independent and joint associations with cognition. We conducted a cross-sectional study of 185 patients recruited from a memory clinic. ICS was measured on 3-dimensional time-of-flight magnetic resonance angiography and defined as stenosis ≥50%. Brain Aβ was measured with [ 11 C] Pittsburgh compound B-positron emission tomography imaging. Cognition was assessed with a locally validated neuropsychological battery. A total of 17 (9.2%) patients had ICS, and the mean standardized uptake value ratio was 1.4 (±0.4SD). ICS was not significantly associated with brain Aβ deposition. ICS was significantly associated with worse global cognition (β: -1.26, 95% CI: -2.25; -0.28, P =0.013), executive function (β: -1.04, 95% CI: -1.86; -0.22, P =0.015) and visuospatial function (β: -1.29, 95% CI: -2.30; -0.27, P =0.015). Moreover, in ICS patients without dementia (n=8), the presence of Aβ was associated with worse performance on visuomotor speed. ICS was significantly associated with worse cognition and showed interaction with brain Aβ such that patients with both pathologies performed worse on visuomotor speed specifically in those without dementia. Further studies may clarify if ICS and brain Aβ deposition indeed have a synergistic association with cognition.

Locus coeruleus catecholamines link neuroticism and vulnerability to tau pathology in aging

Higher neuroticism is a risk factor for Alzheimer's disease (AD), and is implicated in disordered stress responses. The locus coeruleus (LC)-catecholamine system is activated during perceived threat and is a centerpiece of developing models of the pathophysiology of AD, as it is the first brain region to develop abnormal tau. We examined relationships among the “Big 5” personality traits, LC catecholamine synthesis capacity measured with [18F]Fluoro-m-tyrosine PET, and tau burden measured with [18F]Flortaucipir PET in cognitively normal older adults (n = 47). β-amyloid (Aβ) status was determined using [11C]Pittsburgh compound B PET (n = 14 Aβ positive). Lower LC catecholamine synthesis capacity was associated with higher neuroticism, more depressive symptoms as measured by the Geriatric Depression Scale, and higher amygdala tau-PET binding. Exploratory analyses with other personality traits revealed that low trait conscientiousness was also related to both lower LC catecholamine synthesis capacity, and more depressive symptoms. A significant indirect path linked both high neuroticism and low conscientiousness to greater amygdala tau burden via their mutual association with low LC catecholamine synthesis capacity. Together, these findings reveal LC catecholamine synthesis capacity to be a promising marker of affective health and pathology burden in aging, and identifies candidate neurobiological mechanisms for the effect of personality on increased vulnerability to dementia.

Distribution and progression of cerebral amyloid angiopathy in early-onset V30M (p.V50M) hereditary ATTR amyloidosis

Background Cerebral amyloid angiopathy (CAA) is becoming the most common and serious complications in long-lived hereditary ATTR amyloidosis patients. It is therefore imperative to elucidate the characteristics of ATTR-type CAA and develop useful biomarkers. Methods We enrolled 34 ATTRv amyloidosis patients with the V30M (p.V50M) variant for analysis with three-dimensional stereotactic surface projection z score imaging of Pittsburgh compound B (PiB)-PET. Results Eight patients exhibited central nervous system (CNS) symptoms. Seven patients suffered transient focal neurologic episodes, and 2 patients each experienced cerebellar haemorrhages or cognitive decline. The amount of 11C-PiB accumulation increased as a function of disease duration. 11C-PiB-PET abnormalities were seen at 8 years from onset and were associated with CNS manifestations from 12 years. The annual increase rate of the standardised uptake value ratio (SUVR) in female patients was significantly higher than in male patients. CNS amyloid deposition started in the upper middle surface of the cerebellar cortex, and then spread out over the entire surface of the cerebellum, Sylvian fissure, and anterior part of the longitudinal fissure of the cerebrum. Conclusions PiB-PET is a useful biomarker for the early detection and treatment evaluation of ATTR-type CAA. Female gender is associated with more rapid progression of ATTR-type CAA.

Phosphorus metabolism in the brain of cognitively normal midlife individuals at risk for Alzheimer's disease

BackgroundNeurometabolic abnormalities and amyloid-beta plaque deposition are important early pathophysiologic changes in Alzheimer's disease (AD). This study investigated the relationship between high-energy phosphorus-containing metabolites, glucose uptake, and amyloid plaque using phosphorus magnetic resonance spectroscopy (31P-MRS) and positron emission tomography (PET). MethodsWe measured 31P-MRS, fluorodeoxyglucose (FDG)-PET, and Pittsburgh Compound B (PiB)-PET in a cohort of 20 cognitively normal middle-aged adults at risk for AD. We assessed 31P-MRS reliability by scanning a separate cohort of 13 healthy volunteers twice each. We calculated the coefficient-of-variation (CV) of metabolite ratios phosphocreatine-to-adenosine triphosphate (PCr/α-ATP), inorganic phosphate (Pi)-to-α-ATP, and phosphomonoesters-to-phosphodiesters (PME/PDE), and pH in pre-defined brain regions. We performed linear regression analysis to determine the relationship between 31P measurements and tracer uptake, and Dunn's multiple comparison tests to investigate regional differences in phosphorus metabolism. Finally, we performed linear regression analysis on 31P-MRS measurements in both cohorts to investigate the relationship of phosphorus metabolism with age. ResultsMost regional 31P metabolite ratio and pH inter- and intra-day CVs were well below 10%. There was an inverse relationship between FDG-SUV levels and metabolite ratios PCr/α-ATP, Pi/α-ATP, and PME/PDE in several brain regions in the AD risk group. There were also several regional differences among 31P metabolites and pH in the AD risk group including elevated PCr/α-ATP, depressed PME/PDE, and elevated pH in the temporal cortices. Increased PCr/α-ATP throughout the brain was associated with aging. ConclusionsPhosphorus spectroscopy in the brain can be performed with high repeatability. Phosphorus metabolism varies with region and age, and is related to glucose uptake in adults at risk for AD. Phosphorus spectroscopy may be a valuable approach to study early changes in brain energetics in high-risk populations.

Atypical Alzheimer's disease phenotypes with normal or borderline PET biomarker profiles.

Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are clinical syndromes that commonly have underlying Alzheimer's disease (AD), although non-AD pathologies have also been reported. PET imaging allows for identification of beta-amyloid (Aβ) and tau in AD, so we aimed to assess these in a large cohort to identify patients that do not have evidence for biomarker-defined AD. Eight-one patients, 47 PCA and 34 LPA, underwent extensive neurological and neuropsychological testing, [11C] Pittsburgh compound B, [18F] flortaucipir and [18F] fluorodeoxyglucose PETs. Global Aβ and tau-PET standardized uptake value ratios (SUVRs) were plotted for all patients and outliers, and patients with abnormally low SUVRs compared to the biomarker-classic cohort were identified. Six (7.4%) biomarker-outlier cases were identified, and three patterns were observed: (i) negative/borderline Aβ-PET and striking widespread tau-PET uptake (two LPA); (ii) negative/borderline Aβ-PET and low tau-PET uptake (three PCA) and (iii) elevated Aβ-PET uptake but mild focal tau-PET uptake (one LPA). Among the unusual patients in group ii, two patients showed no abnormal tau uptake suggesting non-AD pathology, with one developing features of cortico-basal syndrome and the other dementia with Lewy bodies. The remaining patient showed very mild focal tau uptake. This study demonstrates that a small minority (~ 8%) of PCA and LPA patients do not show the typical striking patterns of Aβ and tau PET uptake, with only 2% showing absence of both proteins. These findings will help inform the use of molecular PET in clinical treatment trials that include patients with atypical phenotypes of AD.

Tracking the Progression and Influence of Beta-Amyloid Plaques Using Percolation Centrality and Collective Influence Algorithm: A Study Using PET Images.

The study of brain networks, particularly the spread of disease, is made easier thanks to the network theory. The aberrant accumulation of beta-amyloid plaques and tau protein tangles in Alzheimer's disease causes disruption in brain networks. The evaluation scores, such as the mini-mental state examination (MMSE) and neuropsychiatric inventory questionnaire, which provide a clinical diagnosis, are affected by this build-up. The percolation of beta-amyloid/tau tangles and their impact on cognitive tests are still unspecified. Percolation centrality could be used to investigate beta-amyloid migration as a characteristic of positron emission tomography (PET)-image-based networks. The PET-image-based network was built utilizing a public database containing 551 scans published by the Alzheimer's Disease Neuroimaging Initiative. Each image in the Julich atlas has 121 zones of interest, which are network nodes. Furthermore, the influential nodes for each scan are computed using the collective influence algorithm. For five nodal metrics, analysis of variance (ANOVA; P < .05) reveals the region of interest (ROI) in gray matter (GM) Broca's area for Pittsburgh compound B (PiB) tracer type. The GM hippocampus area is significant for three nodal metrics in the case of florbetapir (AV45). Pairwise variance analysis of the clinical groups reveals five to twelve statistically significant ROIs for AV45 and PiB, respectively, that can distinguish between pairs of clinical situations. Based on multivariate linear regression, the MMSE is a trustworthy evaluation tool. Percolation values suggest that around 50 of the memory, visual-spatial skills, and language ROIs are critical to the percolation of beta-amyloids within the brain network when compared to the other extensively used nodal metrics. The anatomical areas rank higher with the advancement of the disease, according to the collective influence algorithm.

Investigating Tau and Amyloid Tracer Skull Binding in Studies of Alzheimer Disease.

Off-target binding of [18F]flortaucipir (FTP) can complicate quantitative PET analyses. An underdiscussed off-target region is the skull. Here, we characterize how often FTP skull binding occurs, its influence on estimates of Alzheimer disease pathology, its potential drivers, and whether skull uptake is a stable feature across time and tracers. Methods: In 313 cognitively normal and mildly impaired participants, CT scans were used to define a skull mask. This mask was used to quantify FTP skull uptake. Skull uptake of the amyloid-β PET tracers [18F]florbetapir and [11C]Pittsburgh compound B (n = 152) was also assessed. Gaussian mixture modeling defined abnormal levels of skull binding for each tracer. We examined the relationship of continuous bone uptake to known off-target binding in the basal ganglia and choroid plexus as well as skull density measured from the CT. Finally, we examined the confounding effect of skull binding on pathologic quantification. Results: We found that 50 of 313 (∼16%) FTP scans had high levels of skull signal. Most were female (n = 41, 82%), and in women, lower skull density was related to higher FTP skull signal. Visual reads by a neuroradiologist revealed a significant relationship with hyperostosis; however, only 21% of women with high skull binding were diagnosed with hyperostosis. FTP skull signal did not substantially correlate with other known off-target regions. Skull uptake was consistent over longitudinal FTP scans and across tracers. In amyloid-β-negative, but not -positive, individuals, FTP skull binding impacted quantitative estimates in temporal regions. Conclusion: FTP skull binding is a stable, participant-specific phenomenon and is unrelated to known off-target regions. Effects were found primarily in women and were partially related to lower bone density. The presence of [11C]Pittsburgh compound B skull binding suggests that defluorination does not fully explain FTP skull signal. As signal in skull bone can impact quantitative analyses and differs across sex, it should be explicitly addressed in studies of aging and Alzheimer disease.

Spouse bereavement and brain pathologies: A propensity score matching study.

Spouse bereavement is one of life's greatest stresses and has been suggested to trigger or accelerate cognitive decline and dementia. However, little information is available about the potential brain pathologies underlying the association between spouse bereavement and cognitive decline. We aimed to investigate that lifetime spouse bereavement is associated with in vivo human brain pathologies underlying cognitive decline. A total of 319 ever-married older adults between the ages of 61 and 90 years underwent comprehensive clinical assessments and multimodal brain imaging including [11 C] Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, [18 F] fluorodeoxyglucose-PET, and magnetic resonance imaging. Participants were classified as experiencing no spouse bereavement or spouse bereavement, and comparisons using propensity score matching (59 cases and 59 controls) were performed. Spouse bereavement was significantly associated with higher cerebral white matter hyperintensity (WMH) volume compared with no spouse bereavement. Interaction and subsequent subgroup analyses showed that spouse bereavement was significantly associated with higher WMH in the older (>75 years) subgroup and among those with no- or low-skill occupations. In addition, spouse bereavement at 60 years or older affects WMH volume compared with no spouse bereavement, whereas spouse bereavement at younger than 60 years did not. No group differences were observed in other brain pathologies between spouse bereavement categories. The findings suggest that the spouse bereavement may contribute to dementia or cognitive decline by increasing cerebrovascular injury, particularly in older individuals and those with no- or low-skill occupations.

Structure-specific amyloid precipitation in biofluids.

The composition of soluble toxic protein aggregates formed in vivo is currently unknown in neurodegenerative diseases, due to their ultra-low concentration in human biofluids and their high degree of heterogeneity. Here we report a method to capture amyloid-containing aggregates in human biofluids in an unbiased way, a process we name amyloid precipitation. We use a structure-specific chemical dimer, a Y-shaped, bio-inspired small molecule with two capture groups, for amyloid precipitation to increase affinity. Our capture molecule for amyloid precipitation (CAP-1) consists of a derivative of Pittsburgh Compound B (dimer) to target the cross β-sheets of amyloids and a biotin moiety for surface immobilization. By coupling CAP-1 to magnetic beads, we demonstrate that we can target the amyloid structure of all protein aggregates present in human cerebrospinal fluid, isolate them for analysis and then characterize them using single-molecule fluorescence imaging and mass spectrometry. Amyloid precipitation enables unbiased determination of the molecular composition and structural features of the in vivo aggregates formed in neurodegenerative diseases.

Alzheimer’s disease pattern derived from relative cerebral flow as an alternative for the metabolic pattern using SSM/PCA

Background2-Deoxy-2-[18F]fluoroglucose (FDG) PET is an important tool for the identification of Alzheimer’s disease (AD) patients through the characteristic neurodegeneration pattern that these patients present. Regional cerebral blood flow (rCBF) images derived from dynamic 11C-labelled Pittsburgh Compound B (PIB) have been shown to present a similar pattern as FDG. Moreover, multivariate analysis techniques, such as scaled subprofile modelling using principal component analysis (SSM/PCA), can be used to generate disease-specific patterns (DP) that may aid in the classification of subjects. Therefore, the aim of this study was to compare rCBF AD-DPs with FDG AD-DP and their respective performances. Therefore, 52 subjects were included in this study. Fifteen AD and 16 healthy control subjects were used to generate four AD-DP: one based on relative cerebral trace blood (R1), two based on time-weighted average of initial frame intervals (ePIB), and one based on FDG images. Furthermore, 21 subjects diagnosed with mild cognitive impairment were tested against these AD-DPs.ResultsIn general, the rCBF and FDG AD-DPs were characterized by a reduction in cortical frontal, temporal, and parietal lobes. FDG and rCBF methods presented similar score distribution.ConclusionrCBF images may provide an alternative for FDG PET scans for the identification of AD patients through SSM/PCA.

In Alzheimer's disease, amyloid beta accumulation is a protective mechanism that ultimately fails.

Here, we claim that amyloid beta (Aβ) accumulation is a protective mechanism that ultimately fails. We predict that more Aβ accumulates in regions with higher rates of glucose metabolism, reaching a maximum followed by progression of pathology. Aβ accumulation is characteristic of Alzheimer's disease (AD) but the accumulation does not correlate with cognitive decline, unlike the rates of glucose metabolism. We compared averaged and individual estimates of regional binding potentials of [11C]Pittsburgh compound B to regionally averaged and individual values of metabolism of [18F]fluorodeoxyglucose in brain regions of volunteers with AD. The claim explains the cognitive decline in some patients at a significantly lower level of Aβdeposition than in other patients, as well as the presence of cognitively healthy individuals with high Aβaccumulation. With further support of the hypothesis, the significance of Aβaccumulation in brains of patients with AD may require revision.

From clinical phenotype to proteinopathy: molecular neuroimaging in neurodegenerative dementias.

Neurodegenerative dementias are characterized by the abnormal accumulation of misfolded proteins. However, its diagnostic criteria are still based on the clinical phenotype. The development of biomarkers allowed in vivo detection of pathophysiological processes. This article aims to make a non-systematic review of the use of molecular neuroimaging as a biomarker. Molecular neuroimaging is based on the use of radiotracers for image acquisition. The radiotracer most used in PET is 18F-fluorodeoxyglucose (FDG), with which it is possible to study the regional brain glucose metabolism. The pattern of regional hypometabolism provides neuroanatomical information on the neurodegenerative process, which, in turn, has a good specificity for each type of proteinopathy. FDG is very useful in the differential diagnosis of neurodegenerative dementias through the regional pattern of involvement, including dementia with Lewy bodies and the spectrum of frontotemporal dementia. More recently, radiotracers with specific ligands to some of the pathological proteins have been developed. Pittsburgh compound B (PIB) labeled with 11C and the ligands that use 18F (florbetapir, florbetaben and flutemetamol) are the most used radiotracers for the detection of insoluble β-amyloid peptide in Alzheimer's disease (AD). A first generation of ligands for tau protein has been developed, but it has some affinity for other non-tau protein aggregates. A second generation has the advantage of having a higher affinity for hyperphosphorylated tau protein, including in primary tauopathies.

P96. Interpreting the Relationship Between White Matter Hyperintensities and Amyloid Deposition Using Rectilinear Neural Networks

In older adults without dementia, White Matter Hyperintensities (WMH) in MRI have been shown to be highly associated with cerebral amyloid deposition, measured by the Pittsburgh compound B (PiB) PET. However, the relation to age, gender, and education in explaining this association is not well understood.

APOE ɛ4 dose associates with increased brain iron and β-amyloid via blood–brain barrier dysfunction

ObjectiveTo examine the effect of apolipoprotein E (APOE) ɛ4 dose on blood–brain barrier (BBB) clearance function, evaluated using an advanced MRI technique and analyse its correlation with brain iron and...